Normal Participants Research Articles

Synaptic density patterns in early Alzheimer's disease assessed by independent component analysis.

Synaptic loss is a primary pathology in Alzheimer's disease and correlates best with cognitive impairment as found in post-mortem studies. Previously, we observed in vivo reductions of synaptic density with [11C]UCB-J PET (radiotracer for synaptic vesicle protein 2A) throughout the neocortex and medial temporal brain regions in early Alzheimer's disease. In this study, we applied independent component analysis to synaptic vesicle protein 2A-PET data to identify brain networks associated with cognitive deficits in Alzheimer's disease in a blinded data-driven manner. [11C]UCB-J binding to synaptic vesicle protein 2A was measured in 38 Alzheimer's disease (24 mild Alzheimer's disease dementia and 14 mild cognitive impairment) and 19 cognitively normal participants. [11C]UCB-J distribution volume ratio values were calculated with a whole cerebellum reference region. Principal components analysis was first used to extract 18 independent components to which independent component analysis was then applied. Subject loading weights per pattern were compared between groups using Kruskal-Wallis tests. Spearman's rank correlations were used to assess relationships between loading weights and measures of cognitive and functional performance: Logical Memory II, Rey Auditory Verbal Learning Test-long delay, Clinical Dementia Rating sum of boxes and Mini-Mental State Examination. We observed significant differences in loading weights among cognitively normal, mild cognitive impairment and mild Alzheimer's disease dementia groups in 5 of the 18 independent components, as determined by Kruskal-Wallis tests. Only Patterns 1 and 2 demonstrated significant differences in group loading weights after correction for multiple comparisons. Excluding the cognitively normal group, we observed significant correlations between the loading weights for Pattern 1 (left temporal cortex and the cingulate gyrus) and Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019), Mini-Mental State Examination (r = 0.48, P = 0.0055) and Logical Memory II score (r = 0.44, P = 0.013). For Pattern 2 (temporal cortices), significant associations were demonstrated between its loading weights and Logical Memory II score (r = 0.34, P = 0.0384). Following false discovery rate correction, only the relationship between the Pattern 1 loading weights with Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019) and Mini-Mental State Examination (r = 0.48, P = 0.0055) remained statistically significant. We demonstrated that independent component analysis could define coherent spatial patterns of synaptic density. Furthermore, commonly used measures of cognitive performance correlated significantly with loading weights for two patterns within only the mild cognitive impairment/mild Alzheimer's disease dementia group. This study leverages data-centric approaches to augment the conventional region-of-interest-based methods, revealing distinct patterns that differentiate between mild cognitive impairment and mild Alzheimer's disease dementia, marking a significant advancement in the field.

Helicobacter pylori, persistent infection burden and structural brain imaging markers.

Persistent infections, whether viral, bacterial or parasitic, including Helicobacter pylori infection, have been implicated in non-communicable diseases, including dementia and other neurodegenerative diseases. In this cross-sectional study, data on 635 cognitively normal participants from the UK Biobank study (2006-21, age range: 40-70 years) were used to examine whether H. pylori seropositivity (e.g. presence of antibodies), serointensities of five H. pylori antigens and a measure of total persistent infection burden were associated with selected brain volumetric structural MRI (total, white, grey matter, frontal grey matter (left/right), white matter hyperintensity as percent intracranial volume and bi-lateral sub-cortical volumes) and diffusion-weighted MRI measures (global and tract-specific bi-lateral fractional anisotropy and mean diffusivity), after an average 9-10 years of lag time. Persistent infection burden was calculated as a cumulative score of seropositivity for over 20 different pathogens. Multivariable-adjusted linear regression analyses were conducted, whereby selected potential confounders (all measures) and intracranial volume (sub-cortical volumes) were adjusted, with stratification by Alzheimer's disease polygenic risk score tertile when exposures were H. pylori antigen serointensities. Type I error was adjusted to 0.007. We report little evidence of an association between H. pylori seropositivity and persistent infection burden with various volumetric outcomes (P > 0.007, from multivariable regression models), unlike previously reported in past research. However, H. pylori antigen serointensities, particularly immunoglobulin G against the vacuolating cytotoxin A, GroEL and outer membrane protein antigens, were associated with poorer tract-specific white matter integrity (P < 0.007), with outer membrane protein serointensity linked to worse outcomes in cognition-related tracts such as the external capsule, the anterior limb of the internal capsule and the cingulum, specifically at low Alzheimer's disease polygenic risk. Vacuolating cytotoxin A serointensity was associated with greater white matter hyperintensity volume among individuals with mid-level Alzheimer's disease polygenic risk, while among individuals with the highest Alzheimer's disease polygenic risk, the urease serointensity was consistently associated with reduced bi-lateral caudate volumes and the vacuolating cytotoxin A serointensity was linked to reduced right putamen volume (P < 0.007). Outer membrane protein and urease were associated with larger sub-cortical volumes (e.g. left putamen and right nucleus accumbens) at middle Alzheimer's disease polygenic risk levels (P < 0.007). Our results shed light on the relationship between H. pylori seropositivity, H. pylori antigen levels and persistent infection burden with brain volumetric structural measures. These data are important given the links between infectious agents and neurodegenerative diseases, including Alzheimer's disease, and can be used for the development of drugs and preventive interventions that would reduce the burden of those diseases.

Association of the triglyceride-glucose index with the occurrence and recurrence of colorectal adenomas: a retrospective study from China

BackgroundResection of colorectal adenoma (CRA) prevents colorectal cancer; however, recurrence is common. We aimed to assess the association of the triglyceride-glucose (TyG) index with CRA occurrence and recurrence.MethodsData from 3392 participants at a hospital in China from 2020 to 2022 were analyzed. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A restricted cubic spline was used to fit TyG index dose‒response curves to recurrent adenomas. The discriminatory power of TyG index for predicting later recurrence was assessed with the area under the receiver operating characteristic (ROC) curve in 170 patients with a TyG index at initial adenoma diagnosis.ResultsOne thousand five hundred ninety-six adenoma and 1465 normal participants were included in the occurrence analysis, and 179 recurrent and 152 nonrecurrent participants were included in the recurrence analysis. The TyG mutation was an independent risk factor for CRA occurrence and recurrence. After adjusting for confounders, the risk of adenoma in the participants in Q2, Q3, and Q4 groups of TyG was 1.324 (95% CI 1.020–1.718), 1.349 (95% CI 1.030–1.765), and 1.445 (95% CI 1.055–1.980) times higher than that of the Q1, respectively, and the risk of recurrence in the Q3 and Q4 groups was 2.267 (95% CI 1.096–4.691) and 2.824 (95% CI 1.199–6.648) times in Q1 group. Multiple logistic regression showed that the highest quartile of the TyG index was associated with a greater risk of advanced adenoma recurrence (OR 4.456, 95% CI 1.157–17.164), two or more adenomas (OR 5.079, 95% CI 1.136–22.714 [after removal of TyG index extreme values]), and proximal colon or both adenomas (OR 3.043, 95% CI 1.186–7.810). Subgroup analysis revealed that the association was found to be present only in participants of all age groups who were either male or without obesity, hyperglycemia, hypertension, or dyslipidemia (p < 0.05). ROC curves illustrated that the TyG index had good predictive efficacy for identifying recurrence, especially for patients with two or more adenomas (AUC 0.777, 95% CI 0.648–0.907).ConclusionsAn increase in the TyG index is associated with an increased risk of adenoma occurrence and recurrence, with a stronger association with the latter.

Biomarker Changes during 20 Years Preceding Alzheimer’s Disease

BackgroundBiomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer’s disease have not been extensively investigated in longitudinal studies.MethodsWe conducted a multicenter, nested case–control study of Alzheimer’s disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year–to–3-year intervals. A total of 648 participants in whom Alzheimer’s disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups.ResultsThe median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer’s disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aβ)42, 18 years; the ratio of Aβ42 to Aβ40, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer’s disease group initially accelerated and then slowed.ConclusionsIn this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer’s disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156.)

The intake of ultra-processed foods and homocysteine levels in women with(out) overweight and obesity: The Rotterdam Periconceptional Cohort

PurposeToday’s diet consists of a substantial proportion of ultra-processed foods (UPF), especially in women with overweight and obesity in the reproductive period. High UPF intake results in an inadequate and unbalanced diet leading to derangements of several metabolic pathways detrimental to pregnancy and birth outcomes. Therefore, we aim to investigate whether UPF intake in the periconceptional period affects total homocysteine plasma levels (tHcy).Methods1532 participants were included from the prospective Rotterdam Periconceptional Cohort. UPF intake was calculated using Food Frequency Questionnaires including items classified as 4 in the Nova classification, and tHcy was measured by using liquid chromatography-tandem mass spectrometry system, with an interassay coefficient of variation of < 5.5%. Multivariable linear regression modeling was used and adjusted for covariates and significant interaction terms.ResultsWomen with overweight or obesity showed significantly higher percentage of UPF intake (respectively, 50.3 and 51.3%) and higher tHcy (respectively, 6.6 and 6.3 µmol/L, Kruskal–Wallis test; respectively, p < 0.001 and p = 0.04) compared to women with normal BMI (UPF intake: 46.8%, tHcy: 6.1 µmol/L). A 10% higher intake of UPF was associated with an increase in tHcy (adjusted: β = 1.31, 95% CI = 0.38–2.23). Analysis stratified for BMI classification showed comparable associations in normal weight participants (adjusted: β = 1.07, 95% CI = 0.06–2.07); however, no significant association in participants with overweight (adjusted: β = 0.06, 95% CI = − 0.95–1.07) and obesity (adjusted: β = 1.70, 95% CI = − 0.52–3.92) was shown.ConclusionThis study showed that a higher intake of UPF is associated with increased tHcy. Better knowledge and awareness of the nutritional quality of the diet in the periconceptional period may contribute to 1-CM and subsequently improve pregnancy course and outcome.Trial registration number and dateNTR4356, November 2010.

Evaluating a novel 24-hour rest/activity rhythm marker of preclinical β-amyloid deposition.

To compare sleep and 24-hour rest/activity rhythms (RARs) between cognitively normal older adults who are β-amyloid-positive (Aβ+) or Aβ- and replicate a novel time-of-day-specific difference between these groups identified in a previous exploratory study. We studied 82 cognitively normal participants from the Baltimore Longitudinal Study of Aging (aged 75.7 ± 8.5 years, 55% female, 76% white) with wrist actigraphy data and Aβ+ versus Aβ- status measured by [11C] Pittsburgh compound B positron emission tomography. RARs were calculated using epoch-level activity count data from actigraphy. We used novel, data-driven function-on-scalar regression analyses and standard RAR metrics to cross-sectionally compare RARs between 25 Aβ+ and 57 Aβ- participants. Compared to Aβ- participants, Aβ+ participants had higher mean activity from 1:00 p.m. to 3:30 p.m. when using less conservative pointwise confidence intervals (CIs) and from 1:30 p.m. to 2:30 p.m. using more conservative, simultaneous CIs. Furthermore, Aβ+ participants had higher day-to-day variability in activity from 9:00 a.m. to 11:30 a.m. and lower variability from 1:30 p.m. to 4:00 p.m. and 7:30 p.m. to 10:30 p.m. according to pointwise CIs, and lower variability from 8:30 p.m. to 10:00 p.m. using simultaneous CIs. There were no Aβ-related differences in standard sleep or RAR metrics. Findings suggest Aβ+ older adults have higher, more stable day-to-day afternoon/evening activity than Aβ- older adults, potentially reflecting circadian dysfunction. Studies are needed to replicate our findings and determine whether these or other time-of-day-specific RAR features have utility as markers of preclinical Aβ deposition and if they predict clinical dementia and agitation in the afternoon/evening (i.e. "sundowning").

Examining the impact of a health report card on follow through with fall risk recommendations: an observational study

BackgroundIncreasing older adults’ awareness of their personal fall risk factors may increase their engagement in fall prevention. The purpose of this study was to explore the impact of and participant satisfaction with a comprehensive occupational therapy fall risk screening and recommendations for evidence-based fall prevention strategies based on personalized fall risk results for community-dwelling older adults.MethodsCognitively normal participants (Clinical Dementia Rating = 0) were recruited from an ongoing longitudinal study of memory and aging. Participants completed 2 annual in-home visits, fall risk questionnaires, and 12 months of fall monitoring between visits. Participants received a health report card with their fall risks and tailored recommendations in 6 domains. Participants completed follow-up questions at their next annual in-home visit about the fall risk recommendations and their satisfaction with receiving their fall risk results.ResultsTwo hundred five participants completed 2 annual visits and 12 months of fall monitoring. Of the 6 domains of recommendations provided, participants were most likely to follow through with getting an annual eye exam and reviewing their medications with their doctor or pharmacist. Older adults who fell were significantly more likely to receive recommendations for finding fall prevention classes (p = 0.01) and having a doctor or pharmacist review their medications (p = 0.004). The majority of participants were satisfied receiving their fall risk results (92%) and believed it to be beneficial (90%), though few participants shared their results with their doctor (20%).ConclusionsAn occupational therapy fall risk screening and tailored recommendations were not sufficient to encourage follow through with fall risk recommendations. Older adults may benefit from additional support and encouragement to reduce their fall risk. Additional research is needed to examine awareness of fall risks and follow through with fall risk recommendations among community-dwelling older adults.

Development and Validity of Norms for Cognitive Dispersion on the Uniform Data Set 3.0 Neuropsychological Battery.

Cognitive dispersion indexes intraindividual variability in performance across a battery of neuropsychological tests. Measures of dispersion show promise as markers of cognitive dyscontrol and everyday functioning difficulties; however, they have limited practical applicability due to a lack of normative data. This study aimed to develop and evaluate normed scores for cognitive dispersion among older adults. We analyzed data from 4,283 cognitively normal participants aged ≥50years from the Uniform Data Set (UDS) 3.0. We describe methods for calculating intraindividual standard deviation (ISD) and coefficient of variation (CoV), as well as associated unadjusted scaled scores and demographically adjusted z-scores. We also examined the ability of ISD and CoV scores to differentiate between cognitively normal individuals (n = 4,283) and those with cognitive impairment due to Lewy body disease (n = 282). We generated normative tables to map raw ISD and CoV scores onto a normal distribution of scaled scores. Cognitive dispersion indices were associated with age, education, and race/ethnicity but not sex. Regression equations were used to develop a freely accessible Excel calculator for deriving demographically adjusted normed scores for ISD and CoV. All measures of dispersion demonstrated excellent diagnostic utility when evaluated by the area under the curve produced from receiver operating characteristic curves. Results of this study provide evidence for the clinical utility of sample-based and demographically adjusted normative standards for cognitive dispersion on the UDS 3.0. These standards can be used to guide interpretation of intraindividual variability among older adults in clinical and research settings.

Evaluation of contrast sensitivity in visually impaired individuals using K-CS test. A novel smartphone-based contrast sensitivity test-Design and validation.

To describe the development and investigate the accuracy of a novel smartphone-based Contrast Sensitivity (CS) application, the K-CS test. A total of 67 visually impaired and 50 normal participants were examined monocularly using the novel digital K-CS test and the Pelli-Robson (PR) chart. The K-CS test examines letter contrast sensitivity in logarithmic units, using eight levels of contrast from logCS = ~0,1 to logCS = ~2,1 at two spatial frequencies of 1.5 and 3 cycles per degree (cpd). The K-CS test was compared to the gold standard, PR test and intra-session test repeatability was also examined. The K-CS test in normally sighted was found to agree well with the PR, providing comparable mean scores in logCS (±SD) (K-CS = 1.908 ± 0.06 versus PR = 1.93 ± 0.05) at 1.5 cpd and mean (± SD) logCS at 3 cpd (K-CS = 1.83 ± 0.13 versus PR = 1.86 ± 0.07). The mean best corrected visual acuity of visually impaired participants was 0.67 LogMAR (SD = 0.21) and the K-CS was also found to agree well with the Pelli-Robson in this group, with an equivalent mean (±SD) logCS at 1.5 cpd: (K-CS = 1.19 ± 0.27, PR = 1.15 ± 0.31), 3 cpd: K-CS = 1.01 ± 0.33, PR = 0.94 ± 0.34. Regarding the intra-session test repeatability, both the K-CS test and the PR test showed good repeatability in terms of the 95% limits of agreement (LoA): K-CS = ±0.112 at 1.5 cpd and ±0.133 at 3 cpd, PR = ±0.143 at 1.5 cpd and ±0.183 in 3 cpd in visually impaired individuals. The K-CS test provides a quick assessment of the CS both in normally sighted and visually impaired individuals. The K-CS could serve as an alternative tool to assess contrast sensitivity function using a smartphone and provides results that agree well with the commonly used PR test.

Computer-Aided Discrimination of Glaucoma Patients from Healthy Subjects Using the RETeval Portable Device.

Glaucoma is a chronic, progressive eye disease affecting the optic nerve, which may cause visual damage and blindness. In this study, we present a machine-learning investigation to classify patients with glaucoma (case group) with respect to normal participants (control group). We examined 172 eyes at the Ophthalmology Clinic of the "Elpis" General Hospital of Athens between October 2022 and September 2023. In addition, we investigated the glaucoma classification in terms of the following: (a) eye selection and (b) gender. Our methodology was based on the features extracted via two diagnostic optical systems: (i) conventional optical coherence tomography (OCT) and (ii) a modern RETeval portable device. The machine-learning approach comprised three different classifiers: the Bayesian, the Probabilistic Neural Network (PNN), and Support Vectors Machines (SVMs). For all cases examined, classification accuracy was found to be significantly higher when using the RETeval device with respect to the OCT system, as follows: 14.7% for all participants, 13.4% and 29.3% for eye selection (right and left, respectively), and 25.6% and 22.6% for gender (male and female, respectively). The most efficient classifier was found to be the SVM compared to the PNN and Bayesian classifiers. In summary, all aforementioned comparisons demonstrate that the RETeval device has the advantage over the OCT system for the classification of glaucoma patients by using the machine-learning approach.

Analysis of the Retinal and Choroidal Vasculature Using Ultrawidefield Fundus Imaging in Mild Cognitive Impairment and Normal Cognition

PurposeTo utilize ultra-widefield (UWF) imaging to evaluate retinal and choroidal vasculature and structure in individuals with mild cognitive impairment (MCI) compared to controls with normal cognition. DesignProspective cross-sectional study ParticipantsOne hundred thirty-one eyes of 82 MCI patients and 231 eyes of 133 cognitively normal participants from the Eye Multimodal Imaging in Neurodegenerative Disease (iMIND) Study. MethodsA scanning laser ophthalmoscope (SLO) (California, Optos Inc, Marlborough, MA) was used to obtain UWF fundus color images. Images were analyzed with the Vasculature Assessment Platform for Images of the Retina UWF (VAMPIRE-UWF 2.0, Universities of Edinburgh and Dundee, United Kingdom) software. Main outcome measuresImaging parameters included vessel width gradient, vessel width intercept, large vessel choroidal vascular density, vessel tortuosity, and vessel fractal dimension. ResultsBoth retinal artery and vein width gradients were less negative in MCI patients compared to controls, demonstrating decreased rates of vessel thinning at the periphery (p < 0.001, p = 0.027). Retinal artery and vein width intercepts, a metric that extrapolates the width of vessel at the center of the optic disc, were smaller in MCI patients compared to controls (p < 0.001, p = 0.017). The large vessel choroidal vascular density, which quantifies the vascular area versus total choroidal area, was greater in MCI patients compared to controls (p = 0.025). ConclusionsWhen compared to controls with normal cognition, MCI patients had thinner retinal vasculature manifested in both the retinal arteries and in the veins. In MCI, these thinner arteries and veins attenuated at a lower rate when traveling towards the periphery. MCI patients also had increased choroidal vascular density.

Obesity is associated with alterations in anatomical connectivity of frontal-corpus callosum.

Obesity has been linked to abnormal frontal function, including the white matter fibers of anterior portion of the corpus callosum, which is crucial for information exchange within frontal cortex. However, alterations in white matter anatomical connectivity between corpus callosum and cortical regions in patients with obesity have not yet been investigated. Thus, we enrolled 72 obese and 60 age-/gender-matched normal weight participants who underwent clinical measurements and diffusion tensor imaging. Probabilistic tractography with connectivity-based classification was performed to segment the corpus callosum and quantify white matter anatomical connectivity between subregions of corpus callosum and cortical regions, and associations between corpus callosum-cortex white matter anatomical connectivity and clinical behaviors were also assessed. Relative to normal weight individuals, individuals with obesity exhibited significantly greater white matter anatomical connectivity of corpus callosum-orbitofrontal cortex, which was positively correlated with body mass index and self-reported disinhibition of eating behavior, and lower white matter anatomical connectivity of corpus callosum-prefrontal cortex, which was significantly negatively correlated with craving for high-calorie food cues. The findings show that alterations in white matter anatomical connectivity between corpus callosum and frontal regions involved in reward and executive control are associated with abnormal eating behaviors.

Brain 11β-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem™ Assessed by PET in Alzheimer's Disease and Cognitively Normal Individuals.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer's disease (AD). Animal models suggest a range of 30-60% enzyme inhibition may suffice to provide neuroprotection. To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40-60) and volume of distribution (VT) from Logan plot with image derived input function from 11C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days). All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79-81%] and 75% [71-76%] in the neocortex, 69% [64-70%] and 61% [52-63%] in the medial temporal lobe, 80% [79-80%] and 73% [68-73%] in the basal ganglia, and 71% [67-75%] and 66% [62-68%] in the cerebellum. TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies.

Naturalistic assessment of reaction time variability in older adults at risk for Alzheimer's disease.

Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD. Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials. Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ε4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ε4 status and several in-clinic cognition composites. Attentional fluctuations over 20-40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage.

Variability of corticospinal and spinal reflex excitability for the ankle dorsiflexor tibialis anterior across repeated measurements in people with and without incomplete spinal cord injury

To adequately evaluate the corticospinal and spinal plasticity in health and disease, it is essential to understand whether and to what extent the corticospinal and spinal responses fluctuate systematically across multiple measurements. Thus, in this study, we examined the session-to-session variability of corticospinal excitability for the ankle dorsiflexor tibialis anterior (TA) in people with and without incomplete spinal cord injury (SCI). In neurologically normal participants, the following measures were obtained across 4 days at the same time of day (N = 13) or 4 sessions over a 12-h period (N = 9, at 8:00, 12:00, 16:00, and 20:00): maximum voluntary contraction (MVC), maximum M-wave and H-reflex (Mmax and Hmax), motor evoked potential (MEP) amplitude, and silent period (SP) after MEP. In participants with chronic incomplete SCI (N = 17), the same measures were obtained across 4 days. We found no clear diurnal variation in the spinal and corticospinal excitability of the TA in individuals with no known neurological conditions, and no systematic changes in any experimental measures of spinal and corticospinal excitability across four measurement days in individuals with or without SCI. Overall, mean deviations across four sessions remained in a range of 5–13% for all measures in participants with or without SCI. The study shows the limited extent of non-systematic session-to-session variability in the TA corticospinal excitability in individuals with and without chronic incomplete SCI, supporting the utility of corticospinal and spinal excitability measures in mechanistic investigation of neuromodulation interventions. The information provided through this study may serve as the reference in evaluating corticospinal plasticity across multiple experimental sessions.

Do abnormal screening results for chronic diseases motivate inactive people to start exercising? A community-based prospective cohort study in Changhua, Taiwan

ObjectiveExercise improves health, but illnesses can cause changes in exercise behavior, including starting or stopping. This study investigated the effects of chronic disease screening on inactive individuals' exercise behavior and analyzed the impact of age and chronic disease history on this relationship using stratified analysis. MethodsUsing a community-based prospective observational cohort design and data from the Changhua Community-Based Integrated Screening (CHCIS) dataset from 2005 to 2020, we examined 12,038 people who were screened at least twice and self-reported having never exercised at their first screening. Changes in exercise behavior were classified as “initiating exercise” and “remaining inactive.” We obtained chronic disease screening results from CHCIS records, which included measurements of waist circumference, blood glucose, blood pressure, triglycerides, and high-density lipoproteins. SAS version 9.4 was used for COX proportional hazards regression. ResultsThe findings indicated that abnormal waist circumference and blood pressure increased the likelihood of initiating exercise compared to normal results. Age stratification showed that those aged 40–49 with abnormal results were more likely to start exercising than normal participants, but not those under 40 or over 65. When stratified by chronic disease history, abnormal screening results correlated with exercise initiation only in groups without chronic disease history, except for those with a history of hyperlipidemia. ConclusionsThis is the first study to demonstrate that abnormal screening results may influence exercise initiation in individuals who have never exercised, and this association varies by screening item, age, and disease history.

Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status

BackgroundAPOE4 is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex.MethodsParticipants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer’s Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers, APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions.ResultsAmong CN, APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate.ConclusionsThe entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation. APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.

Heterogeneous correlate and potential diagnostic biomarker of tinnitus based on nonlinear dynamics of resting-state EEG recordings.

Tinnitus is a heterogeneous condition of hearing a rattling sound when there is no auditory stimulus. This rattling sound is associated with abnormal synchronous oscillations in auditory and non-auditory cortical areas. Since tinnitus is a highly heterogeneous condition with no objective detection criteria, it is necessary to search for indicators that can be compared between and within participants for diagnostic purposes. This study introduces heterogeneous though comparable indicators of tinnitus through investigation of spontaneous fluctuations in resting-state brain dynamics. The proposed approach uses nonlinear measures of chaos theory, to detect tinnitus and cross correlation patterns to reflect many of the previously reported neural correlates of tinnitus. These indicators may serve as effective measures of tinnitus risk even at early ages before any symptom is reported. The approach quantifies differences in oscillatory brain dynamics of tinnitus and normal subjects. It demonstrates that the left temporal areas of subjects with tinnitus exhibit larger lyapunov exponent indicating irregularity of brain dynamics in these regions. More complex dynamics is further recognized in tinnitus cases through entropy. We use this evidence to distinguish tinnitus patients from normal participants. Besides, we illustrate that certain anticorrelation patterns appear in these nonlinear measures across temporal and frontal areas in the brain perhaps corresponding to increased/decreased connectivity in certain brain networks and a shift in the balance of excitation and inhibition in tinnitus. Additionally, the main correlations are lost in tinnitus participants compared to control group suggesting involvement of distinct neural mechanisms in generation and persistence of tinnitus.

Sitting time in different contexts in Austrian adolescents and association with weight status

&lt;abstract&gt; &lt;p&gt;The detrimental effects of high amounts of sedentary time on various health outcomes have been well documented. Particularly among youth, there are many sedentary pursuits that compete with active leisure time choices, which contribute to a high prevalence of insufficiently active children and adolescents. Therefore, the present study examined the time spent in various sedentary behaviors and the association with body weight in Austrian adolescents. Sedentary time was assessed with the “Heidelberg Questionnaire to Record the Sitting Behavior of Children and Adolescents” for 1225 (49.8% male) middle- and high-school students between 11 and 17 years of age. Their body weights and heights were measured with participants wearing gym clothes. The weight categories were established based on body mass index (BMI) percentiles using the German reference system. The average daily sedentary time across the entire sample was 12.0 ± 1.6 h, and 45% of the sedentary behaviors during the entire week were attributed to schoolwork. Normal weight participants reported a lower amount of sitting time compared to their overweight and obese peers, where they spent more time with physical activity and sleeping. Specifically, a higher body weight was associated with more time spent with recreational sedentary behaviors, while differences across the weight categories were limited for work-related sitting. Given the detrimental health effects of high amounts of sedentary behaviors, additional efforts are needed to promote physical activity in adolescents, particularly for those with an excess body weight. As almost half of the sedentary behaviors were attributed to work, schools could be a particularly viable setting for interventions that target an active lifestyle.&lt;/p&gt; &lt;/abstract&gt;

CSF 14–3-3 zeta(ζ) isoform is associated with tau pathology and cognitive decline in Alzheimer's disease

14–3-3 is a family of conserved proteins that consist of seven isoforms which are highly expressed in the brain, and 14–3-3 zeta(ζ) is one of the isoforms encoded by the YWHAZ gene. Previous studies demonstrated that 14–3-3ζ is deposited in the neurofibrillary tangles of Alzheimer's disease (AD) brains, and that 14–3-3ζ interacts with tau from the purified neurofibrillary tangles of AD brain extract. The present study examined the cerebrospinal fluid (CSF) 14–3-3ζ levels of 719 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) participants, patients with mild cognitive impairment (MCI) and patients with AD dementia, and aimed to identify whether CSF 14–3-3ζ is associated with tau pathology. CSF 14–3-3ζ levels were increased in AD, and particularly elevated among tau pathology positive individuals. CSF 14–3-3ζ levels were associated with CSF phosphorylated tau 181 (p-tau) (r = 0.741, P < 0.001) and plasma p-tau (r = 0.293, P < 0.001), which are fluid biomarkers of tau pathology, and could predict tau pathology positive status with high accuracy (area under the receiver operating characteristic curve [AUC], 0.891). CSF 14–3-3ζ levels were also correlated to synaptic biomarker CSF GAP-43 (r = 0.609, P < 0.001) and neuroinflammatory biomarker CSF sTREM-2 (r = 0.507, P < 0.001). High CSF 14–3-3ζ levels at baseline were associated with progressive decline of cognitive function and neuroimaging findings during follow up. In conclusion, this study suggests that CSF 14–3-3ζ is a potential biomarker of AD that may be useful in clinical practice.