Impaired long-range excitatory time scale predicts abnormal neural oscillations and cognitive deficits in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM). METHODS: SGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years). RESULTS: Patients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition. CONCLUSIONS: These results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

Spatiotemporal characteristics of neurophysiological changes in patients with four-repeat tauopathies.

INTRODUCTION: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are the most common four-repeat tauopathies (4RT), and both frequently occur with varying degree of Alzheimer's disease (AD) copathology. Intriguingly, patients with 4RT and patients with AD are at opposite ends of the wakefulness spectrum-AD showing reduced wakefulness and excessive sleepiness whereas 4RT showing decreased homeostatic sleep. The neural mechanisms underlying these distinct phenotypes in the comorbid condition of 4RT and AD are unknown. The objective of the current study was to define the alpha oscillatory spectrum, which is prominent in the awake resting-state in the human brain, in patients with primary 4RT, and how it is modified in comorbid AD-pathology. METHOD: In an autopsy-confirmed case series of 4R-tauopathy patients (n = 10), whose primary neuropathological diagnosis was either PSP (n = 7) or CBD (n = 3), using high spatiotemporal resolution magnetoencephalography (MEG), we quantified the spectral power density within alpha-band (8-12 Hz) and examined how this pattern was modified in increasing AD-copathology. For each patient, their regional alpha power was compared to an age-matched normative control cohort (n = 35). RESULT: Patients with 4RT showed increased alpha power but in the presence of AD-copathology alpha power was reduced. CONCLUSIONS: Alpha power increase in PSP-tauopathy and reduction in the presence of AD-tauopathy is consistent with the observation that neurons activating wakefulness-promoting systems are preserved in PSP but degenerated in AD. These results highlight the selectively vulnerable impacts in 4RT versus AD-tauopathy that may have translational significance on disease-modifying therapies for specific proteinopathies.

Impaired Speaking-Induced Suppression in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease involving cognitive impairment and abnormalities in speech and language. Here, we examine how AD affects the fidelity of auditory feedback predictions during speaking. We focus on the phenomenon of speaking-induced suppression (SIS), the auditory cortical responses' suppression during auditory feedback processing. SIS is determined by subtracting the magnitude of auditory cortical responses during speaking from listening to playback of the same speech. Our state feedback control (SFC) model of speech motor control explains SIS as arising from the onset of auditory feedback matching a prediction of that feedback onset during speaking, a prediction that is absent during passive listening to playback of the auditory feedback. Our model hypothesizes that the auditory cortical response to auditory feedback reflects the mismatch with the prediction: small during speaking, large during listening, with the difference being SIS. Normally, during speaking, auditory feedback matches its predictions, then SIS will be large. Any reductions in SIS will indicate inaccuracy in auditory feedback prediction not matching the actual feedback. We investigated SIS in AD patients [n = 20; mean (SD) age, 60.77 (10.04); female (%), 55.00] and healthy controls [n = 12; mean (SD) age, 63.68 (6.07); female (%), 83.33] through magnetoencephalography (MEG)-based functional imaging. We found a significant reduction in SIS at ∼100 ms in AD patients compared with healthy controls (linear mixed effects model, F (1,57.5) = 6.849, p = 0.011). The results suggest that AD patients generate inaccurate auditory feedback predictions, contributing to abnormalities in AD speech.

Impaired long-range excitatory time scale predicts abnormal neural oscillations and cognitive deficits in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, progressively impairing memory and cognition. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify abnormal biophysical mechanisms underlying these abnormal electrophysiological patterns, we estimated the parameters of a spectral graph-theory model (SGM). SGM is an analytic model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. The long-range excitatory time scale was associated with greater deficits in global cognition and was able to distinguish AD patients from controls with high accuracy. These results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the spatiospectral signatures and cognition in AD.

Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease.

Background: Neuronal- and circuit-level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aß) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD. Methods: Using empirical spectra from magnetoencephalography and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aß, measured by positron emission tomography, in patients with AD. Results: Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aß depositions. Conclusions: Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aß in patients with AD. Funding: This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM and GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL (KGR), 2019-A-013-SUP (KGR); grants from the Alzheimer's Association: AARG-21-849773 (KGR); PCTRB-13-288476 (KAV), and made possible by Part the CloudTM (ETAC-09-133596); a grant from Tau Consortium (GDR and WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

A mindfulness-based intervention adapted to dementia caregivers: A study protocol for a randomized clinical control trial.

Dementia caregiving, besides encompassing various challenges in tandem to the diagnosis of the care recipient, is associated with decreased psychological well-being and mental health. Accordingly, caregivers' wellbeing has an impact on the quality of care they provide and on the relationship quality with the person in their care. The aim of the present study is to examine the effectiveness of a mindfulness-based intervention on relational and psychological wellbeing, tailored to the needs of dementia caregivers. This clinical trial (NCT04977245) will apply a randomized controlled mixed method design. Caregivers will be randomly allocated to either the mindfulness intervention or the active control group. The intervention arm is based on experiential learning and is targeted to promote caregivers' well-being and empowerment. Assessments will include, standardized self-report questionnaires, task performance measures, and qualitative measures. All assessments will be held at three time points (baseline; t0, 0 months, post-intervention; t1, 2 months, and after maintenance; t2, 3 months) focused on three core domains (1. relational well-being, 2. psychological well-being, and 3. dementia patient's lifestyle/activities). The primary outcome will be relational well-being, and data will be analyzed using linear mixed modelling.

Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer's disease.

Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer's disease, a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with Alzheimer's disease. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with Alzheimer's disease. Using magnetoencephalography (MEG) at rest, we studied 30 Alzheimer's disease patients without subclinical epileptiform activity, 20 Alzheimer's disease patients with subclinical epileptiform activity and 35 age-matched controls. Presence of subclinical epileptiform activity was assessed in patients with Alzheimer's disease by long-term video-EEG and a 1-h resting MEG with simultaneous EEG. Using the resting-state source-space reconstructed MEG signal, in patients and controls we computed the global imaginary coherence in alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillatory frequencies. We found that Alzheimer's disease patients with subclinical epileptiform activity have greater reductions in alpha imaginary coherence and greater enhancements in delta-theta imaginary coherence than Alzheimer's disease patients without subclinical epileptiform activity, and that these changes can distinguish between Alzheimer's disease patients with subclinical epileptiform activity and Alzheimer's disease patients without subclinical epileptiform activity with high accuracy. Finally, a principal component regression analysis showed that the variance of frequency-specific neuronal synchrony predicts longitudinal changes in Mini-Mental State Examination in patients and controls. Our results demonstrate that quantitative neurophysiological measures are sensitive biomarkers of network hyperexcitability and can be used to improve diagnosis and to select appropriate patients for the right therapy in the next-generation clinical trials. The current results provide an integrative framework for investigating network hyperexcitability and network dysfunction together with cognitive and clinical correlates in patients with Alzheimer's disease.

A qualitative study of patient and provider perspectives on using web-based pain coping skills training to treat persistent cancer pain.

OBJECTIVE: Persistent pain is common and inadequately treated in cancer patients. Behavioral pain interventions are a recommended part of multimodal pain treatments, but they are underused in clinical care due to barriers such as a lack of the resources needed to deliver them in person and difficulties coordinating their use with clinical care. Pain coping skills training (PCST) is an evidence-based behavioral pain intervention traditionally delivered in person. Delivering this training via the web would increase access to it by addressing barriers that currently limit its use. We conducted a patient pilot study of an 8-week web-based PCST program to determine the acceptability of this approach to patients and the program features needed to meet their needs. Focus groups with healthcare providers identified strategies for coordinating the use of web-based PCST in clinical care. METHOD: Participants included 7 adults with bone pain due to multiple myeloma or metastasized breast or prostate cancer and 12 healthcare providers (4 physicians and 8 advanced practice providers) who treat cancer-related bone pain. Patients completed web-based PCST at home and then took part in an in-depth qualitative interview. Providers attended focus groups led by a trained moderator. Qualitative analyses identified themes in the patient and provider data. RESULTS: Patients reported strongly favorable responses to web-based PCST and described emotional and physical benefits. They offered suggestions for adapting the approach to better fit their needs and to overcome barriers to completion. Focus groups indicated a need to familiarize healthcare providers with PCST and to address concerns about overburdening patients. Providers would recommend the program to patients they felt could benefit. They suggested applying a broad definition of cancer pain and having various types of providers help coordinate program its use with clinical care. SIGNIFICANCE OF RESULTS: Web-based PCST was acceptable to patients and providers. Our findings suggest that patients could benefit from this approach, especially if patient and provider barriers are addressed.

Body size perception and ideal body size in overweight and obese young adult women.

PURPOSE: The purpose of this study was to examine the differences among actual body size, perceived body size, and ideal body size in overweight and obese young adult women. METHODS: Actual body size was assessed by body mass index (BMI), while self-perceived and ideal body sizes were assessed by the Body image assessment tool-body dimension. Descriptive statistics were calculated and analysis of variance (ANOVA) was performed on actual BMI as a function of perceived BMI. RESULTS: Of the 42 participants included in the study, 12 were overweight (25 ≤ BMI < 30), 18 were obese 1 (30 ≤ BMI < 35), and 12 were obese 2 (35 ≤ BMI ≤ 39.48). The mean ideal body size of participants was 25.34 ± 1.33. Participants in general perceived their body size (BMI: 35.82 ± 1.06) to be higher than their actual body size (32.84 ± 0.95). Overweight participants had a significantly higher mean body size misperception than obese 2 individuals (µ dif = -6.68, p < .001). CONCLUSION: Perception accuracy of body size differs in women by BMI. Weight loss programs need to be tailored to consider body size misperception in order to improve treatment outcomes for overweight and obese young women.

Lifestyle habits and obesity progression in overweight and obese American young adults: Lessons for promoting cardiometabolic health.

Obesity among young adults is a growing problem in the United States and is related to unhealthy lifestyle habits, such as high caloric intake and inadequate exercise. Accurate assessment of lifestyle habits across obesity stages is important for informing age-specific intervention strategies to prevent and reduce obesity progression. Using a modified version of the Edmonton Obesity Staging System (mEOSS), a new scale for defining obesity risk and predicting obesity morbidity and mortality, this cross-sectional study assessed the prevalence of overweight/obese conditions in 105 young adults and compared their lifestyle habits across the mEOSS stages. Descriptive statistics, chi-square tests, and one-way analyses of variance were performed. Eighty percent of participants (n = 83) fell into the mEOSS-2 group and had obesity-related chronic disorders, such as diabetes, hypertension, and/or dyslipidemia. There were significant differences in dietary quality and patterns across the mEOSS stages. Findings highlighted the significance of prevention and early treatment for overweight and obese young adults to prevent and cease obesity progression.

A feasibility study to develop a diabetes prevention program for young adults with prediabetes by using digital platforms and a handheld device.

PURPOSE: The purpose of this pilot study was to examine the feasibility and preliminary efficacy of an age-specific diabetes prevention program in young adults with prediabetes. METHODS: A one-group pretest-posttest design was used. The inclusion criteria were age 18 to 29 years and the presence of prediabetes (either impaired fasting glucose of 100-125 mg/dL [5.55-6.94 mmol/L] or A1C of 5.7%-6.4%). Fifteen participants were enrolled in the study. A technology-based lifestyle coaching program focused on diet and physical activity and incorporating a handheld device and digital platforms was developed and tested. Psychosocial factors (health literacy, illness perception, self-efficacy, therapeutic efficacy) based on social cognitive theory, changes in diet and physical activity, and cardiometabolic risk factors were assessed at baseline and week 12 after the intervention. A paired-samples t test was performed to examine changes between baseline and postintervention on each psychosocial and physical variable. RESULTS: Participants' (n = 13 completers) mean age was 24.4 ± 2.2 years, 23.1% were male, and 53.8% were African American. Overall, the participants were satisfied with the intervention (mean score, 4.15 on a 5-point, Likert-type scale). Between pre- and posttesting, mean body mass index and mean A1C decreased from 41.0 ± 7.3 kg/m(2) and 6.0 ± 0.5% to 40.1 ± 7.0 kg/m(2) and 5.6 ± 0.5%, respectively, whereas mean fasting glucose did not significantly change (from 92.6 ± 11 to 97.6 ± 14.3 mg/dL [5.14 ± 0.61 to 5.42 ± 0.79 mmol/L]). CONCLUSIONS: The intervention resulted in reduced A1C and a trend toward decreased body mass index in obese sedentary young adults with prediabetes after 12 weeks. Further study through a randomized clinical trial with a longer intervention period is warranted.

Health literacy, self-efficacy, food label use, and diet in young adults.

OBJECTIVES: To examine relationships among health literacy, self-efficacy, food label use, and dietary quality in young adults aged 18-29. METHODS: Health literacy, self-efficacy, food label use, and dietary quality were assessed. Participants were categorized into low, medium and high health literacy groups based on Newest Vital Sign score. RESULTS: Self-efficacy and health literacy were predictors of food label use, which positively predicted dietary quality. The low health literacy group had significantly lower use of food labels than the high health literacy group. However, there was no significant difference between medium and high health literacy groups. CONCLUSION: Strategies to enhance health literacy, self-efficacy and food label use should be developed to improve dietary quality and health outcomes.