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INTRODUCTION Brain network dysfunction, particularly within the default mode network (DMN), is an increasingly apparent contributor to the clinical progression of Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) can target key DMN hubs, maintain signaling function, and delay or improve clinical outcomes in AD. Here, we present the rationale and design of a study using off‐the‐shelf equipment and the latest clinical evidence to expand on prior rTMS work and reduce participant burden in the process. METHODS We will conduct a two‐stage trial of large‐coil rTMS targeting the precuneus (a key hub in the DMN affected by AD) in 54 participants with mild to moderate Alzheimer's Clinical Syndrome focused primarily on determining tolerability and feasibility and secondarily focused on determining short‐term efficacy for memory. The first stage will involve 5 to 10 participants receiving open‐label active treatment to refine the protocol. The following second stage will consist of a 1:1 randomized, double‐blind, sham‐controlled clinical trial to study feasibility and tolerability while exploring target engagement and short‐term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full course of open‐label active treatment will be offered as an extension to the sham group after unblinding. Outcomes will focus on completion rates and adverse events to demonstrate feasibility and tolerability. Further exploratory outcomes will include neuropsychological assessments, electroencephalography, neuroimaging, and blood biomarkers to demonstrate the feasibility of collection and explore preliminary changes in these measures. RESULTS We anticipate this treatment is feasible and tolerable and may show evidence of target engagement and clinical improvement. DISCUSSION Should we achieve expected positive outcomes in feasibility and tolerability, this will justify future work focusing on clear demonstrations of clinical efficacy and biomarker engagement, as well as enhancement of generalizability and scalability. Highlights Induction‐to‐maintenance repetitive transcranial magnetic stimulation (rTMS) of the precuneus is a promising treatment for Alzheimer's disease (AD), though recent methods require intensive personalization. We propose here a trial design of precuneus rTMS in mild‐to‐early‐moderate AD dementia using exclusively off‐the‐shelf equipment and protocol modifications to reduce participant burden. Our two novel modifications from prior work are (1) using a larger rTMS coil, and (2) consolidating the induction phase of treatment. This trial focuses primarily on tolerability and feasibility while exploring clinical measures of efficacy and biomarkers of target engagement. Our trial is registered at ClinicalTrials.gov NCT06597942.

In a pragmatic trial involving older persons with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole was better than augmentation with bupropion or a switch to bupropion.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16–100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%–57%/25%–33%; <60: 32%–49%/18%–25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Purpose of Review Integrative medicine is the practice of combining conventional medical treatments with “alternative” or “complementary” therapies. Integrative psychiatry is a holistic, person-centered approach to neuropsychiatric disorders that emphasizes a person’s physical, emotional, interpersonal, behavioral, nutritional, environmental, and spiritual dimensions to achieve well-being. Older adults are more prone to physical injury, interpersonal loss, chronic illnesses, and physical and cognitive decline that can manifest as anxiety, depression, with functional decline and inability to care for self. Additionally, stress of caring for older adults with dementia can adversely affect caregivers’ health. Although integrative approaches are perceived as safer and less stigmatizing, it is important to understand the risks and benefits of such therapies for older adults with neurocognitive disorders and their caregivers. Recent Findings Here, we summarize the results of the recent clinical trials and meta-analyses that provide evidence for integrative approaches to treating older adults with cognitive disorders and their caregivers which include the use of diet and supplements, and mind–body therapies. Summary Dietary and mind-body therapies have become increasingly popular and show the strongest evidence of effectiveness for cognitive disorders and caregiver stress. Vitamins and supplements are the most popular integrative intervention, but there is mixed evidence supporting their use and the concern for herb (supplement)-drug interactions. While there is increasing popularity of integrative treatments, information to guide clinicians providing care for older adults remains limited, with variable scientific rigor of the available RCTs for a large number of commonly used integrative interventions particularly for cognitive disorders and caregiver stress and well-being.

Brain network dysfunction, particularly within the default mode network (DMN), is an increasingly apparent manifestation of Alzheimer's Disease (AD) progression. Repetitive transcranial magnetic stimulation (rTMS) can target key DMN hubs, maintain signaling function, and delay or improve clinical outcomes in AD. We present here the rationale, design, and preliminary open-label data of a study using off-the-shelf equipment and the latest clinical evidence to expand on prior rTMS work and reduce participant burden in the process. We are conducting a two-stage trial of large-coil rTMS targeting the precuneus (a key hub in the DMN affected by AD) in 54 participants with mild to moderate Alzheimer's Clinical Syndrome focused primarily on determining tolerability and feasibility and secondarily studying short-term efficacy for episodic memory. The currently active first stage involves 5-10 participants receiving open-label treatment for protocol refinement. The subsequent stage will consist of a 1:1 randomized, double-blind, sham controlled clinical trial to study feasibility and tolerability while exploring target engagement and short-term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full open-label extension treatment course will be offered to the sham group after unblinding. Outcomes focus on completion rates and adverse events to demonstrate feasibility and tolerability. Further exploratory outcomes will include neuropsychological assessments, electroencephalography (EEG), neuroimaging, and blood biomarkers to demonstrate feasibility of collection and explore preliminary changes in these measures. We anticipate this treatment is feasible and tolerable and may show evidence of target engagement and clinical improvement. We plan to present current preliminary open-label data as analyzed at AAIC. Should we achieve expected positive outcomes in feasibility and tolerability, this will justify future work focusing on clear demonstrations of clinical efficacy and biomarker engagement, as well as enhancement of generalizability and scalability. Clinicaltrials.gov NCT06597942.

Objectives Individuals with subjective memory complaints and symptoms of depression and/or anxiety are at high risk for further cognitive decline, and possible progression to dementia. Low-burden interventions to help slow or prevent cognitive decline in this high-risk group are needed. The objective of this study is to assess the feasibility of combining Mindfulness-Based Stress Reduction (MBSR) with transcranial direct current stimulation (tDCS) to increase putative benefits of MBSR for cognitive function and everyday mindfulness in depressed or anxious older adults with subjective cognitive decline. Methods We conducted a two-site pilot double-blind randomized sham-controlled trial, combining active MBSR with either active or sham tDCS. The intervention included weekly in-class group sessions at the local university hospital and daily at-home practice. Anodal tDCS was applied for 30 min during MBSR meditative practice, both in-class and at-home. Results Twenty-six individuals with subjective cognitive complaints and symptoms of depression and/or anxiety were randomized to active ( n  = 12) or sham tDCS ( n  = 14). The combination of MBSR and tDCS was safe and well tolerated, though at-home adherence and in-class attendance were variable. While they were not statistically significant, the largest effect sizes for active vs. sham tDCS were for everyday mindfulness ( d  = 0.6) and social functioning ( d  = 0.9) ( F (1,21)  = 3.68, p  = 0.07 and F (1,21)  = 3.9, p  = 0.06, respectively). Conclusions Our findings suggest that it is feasible and safe to combine tDCS with MBSR in older depressed and anxious adults, including during remote, at-home use. Furthermore, tDCS may enhance MBSR via transferring its meditative learning and practice into increases in everyday mindfulness. Future studies need to improve adherence to MBSR with tDCS. Trial Registration ClinicalTrials.gov (NCT03653351 and NCT03680664).

Background The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis. Methods The effect of LXR activation on microglia and central nervous system (CNS) inflammation was studied using a synthetic LXR agonist in cultured microglia, a microglial cell line and experimental allergic encephalomyelitis (EAE), an animal model of CNS inflammation. Results LXR activation inhibited nitric oxide synthase 2, inducible ( Nos2 ) expression and nitric oxide production in lipopolysaccharide (LPS)-stimulated microglia. Inhibition of microglial activation in response to interferon-γ was less reliable. In LPS-stimulated cells, LXR activation did not inhibit nuclear translocation of NF-kappaB1 p50. Instead, LXR-dependent Nos2 repression was associated with inhibition of histone 4 acetylation and inhibition of NF-kappaB1 p50 binding at the Nos2 promoter. Histone acetylation and NF-kappaB1 p50 binding were mechanistically linked, and histone deacetylase (HDAC) activity appeared to be important for LXR-dependent transcriptional repression of Nos2 . Analysis of CNS gene expression in animals undergoing EAE showed that the expressions of Lxr and LXR-dependent genes were downregulated during CNS inflammation. Nevertheless, administration of LXR agonist GW3965 during the effector phase of EAE delayed the onset of clinical disease and reversed the diminished expression of LXR-dependent reverse cholesterol transport genes. However, the CNS expressions of Nos2 and other inflammatory genes were not significantly inhibited by LXR activation in EAE, and clinical disease severity was comparable to vehicle controls at later time points in LXR agonist treated animals. Conclusions LXR can be targeted to modulate microglial activation. LXR-dependent repression of inflammatory genes may be stimulus-dependent and impaired by HDAC inhibition. Endogenous LXR activity does not appear to modulate CNS inflammation, but LXR activity can be partially restored in the CNS by administration of exogenous LXR agonist with an impact on clinical disease severity at early, but not late, time points in EAE.

Background and objectives Women who breastfeed may experience long-term benefits for their health in addition to the more widely appreciated effects on the breastfed child. Breastfeeding may induce long-term effects on biopsychosocial systems implicated in brain health. Also, due to diminished breastfeeding in the postindustrial era, it is important to understand the lifespan implications of breastfeeding for surmising maternal phenotypes in our species’ collective past. Here, we assess how women’s breastfeeding history relates to postmenopausal cognitive performance. Methodology A convenience sample of Southern California women age 50+ was recruited via two clinical trials, completed a comprehensive neuropsychological test battery and answered a questionnaire about reproductive life history. General linear models examined whether cognitive domain scores were associated with breastfeeding in depressed and non-depressed women, controlling for age, education and ethnicity. Results Women who breastfed exhibited superior performance in the domains of Learning, Delayed Recall, Executive Functioning and Processing Speed compared to women who did not breastfeed (P-values 0.0003–0.015). These four domains remained significant in analyses limited to non-depressed and parous subsets of the cohort. Among those depressed, only Executive Functioning and Processing Speed were positively associated with breastfeeding. Conclusions and implications We add to the growing list of lifespan health correlates of breastfeeding for women’s health, such as the lower risk of type-2 diabetes, cardiovascular disease and breast cancer. We surmise that women’s postmenopausal cognitive competence may have been greater in past environments in which breastfeeding was more prevalent, bolstering the possibility that postmenopausal longevity may have been adaptive across human evolutionary history. Lay Summary Breastfeeding may affect women’s cognitive performance. Breastfeeding’s biological effects and psychosocial effects, such as improved stress regulation, could exert long-term benefits for the mother’s brain. We found that women who breastfed performed better on a series of cognitive tests in later life compared to women who did not breastfeed.