Citations

Ketones are well-known biomarkers of fat oxidation produced in the liver as a result of lipolysis. These biomarkers include acetoacetic acid and β-hydroxybutyric acid in the blood/urine and acetone in our breath and skin. Monitoring ketone production in the body is essential for people who use caloric intake deficit to reduce body weight or use ketogenic diets for wellness or therapeutic treatments. Current methods to monitor ketones include urine dipsticks, capillary blood monitors, and breath analyzers. However, these existing methods have certain disadvantages that preclude them from being used more widely. In this work, we introduce a novel acetone sensor device that can detect acetone levels in breath and overcome the drawbacks of existing sensing approaches. The critical element of the device is a robust sensor with the capability to measure acetone using a complementary metal oxide semiconductor (CMOS) chip and convenient data analysis from a red, green, and blue deconvolution imaging approach. The acetone sensor device demonstrated sensitivity of detection in the micromolar-concentration range, selectivity for detection of acetone in breath, and a lifetime stability of at least one month. The sensor device utility was probed with real tests on breath samples using an established blood ketone reference method.

Abstract Objectives VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. Patients present with rheumatologic manifestations and cytopenias and may have an increased predisposition to myelodysplastic syndrome (MDS) and plasma cell neoplasms. Prior studies have reported on the peripheral blood and bone marrow findings in patients with VEXAS syndrome. Due to the protean clinical presentation and lack of specificity of morphologic features (eg, vacuoles in early erythroid and granulocytic precursors), an optimal screening methodology to identify these patients in a timely fashion is desirable. Methods To further evaluate and describe the salient diagnostic morphologic features in VEXAS syndrome, we carried out a comprehensive study of the largest single-institution cohort to date. Diagnostic and follow-up bone marrow biopsy specimens from 52 male patients with molecularly identified VEXAS syndrome underwent central review. Results Cytopenias were common in all cases, primarily macrocytic anemia, monocytopenia, and thrombocytopenia. Bone marrow aspirate and biopsy were often hypercellular, with an increased myeloid/erythroid ratio, granulocytic hyperplasia with left shift, erythroid left shift, and megakaryocyte hyperplasia, which exhibited a range of striking morphologic findings. Distinctly vacuolated myeloid and erythroid precursors were seen in more than 95% of cases. Conclusions Our data reveal potential novel diagnostic features, such as a high incidence of monocytopenia and distinct patterns of atypical megakaryopoiesis, that appear different from dysmegakaryopoiesis typically associated with MDS. In our experience, those findings are suggestive of VEXAS, in the appropriate clinical context.

Abstract Osteoarthritis (OA) is a degenerative joint disease characterized by pain, stiffness, and limited joint motion affecting 7% of the world’s population. PH domain leucine-rich repeat protein phosphates (PHLPPs) have been identified as modifiable targets for cartilage regeneration and joint pain. PHLPP1 and PHLPP2 are abnormally expressed in osteoarthritic cartilage and sensory neurons. PHLPP1-/- mice are protected from cartilage degradation and pain-related behaviors (allodynia and reduced mobility) after surgery that destabilizes the medial meniscus (DMM). Here, we investigate the effects of PHLPP inhibitors (i) on human chondrocytes and the effect of Phlpp1 deletion on cell populations within lumbar dorsal root ganglia (DRGs). Immunohistochemistry was performed on mouse DRGs by cryosectioning fixed L3-5 DRGs and using primary antibodies against Fabp7, Anti tubulin beta 3, and PGP9.5/UCHL1. Human chondrocytes were subjected to Cycloheximide chase experiments and treated with PHLPPi (NSC117079 or NSC45586), followed by Western blot analysis to assess protein levels including Phlpp1, Phlpp2, Sox9, p-AKT (Ser473), total AKT, and B-actin, at various time points. We found that PHLPPi prolongs the phosphorylated AKT response when compared to controls and does not affect degradation of Phlpp1 or Phlpp2; additionally, NSC117079 increased production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from OA patients. These data advance our understanding of how PHLPPi function within chondrocytes and provide a basis toward understanding their activity and safety in vivo. Our results indicate that PHLPPi NSC117079 is a novel osteoarthritis disease-modifying drug candidate that may have palliative effects.

Abstract Research has established that dementia care partners may encounter socio-emotional and physical health concerns as a consequence of providing dementia care. Similarly, care partners for people living with Traumatic Brain Injury (TBI) often experience a range of stressors and negative mental health outcomes due to their care demands. This study aims to support the unique subset of family care partners facing the challenge of caring for relatives who have both diseases, Alzheimer’s Disease/Alzheimer’s Disease related dementia (AD/ADRD) and a history of TBI. Phase I of this study focused on the design and subsequent refinement of the TBI-AD/ADRD Caregiver Support Intervention (TACSI). TACSI is a six-session telehealth intervention providing tailored psychosocial and psychoeducational coaching. Session topics include education on TBI and dementia, stress management, lifestyle planning, and communication skills. In partnership with the Minneapolis VA and the Mayo Clinic-Rochester, we enrolled 15 care partners for Phase I. Mixed methods data from 3-month follow-up surveys and qualitative data from post-intervention interviews established the feasibility, utility, and acceptance of TACSI. Care partners found the program valuable and would recommend it to others. They reported that TACSI helped with their stress management. Some participants shared that TACSI would provide greater benefit to newer caregivers needing more education on the diseases and/or caregiving. Phase I feedback will be applied to improve TACSI content and delivery for the Phase II randomized controlled trial evaluation. TACSI Phase I utility, acceptance, and feasibility outcomes will be highlighted as well as next steps for evaluation.

Abstract Tactile hallucinations can be highly distressing and lead to psychiatric morbidities and functional impairments. There are no established treatments for tactile hallucinations that occur outside of primary psychotic disorders, and available pharmacologic and nonpharmacologic therapies may have limited effectiveness. We present a case of a 75-year-old female with treatment-refractory tactile hallucinations successfully treated with electroconvulsive therapy (ECT). She endorsed 13 months of distressing tactile hallucinations described as slimly substances on her skin. Symptoms started insidiously, became more severe with time and refractory to multiple antipsychotic medications. She became so severely distressed from the tactile hallucinations that she developed a major depressive episode and became suicidal. Relevant medical history included one prior depressive episode, occipital lobe stroke, restless legs syndrome, and obstructive sleep apnea. She was hospitalized in an inpatient psychogeriatric unit and treated with ECT for 12 sessions over 3.5 weeks. Hallucinations responded well to ECT. Patient experienced some mild memory impairment from treatment. Treatment was optimized with duloxetine titration, addition of mirtazapine and repletion of B6 vitamin. Following the acute course of ECT, she reported an 80 % improvement in tactile hallucinations. Depressive symptoms improved, and suicidal thoughts resolved. She was able to discharge from the hospital and continued with maintenance ECT. Our case illustrates the potential therapeutic role of brain stimulation in the treatment of refractory cases of tactile hallucinations. Further studies are needed to determine effective treatment strategies for treatment-refractory tactile hallucinations to prevent progression to severe psychiatric disturbances and improve quality of life.

Abstract Evidence suggests that early postmenopausal hormone treatment (MHT) may attenuate metabolic effects on dementia pathogenesis. Using Kronos Early Estrogen Prevention Study (KEEPS) and KEEPS-Continuation data, we investigated heterogeneity in the associations between longitudinal central adiposity (CA), MHT, and cognition, hypothesizing that CA would be related to cognition and that MHT would favorably alter this relationship. KEEPS participants (previously randomized to 48 months treatment with placebo or HT with oral conjugated equine estrogens + progesterone or transdermal 17-β-estradiol+ progesterone) were recruited for KEEPS-Continuation ~10 years post-randomization. Cognitive tests from both studies were analyzed as four-factor scores. Using the original KEEPS data (n=662), growth mixture modeling identified distinct CA trajectories (classes) across 48 months of MHT, which predicted cognition at 48 months and ~10 years, adjusting for covariates. Adiposity trajectories included “low-CA” and “high-CA” classes. Low-CA women exhibited stable low-CA throughout MHT. High-CA women’s adiposity was initially elevated but declined significantly after 48 months of MHT. After adjusting for covariates, the high (versus low) CA class predicted significantly lower cognitive factors scores at month 48 with one exception – Verbal-Learning & Memory. Ten years later, high-CA women (n=299) scored significantly lower on two factors. MHT predicted neither CA trajectories nor cognitive performance at 48 months or 10 years later. Adiposity levels significantly declined in the high-CA class on MHT but not placebo and was associated with diminished cognitive function. CA influenced short-and long-term cognition. Organ/tissue studies should examine how heterogeneity in adiposity levels interacts with MHT and other factors driving dementia pathogenesis.

Abstract Lucid episodes (LE) occur in people living with dementia who have seemingly lost cognitive capacity. Understanding LEs is a relatively new area of scientific inquiry. Most LE studies have utilized different conceptual and operational definitions. Reaching a definition of LE is critical foundation to facilitate more systematic investigation and new knowledge of LEs. The goal of this study was to convene a group of 13 clinical experts to brainstorm on the key components needed to understand LE among people living with dementia (PLWD). We aimed to reach consensus from the group on (1) potential medical or clinical explanations for LEs; (2) necessary medical and clinical questions to understand LE; (3) interpretation of the presence of LE. Thirteen experts from different disciplines (neurology, psychiatry, psychology, pharmacy, palliative care, hospice, nursing, social work, primary care, geriatrics, and professional home caregivers) participated in a virtual Delphi Method study. Experts provided a range of opinions on potential medical and clinical explanations for LE, necessary questions to understand LE, and did not reach consensus on the presence of LE when presented with clinical vignettes. Panelists highlighted key medical and contextual factors as well as a need to know more information about the general demeanor and typical behavior of the PLWD to make a definitive judgement about whether LE occurred. Clinical consensus on LEs is complex. There is great variability in how behaviors and cognitive fluctuations in PLWD are appraised by clinical experts.

Abstract There are striking differences among caregivers of people with dementia (PWDs) in how their health and well-being changes during active caregiving; however, less is known about these differences after caregiving has ended. One important factor influencing caregiver health is the emotional quality of the caregiver-PWD relationship. The present study evaluated caregivers’ emotional connection to the PWD (during caregiving) and associations with caregivers’ depression both concurrently (N = 326 active caregivers) and longitudinally (n = 91 former caregivers). Active caregivers described a recent time they felt connected to the PWD, and their responses were transcribed verbatim. Caregivers’ emotional connection to the PWD was operationalized by summing the number of positive and negative emotion words from the transcripts using text analysis software and dividing each figure by the total number of words in the response. Results indicated that neither positive nor negative emotional language was significantly correlated with caregivers’ concurrent depression. However, two-wave latent change score modeling revealed that caregivers’ greater positive emotional language (adjusting for caregivers’ baseline depression and negative emotional language) predicted steeper declines in depression (i.e., improvements in depression trajectories) after the death of the PWD (ß = -.11, SE(ß) = 0.04, p = .033). Negative emotional language was not significantly associated with changes in caregivers’ depression. This finding highlights positive emotion expressed by caregivers when describing their connection with the PWD as a potential resilience factor and underscores the important role that positive emotional qualities of the caregiving relationship play in improving caregivers’ mental health after caregiving ends.

Abstract Lucid episodes (LE) in people living with late-stages of dementia (PLWD) have been reported anecdotally, but less is known about how this seemingly unexpected phenomenon is experienced by family members. This study aims to examine variability in family caregivers’ experiences with LE, focusing on the two most common groups of informal caregivers, spouses and children—whether they may exhibit differential appraisals of and responses to LEs. Using a sample of former and current family caregivers from UsAgainstAlzheimer’s A-LIST, we conducted an online survey to spouse and child caregivers (N = 387). Qualitative semi-structured interviews were also conducted with a subset of these caregivers who have witnessed an LE (n = 22). Survey results indicate that child caregivers were more likely to witness a LE. Among “former” caregivers who have witnessed a LE (n = 140), spouses were likely to appraise LEs more negatively and make changes in care decisions (i.e., end-of-life planning and financial decisions) after LE, compared to child caregivers. Among “current” caregivers who have witnessed a LE (n = 80), spouses were more likely to indicate no special circumstances prior to LE, whereas children were more likely to indicate LEs associated with visits from friends and family; there was no difference in positive and negative appraisals of LE between current spouse and child caregivers. Content analysis of qualitative interviews revealed that observed differences between spouses and children were related to their different caregiving contexts, such as relationship history, living arrangement, expectations/motivation, and care resources.

Abstract Falls are a public health concern for older adults, particularly those with cognitive impairments, like mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Executive function (EF) is linked to falls in older adults, but little is known about the relationship between individual EF assessments and falls in individuals with varying cognitive statuses. Using cross-sectional secondary data analyses with binary logistic regression, we examined the associations between EF assessments (Trail Making Test (ΔTMT), Digit Span (DS), Stroop test, Clock Drawing Test, and phonemic/semantic fluency tests) and falls (fall history and subsequent falls) in 466 participants (aged 66-103) with either intact cognition, MCI, or AD dementia. Surprisingly, a significant interaction effect emerged with AD dementia and EF assessments (ΔTMT, DS, and semantic fluency), revealing that individuals with AD dementia with worse EF had a lower probability of prior fall history. These findings were influenced by a low percentage of reported falls in people with severe AD dementia. Further stratified analysis of the interaction effects showed that DS and semantic fluency were significantly associated with fall history in people without AD dementia. While some EF assessments were individually associated with falls, interpretations should be made cautiously, especially considering the appropriateness of the assessments for specific populations. The counterintuitive result may stem from factors specific to severe AD dementia. In conclusion, this study uncovers complex interactions between cognitive status, EF assessments, and fall history, and the potential for further investigation to enhance our understanding of falls in individuals with severe AD dementia.