WashU weekly Neuroscience publications: June 4, 2023

Tau accumulation in autosomal dominant Alzheimer’s disease: a longitudinal [18F]flortaucipir study
(2023) Alzheimer’s Research and Therapy, 15 (1), art. no. 99, . 

O’Connor, A.^a b , Cash, D.M.^a , Poole, T.^a c , Markiewicz, P.J.^d , Fraser, M.R.^a , Malone, I.B.^a , Jiao, J.^d , Weston, P.S.J.^a , Flores, S.^e , Hornbeck, R.^e , McDade, E.^f , Schöll, M.^a g , Gordon, B.A.^e , Bateman, R.J.^f , Benzinger, T.L.S.^e , Fox, N.C.^a b

^a Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
^b UK Dementia Research Institute at UCL, London, United Kingdom
^c Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, United Kingdom
^d Centre for Medical Image Computing, Medical Physics and Biomedical Engineering, UCL, London, United Kingdom
^e Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^g Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden

Abstract
Cortical tau accumulation is a key pathological event that partly defines Alzheimer’s disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p < 0.001). There were no significant regional differences between presymptomatic carriers and non-carriers in FTP SUVRs, or their rates of change (p > 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHK01AG053474
National Institute on AgingNIAUFAG032438
Alzheimer’s AssociationAASG-20-690363-DIAN
Office of Extramural Research, National Institutes of HealthOER
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Memphis Research ConsortiumMRC
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Medical Research CouncilMRC
Alzheimer’s SocietyAS-CTF-18001
University College LondonUCL
Rosetrees Trust
Alzheimer’s Research UKARUKARUK-PG2017-1946
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
UCLH Biomedical Research CentreNIHR BRC
Fleni
UK Dementia Research InstituteUK DRI

Document Type: Article
Publication Stage: Final
Source: Scopus

The spectrum of COVID-19-associated chorioretinal vasculopathy
(2023) American Journal of Ophthalmology Case Reports, 31, art. no. 101857, . 

Carletti, P.^a g , Shah, A.^b , Bair, C.^c , Curran, C.^d , Mai, A.^c , Patel, R.^c , Moorthy, R.^e , Villate, N.^a f , Davis, J.L.^g , Vitale, A.T.^c , Shakoor, A.^c , Hassman, L.^b

^a Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, United States
^b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^c John A. Moran Eye Center, University of Utah Health, Salt Lake City, UT, United States
^d The University of Colorado School of Medicine, AuroraCO, United States
^e Associated Vitreoretinal and Uveitis Consultants, Indianapolis, IN, United States
^f Fort Lauderdale Eye Institute, Fort Lauderdale, FL, United States
^g Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States

Abstract
Purpose: Although conjunctivitis represents the most common ocular manifestation of COVID-19 infection, sight-threatening retinal involvement has been reported. Herein, we report and characterize with multimodal retinal imaging 5 cases of acute vision loss secondary to presumed chorioretinal vasculopathy temporally associated with COVID-19 infection with varying severity, visual morbidity, and treatment response, and review the available literature on the association between COVID-19 infection and retinal microvascular changes. Design: Observational case series and literature review. Methods: Multicenter case series of 5 patients who presented to academic centers and private offices with acute vision loss temporally associated with COVID-19 infection. A review of the literature was conducted using online databases. Results: 10 eyes of 5 patients, 3 men and 2 women, with a mean age of 30.8 years (median 33, range 16–44) were described. All patients had a recently preceding episode of COVID-19, with symptomatology ranging from mild infection to life-threatening encephalopathy. Treatment for their retinal disease included topical, oral, intravitreal, and intravenous steroids, steroid-sparing immunosuppression, retinal photocoagulation, antivirals, and antiplatelet and anticoagulant agents. Treatment response and visual recovery ranged from complete recovery of baseline acuity to permanent vision loss and need for chronic immunosuppression. Conclusions and Importance: Clinicians should be mindful of the potential for vision-threatening retinal involvement after COVID-19 infection. If found, treatment with both anti-inflammatory therapy and anticoagulation should be considered, in addition to close monitoring, as some patients with this spectrum of disease may require chronic immune suppression and/or anti-VEGF therapy. © 2023 The Authors

Author Keywords
Chorioretinal vasculopathy;  COVID-19;  Retinal microvascular changes

Funding details
Research to Prevent BlindnessRPB

Document Type: Article
Publication Stage: Final
Source: Scopus

Mapping cortical activations underlying covert and overt language production using high-density diffuse optical tomography
(2023) NeuroImage, 276, art. no. 120190, . 

Schroeder, M.L.^a b , Sherafati, A.^a c , Ulbrich, R.L.^a d , Wheelock, M.D.^a , Svoboda, A.M.^a e , Klein, E.D.^a f , George, T.G.^a , Tripathy, K.^a g , Culver, J.P.^a h i j , Eggebrecht, A.T.^a h j

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
^b Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, IN, United States
^c Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
^d University of Missouri School of Medicine, Columbia, MO, United States
^e University of Cincinnati Medical Center, Cincinnati, OH, United States
^f Icahn School of Medicine at Mount Sinai, New York, NY, United States
^g Washington University School of Medicine, St Louis, MO, United States
^h Division of Biology & Biomedical Sciences, Washington University School of Medicine, St Louis, MO, United States
ⁱ Department of Physics, Washington University in St. Louis, St Louis, MO, United States
^j Department of Biomedical Engineering, Washington University in St. Louis, St Louis, MO, United States

Abstract
Gold standard neuroimaging modalities such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and more recently electrocorticography (ECoG) have provided profound insights regarding the neural mechanisms underlying the processing of language, but they are limited in applications involving naturalistic language production especially in developing brains, during face-to-face dialogues, or as a brain-computer interface. High-density diffuse optical tomography (HD-DOT) provides high-fidelity mapping of human brain function with comparable spatial resolution to that of fMRI but in a silent and open scanning environment similar to real-life social scenarios. Therefore, HD-DOT has potential to be used in naturalistic settings where other neuroimaging modalities are limited. While HD-DOT has been previously validated against fMRI for mapping the neural correlates underlying language comprehension and covert (i.e., “silent”) language production, HD-DOT has not yet been established for mapping the cortical responses to overt (i.e., “out loud”) language production. In this study, we assessed the brain regions supporting a simple hierarchy of language tasks: silent reading of single words, covert production of verbs, and overt production of verbs in normal hearing right-handed native English speakers (n = 33). First, we found that HD-DOT brain mapping is resilient to movement associated with overt speaking. Second, we observed that HD-DOT is sensitive to key activations and deactivations in brain function underlying the perception and naturalistic production of language. Specifically, statistically significant results were observed that show recruitment of regions in occipital, temporal, motor, and prefrontal cortices across all three tasks after performing stringent cluster-extent based thresholding. Our findings lay the foundation for future HD-DOT studies of imaging naturalistic language comprehension and production during real-life social interactions and for broader applications such as presurgical language assessment and brain-machine interfaces. © 2023 The Author(s)

Author Keywords
Articulation;  Covert;  High-density diffuse optical tomography;  Naturalistic language;  Overt;  Speech

Funding details
National Institutes of HealthNIHK01-MH103594, R01-MH122751, R01NS090874, R01NS109486, R21-MH109775, U01EB02700501

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations between age, sex, APOE genotype, and regional vascular physiology in typically aging adults
(2023) NeuroImage, 275, art. no. 120167, . 

Damestani, N.L.^a b , Jacoby, J.^a , Yadav, S.M.^a , Lovely, A.E.^a , Michael, A.^a , Terpstra, M.^c , Eshghi, M.^d , Rashid, B.^a e , Cruchaga, C.^f g h , Salat, D.H.^a b i , Juttukonda, M.R.^a b

^a Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, United States
^b Department of Radiology, Harvard Medical School, Boston, MA, United States
^c Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
^d MGH Institute of Health Professions, Boston, MA, United States
^e Department of Neurology, Harvard Medical School, Boston, MA, United States
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^g NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^h Hope Center for Neurologic Diseases, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, United States

Abstract
Altered blood flow in the human brain is characteristic of typical aging. However, numerous factors contribute to inter-individual variation in patterns of blood flow throughout the lifespan. To better understand the mechanisms behind such variation, we studied how sex and APOE genotype, a primary genetic risk factor for Alzheimer’s disease (AD), influence associations between age and brain perfusion measures. We conducted a cross-sectional study of 562 participants from the Human Connectome Project – Aging (36 to >90 years of age). We found widespread associations between age and vascular parameters, where increasing age was associated with regional decreases in cerebral blood flow (CBF) and increases in arterial transit time (ATT). When grouped by sex and APOE genotype, interactions between group and age demonstrated that females had relatively greater CBF and lower ATT compared to males. Females carrying the APOE ε4 allele showed the strongest association between CBF decline and ATT incline with age. This demonstrates that sex and genetic risk for AD modulate age-associated patterns of cerebral perfusion measures. © 2023

Author Keywords
Aging;  APOE;  Arterial spin labeling;  Arterial transit time;  Cerebral blood flow;  Healthy aging;  Perfusion MRI;  Sex differences

Funding details
National Institutes of HealthNIH
National Institute on AgingNIA1K01AG070318, R21AG072068, U01AG052564-S1
American Heart AssociationAHA19CDA34790002
Massachusetts Life Sciences CenterMLSC

Document Type: Article
Publication Stage: Final
Source: Scopus

Comprehensive genetic and phenotype analysis of 95 individuals with mosaic tuberous sclerosis complex
(2023) American Journal of Human Genetics, 110 (6), pp. 979-988. 

Klonowska, K.^a , Giannikou, K.^a b , Grevelink, J.M.^c , Boeszoermenyi, B.^a , Thorner, A.R.^d , Herbert, Z.T.^e , Afrin, A.^f g , Treichel, A.M.^f g h , Hamieh, L.^a i , Kotulska, K.^j , Jozwiak, S.^j k , Moss, J.^g , Darling, T.N.^f , Kwiatkowski, D.J.^a

^a Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^b Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, United States
^c Boston Dermatology and Laser Center, Massachusetts General Hospital, Boston, MA 02114, United States
^d Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, United States
^e Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, United States
^f Department of Dermatology, Uniformed Services University, Bethesda, MA 20814, United States
^g Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, United States
^h Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University Cleveland, Cleveland, OH 44106, United States
ⁱ Division of Hospital Medicine, Barnes Jewish Hospital, Washington University in St Louis, St. Louis, MO 63110, United States
^j Department of Neurology and Epileptology, Children’s Memorial Health Institute, Warsaw, 04-736, Poland
^k Research Department, Children’s Memorial Health Institute, Warsaw, 04-736, Poland

Abstract
Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%–15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified. © 2023 American Society of Human Genetics

Author Keywords
low-level mosaicism;  massively parallel sequencing;  TSC angiofibroma;  TSC angiomyolipoma;  TSC1;  TSC2;  tuberous sclerosis complex;  variant detection

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH-17-380 1-0205
National Heart, Lung, and Blood InstituteNHLBIU01HL131022-04
Doris Duke Charitable FoundationDDCF
Genentech2018042
American Association for Dental, Oral, and Craniofacial ResearchAADOCR
Translational Science Center, Wake Forest UniversityTSC
TSC Alliance
Alexander S. Onassis Public Benefit Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations Between Loneliness and Cognitive Resilience to Neuropathology in Older Adults
(2023) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 78 (6), pp. 939-947. 

Jackson, K.L.^a , Luo, J.^a , Willroth, E.C.^b , Ong, A.D.^c , James, B.D.^d e , Bennett, D.A.^d f , Wilson, R.^d f g , Mroczek, D.K.^a h , Graham, E.K.^a

^a Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
^b Department of Psychological and Brain Sciences, Washington University in St. LouisMO, United States
^c Department of Psychology, Cornell University, Ithaca, NY, United States
^d Rush Alzheimer’s Disease Center, RUSH University Medical Center, Chicago, IL, United States
^e Department of Internal Medicine, RUSH Medical Center, Chicago, IL, United States
^f Department of Neurological Sciences, RUSH Medical Center, Chicago, IL, United States
^g Department of Psychiatry and Behavioral Sciences, RUSH Medical Center, Chicago, IL, United States
^h Department of Psychology, Northwestern University, Chicago, IL, United States

Abstract
OBJECTIVES: Loneliness in the aging population is associated with decreased cognitive function and increased neuropathology; less is understood about the association of loneliness and cognitive resilience (CR), defined as the discordance between a person’s actual and expected cognition given their neuropathology. Here we assess the effect of loneliness and change in loneliness on CR at end of life and across older adulthood. METHODS: Data were combined from 2 longitudinal studies of older adults. CR proximate to death (CRlast_level) and across time (CRslope) was obtained by independently regressing global cognition and change in cognition onto multiple neuropathology indicators and extracting the resulting residuals. We used a series of simple linear regression models to assess the effect of loneliness level and change on CRlast_level and CRslope. RESULTS: Higher baseline loneliness was associated with lower CRlast_level (β = -0.11, 95% confidence interval [95% CI; -0.18, -0.04], p < .01); higher baseline loneliness and increasing loneliness over time was associated with lower CRslope (β = -0.13, 95% CI [-0.22, -0.05], p < .01 and β = -0.12, 95% CI [-0.20, -0.04], p < .01, respectively). Results were robust to covariate inclusion and independent of objective social isolation. DISCUSSION: Higher and increasing loneliness was associated with lower CR in the face of neuropathology. These results suggest that some individuals are less resilient to the accumulation of neuropathology than others, and experiencing high/increasing loneliness is a key factor putting some at risk. Interventions aimed at optimizing cognitive function across older adults should include loneliness reduction as a potential area of focus. © The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Cognition;  Cognitive decline;  Psychology;  Social isolation

Document Type: Article
Publication Stage: Final
Source: Scopus

Age and Cognitive Ability Predict Emotion Regulation Strategy Use
(2023) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 78 (6), pp. 987-997. 

Growney, C.M., English, T.

Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
OBJECTIVES: This study examines how age and cognitive ability predict use of different emotion regulation strategies in a laboratory task eliciting emotions varying in valence and arousal. METHODS: Participants (N = 287) aged 25-85 completed the NIH Toolbox Cognitive Battery and an emotion regulation task in a laboratory setting. They watched a series of emotional clips (disgust, sadness, amusement, and contentment) under instructions to increase positive emotions or decrease negative emotions. After each clip, they rated the extent to which they used emotion regulation strategies that involve different types of engagement with emotional stimuli and disengagement from emotional stimuli. RESULTS: Older age was predictive of greater use of immersive-engagement strategies (e.g., perspective taking) and less use of disengagement strategies (e.g., distraction). Fluid cognitive ability was positively associated with immersive-engagement strategy use, particularly for high-arousal clips. For older adults, fluid cognitive ability was also associated with using positive-engagement strategies (e.g., positive reappraisal) to a greater extent to regulate negative emotions. DISCUSSION: Patterns of emotion regulation strategy use varied by age, even when accounting for differences in reactivity. Findings suggest that older adults may not necessarily prefer strategies that are lower in cognitive demands or that focus on enhancing positivity. Results support the idea that strategy preferences are driven by a combination of characteristics of the regulator and the regulation context. The relevance of cognitive resources likely varies across situations, perhaps being most consequential for deeper processing of high-arousal stimuli and for older adults’ engagement with positive aspects of an otherwise negative situation. © The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Context;  Engagement;  Motivation;  Positivity effect;  Well-being

Funding details
National Science FoundationNSF1357918
Electric Power Research InstituteEPRI10002061

Document Type: Article
Publication Stage: Final
Source: Scopus

Examining Mental Health, Education, Employment, and Pain in Sickle Cell Disease
(2023) JAMA Network Open, 6 (5), art. no. 14070, . 

Harris, K.M.^a b , Preiss, L.^c , Varughese, T.^a , Bauer, A.^d , Calhoun, C.L.^e , Treadwell, M.^f , Masese, R.^g , Hankins, J.S.^h , Hussain, F.A.ⁱ , Glassberg, J.^j , Melvin, C.L.^k , Gibson, R.^l , King, A.A.^a b m

^a Program in Occupational Therapy, Washington University in St Louis School of Medicine, St Louis, MO, United States
^b Department of Surgery, Division of Public Health Sciences, Washington University in St Louis School of Medicine, St Louis, MO, United States
^c RTI International, Research Triangle Park, NC, United States
^d School of Medicine, University of Missouri at Columbia, Columbia, United States
^e Department of Pediatrics, Pediatric Hematology/Oncology, Cancer Center, Hematology Program, Yale University School of Medicine, New Haven, CT, United States
^f School of Medicine, Department of Pediatrics, Division of Hematology, University of California, San Francisco, United States
^g School of Nursing, Duke University, Durham, NC, United States
^h Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN, United States
ⁱ Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Illinois at Chicago, Chicago, United States
^j Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^k College of Medicine, Department of Public Health Sciences, Medical University of South Carolina, Charleston, United States
^l Department of Emergency Medicine, Augusta University, Medical College of Georgia, Augusta, United States
^m Department of Pediatrics, Division of Pediatric Hematology/Oncology, St Louis Children’s Hospital, Washington University in St Louis, School of Medicine, St Louis, MO, United States

Abstract
Importance: Pain related to sickle cell disease (SCD) is complex and associated with social determinants of health. Emotional and stress-related effects of SCD impact daily quality of life and the frequency and severity of pain. Objective: To explore the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with SCD. Design, Setting, and Participants: This is a cross-sectional analysis of patient registry data collected at baseline (2017-2018) from patients treated at 8 sites of the US Sickle Cell Disease Implementation Consortium. Data analysis was performed from September 2020 to March 2022. Main Outcomes and Measures: Electronic medical record abstraction and a participant survey provided demographic data, mental health diagnosis, and Adult Sickle Cell Quality of Life Measurement Information System pain scores. Multivariable regression was used to examine the associations of education, employment, and mental health with the main outcomes (pain frequency and pain severity). Results: The study enrolled a total of 2264 participants aged 15 to 45 years (mean [SD] age, 27.9 [7.9] years; 1272 female participants [56.2%]) with SCD. Nearly one-half of the participant sample reported taking daily pain medication (1057 participants [47.0%]) and/or hydroxyurea use (1091 participants [49.2%]), 627 participants (28.0%) received regular blood transfusion, 457 (20.0%) had a depression diagnosis confirmed by medical record abstraction, 1789 (79.8%) reported severe pain (rated most recent pain crises as ≥7 out of 10), and 1078 (47.8%) reported more than 4 pain episodes in the prior 12 months. The mean (SD) pain frequency and severity t scores for the sample were 48.6 (11.4) and 50.3 (10.1), respectively. Educational attainment and income were not associated with increased pain frequency or severity. Unemployment (β, 2.13; 95% CI, 0.99 to 3.23; P <.001) and female sex (β, 1.78; 95% CI, 0.80 to 2.76; P <.001) were associated with increased pain frequency. Age younger than 18 years was inversely associated with pain frequency (β, -5.72; 95% CI, -7.72 to -3.72; P <.001) and pain severity (β, 5.10; 95% CI, -6.70 to -3.51; P <.001). Depression was associated with increased pain frequency (β, 2.18; 95% CI, 1.04 to 3.31; P <.001) but not pain severity. Hydroxyurea use was associated with increased pain severity (β, 1.36; 95% CI, 0.47 to 2.24; P =.003), and daily use of pain medication was associated with both increased pain frequency (β, 6.29; 95% CI, 5.28 to 7.31; P <.001) and pain severity (β, 2.87; 95% CI, 1.95 to 3.80; P <.001). Conclusions and Relevance: These findings suggest that employment status, sex, age, and depression are associated with pain frequency among patients with SCD. Depression screening for these patients is warranted, especially among those experiencing higher pain frequency and severity. Comprehensive treatment and pain reduction must consider the full experiences of patients with SCD, including impacts on mental health. © 2023 American Medical Association. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Progenitor-derived glia are required for spinal cord regeneration in zebrafish
(2023) Development (Cambridge, England), 150 (10), . 

Zhou, L.^a b , McAdow, A.R.^a b , Yamada, H.^a b , Burris, B.^a b , Klatt Shaw, D.^a b , Oonk, K.^c , Poss, K.D.^c , Mokalled, M.H.^a b

^a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Duke Regeneration Center, Department of Cell Biology, Duke University Medical Center, Durham, United States

Abstract
Unlike mammals, adult zebrafish undergo spontaneous recovery after major spinal cord injury. Whereas reactive gliosis presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish elicit pro-regenerative bridging functions after injury. Here, we perform genetic lineage tracing, assessment of regulatory sequences and inducible cell ablation to define mechanisms that direct the molecular and cellular responses of glial cells after spinal cord injury in adult zebrafish. Using a newly generated CreERT2 transgenic line, we show that the cells directing expression of the bridging glial marker ctgfa give rise to regenerating glia after injury, with negligible contribution to either neuronal or oligodendrocyte lineages. A 1 kb sequence upstream of the ctgfa gene was sufficient to direct expression in early bridging glia after injury. Finally, ablation of ctgfa-expressing cells using a transgenic nitroreductase strategy impaired glial bridging and recovery of swim behavior after injury. This study identifies key regulatory features, cellular progeny, and requirements of glial cells during innate spinal cord regeneration. © 2023. Published by The Company of Biologists Ltd.

Author Keywords
Glia;  Neural repair;  Regeneration;  Spinal cord injury;  Zebrafish

Document Type: Article
Publication Stage: Final
Source: Scopus

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease-related pathology
(2023) JCI Insight, 8 (10), . 

Grizzanti, J.^a b , Moritz, W.R.^c , Pait, M.C.^a b , Stanley, M.^c d , Kaye, S.D.^a b , Carroll, C.M.^a b , Constantino, N.J.^a b , Deitelzweig, L.J.^a b , Snipes, J.A.^a b , Kellar, D.^b , Caesar, E.E.^c , Pettit-Mee, R.J.^a , Day, S.M.^a , Sens, J.P.^a , Nicol, N.I.^a b , Dhillon, J.^a b , Remedi, M.S.^a e , Kiraly, D.D.^a , Karch, C.M.^f g h , Nichols, C.G.ⁱ , Holtzman, D.M.^c g h , Macauley, S.L.^{a b j k l m}

^a Department of Physiology and Pharmacology and
^b Department of Internal Medicine, Wake Forest School of Medicine, Winston-SalemNC, United States
^c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Department of Biology, College of Arts and Sciences, University of Vermont, Burlington, VT, United States
^e Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research
^f Department of Psychiatry
^g Hope Center for Neurological Disorders
^h Knight Alzheimer’s Disease Research Center, Department of Neurology; and
ⁱ Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^j Alzheimer’s Disease Research Center
^k Center on Diabetes, Obesity and Metabolism
^l Center for Precision Medicine; and
^m Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-SalemNC, United States

Abstract
Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer’s disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes.

Author Keywords
Aging;  Alzheimer disease;  Glucose metabolism;  Ion channels;  Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound
(2023) Nature Metabolism, 5 (5), pp. 789-803. Cited 1 time.

Yang, Y.^a , Yuan, J.^a , Field, R.L.^b , Ye, D.^a , Hu, Z.^a , Xu, K.^a , Xu, L.^a , Gong, Y.^a , Yue, Y.^a , Kravitz, A.V.^c , Bruchas, M.R.^d , Cui, J.^a , Brestoff, J.R.^b , Chen, H.^a e f g

^a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^d Departments of Anesthesiology and Pain Medicine, Pharmacology, and Bioengineering, Center for Neurobiology of Addiction, Pain, and Emotion, University of Washington, Seattle, WA, United States
^e Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, United States
^f Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^g Division of Neurotechnology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (>24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHDP5 OD028125, R01EB027223, R01EB030102, R01MH116981, UG3MH126861
Burroughs Wellcome FundBWF1019648
University of WashingtonUW

Document Type: Article
Publication Stage: Final
Source: Scopus

Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features
(2023) Behavioral Sciences, 13 (5), art. no. 427, . 

Kamarajan, C.^a , Pandey, A.K.^a , Chorlian, D.B.^a , Meyers, J.L.^a , Kinreich, S.^a , Pandey, G.^a , Subbie-Saenz de Viteri, S.^a , Zhang, J.^a , Kuang, W.^a , Barr, P.B.^a , Aliev, F.^b , Anokhin, A.P.^c , Plawecki, M.H.^d , Kuperman, S.^e , Almasy, L.^f , Merikangas, A.^f , Brislin, S.J.^b , Bauer, L.^g , Hesselbrock, V.^g , Chan, G.^e g , Kramer, J.^e , Lai, D.^d , Hartz, S.^c , Bierut, L.J.^c , McCutcheon, V.V.^c , Bucholz, K.K.^c , Dick, D.M.^b , Schuckit, M.A.^h , Edenberg, H.J.^d , Porjesz, B.^a

^a Henri Begleiter Neurodynamics Lab, Department of Psychiatry and Behavioral Science, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, United States
^b Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, United States
^c Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO 63110, United States
^d Indiana University School of Medicine, Indianapolis, IN 46202, United States
^e Department of Psychiatry, University of Iowa, Iowa City, IA 52242, United States
^f The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, United States
^g Department of Psychiatry, University of Connecticut, Farmington, CT 06030, United States
^h Department of Psychiatry, University of California, San Diego, CA 92103, United States

Abstract
Memory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50–81 years) with alcohol-induced memory problems (the memory group) were compared with a matched control group who did not have memory problems. The random forests model identified specific features from each domain that contributed to the classification of the memory group vs. the control group (AUC = 88.29%). Specifically, individuals from the memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except for some connections involving the anterior cingulate cortex, which were predominantly hypoconnected. Other significant contributing features were: (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past five years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past twelve months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive “uplift” life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity data collected ~18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict the alcohol-related memory problems that arise in later life. © 2023 by the authors.

Author Keywords
alcohol use disorder (AUD);  alcohol-related memory problems;  default mode network;  EEG source functional connectivity;  random forests

Funding details
National Institutes of HealthNIH
National Institute on Drug AbuseNIDAU10AA008401
National Institute on Alcohol Abuse and AlcoholismNIAAA

Document Type: Article
Publication Stage: Final
Source: Scopus

Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries
(2023) PLoS ONE, 18 (5 May), art. no. e0285011, . 

Song, Y.^a , Racette, B.A.^a b c , Camacho-Soto, A.^a d , Nielsen, S.S.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
^c Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa
^d Department of Orthopedics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. Methods We conducted a population-based, case-control study of U.S. Medicare beneficiaries in 2009 (42,885 incident neurodegenerative disease cases, 334,387 randomly selected controls). Using medication data from 2006-2007, we categorized all filled medications according to their biological targets and mechanisms of action on those targets. We used multinomial logistic regression models, while accounting for demographics, indicators of smoking, and health care utilization, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 141 target-action pairs and each neurodegenerative disease. For targetaction pairs inversely associated with all three diseases, we attempted replication in a cohort study that included an active comparator group. We constructed the cohort by following controls forward for incident neurodegenerative disease from the beginning of 2010 until death or end of 2014, i.e., up to five years after the two-year exposure lag. We used Cox proportional hazards regression while accounting for the same covariates. Results The most consistent inverse association across both studies and all three neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, represented by the gout medication, allopurinol. Allopurinol was associated with a 13-34% lower risk for each neurodegenerative disease group in multinomial regression, and a mean reduction of 23% overall, as compared to individuals who did not use allopurinol. In the replication cohort we observed a significant 23% reduction for neurodegenerative disease in the fifth year of follow-up, when comparing allopurinol users to non-users, and more marked associations with an active comparator group. We observed parallel associations for a related target-action pair unique to carvedilol. Discussion/Conclusion Xanthine dehydrogenase/oxidase blockade might reduce risk of neurodegenerative disease. However, further research will be necessary to confirm that the associations related to this pathway are causal or to examine whether this mechanism slows progression. © 2023 Song et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease
(2023) Brain, 146 (4), pp. 1592-1601. Cited 17 times.

Janelidze, S.^a , Bali, D.^a , Ashton, N.J.^b c d e , Barthelemy, N.R.^f g , Vanbrabant, J.^h , Stoops, E.^h , Vanmechelen, E.^h , He, Y.^f g , Dolado, A.O.^a , Triana-Baltzer, G.ⁱ , Pontecorvo, M.J.^j k , Zetterberg, H.^{b l m n o} , Kolb, H.ⁱ , Vandijck, M.^p , Blennow, K.^b l , Bateman, R.J.^f g , Hansson, O.^a q

^a Clinical Memory Research Unit, Lund University, Lund, Sweden
^b Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
^c Institute of Psychiatry Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, United Kingdom
^d NIHR Biomedical Research Centre for Mental Health, Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, United Kingdom
^e Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
^f Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^g Tracy Family SILQ Center, St Louis, MO, United States
^h ADx NeuroSciences, Gent, Belgium
ⁱ Neuroscience Biomarkers, Janssen Research & Development, La JollaCA, United States
^j Avid Radiopharmaceuticals, Philadelphia, PA, United States
^k Eli Lilly and Company, Indianapolis, IN, United States
^l Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^m Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
ⁿ UK Dementia Research Institute at UCL, London, United Kingdom
^o Hong Kong Center for Neurodegenerative Diseases, Hong Kong, Hong Kong
^p Fujirebio Europe N.V., Gent, Belgium
^q Memory Clinic, Skåne University Hospital, Malmö, Sweden

Abstract
Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer’s disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer’s dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e. abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer’s dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer’s dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835-0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642-0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320-0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer’s dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer’s dementia in the future. © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Alzheimer’s disease;  amyloid-β;  blood p-tau;  dementia

Document Type: Article
Publication Stage: Final
Source: Scopus

The Association Between Maternal Cortisol and Infant Amygdala Volume Is Moderated by Socioeconomic Status
(2023) Biological Psychiatry Global Open Science, . 

Herzberg, M.P.^a , Triplett, R.^b , McCarthy, R.^c , Kaplan, S.^b , Alexopoulos, D.^b , Meyer, D.^b , Arora, J.^d , Miller, J.P.^d , Smyser, T.A.^a , Herzog, E.D.^e , England, S.K.^c , Zhao, P.^c , Barch, D.M.^a f g , Rogers, C.E.^a h , Warner, B.B.^h , Smyser, C.D.^b g h , Luby, J.^a

^a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: It has been well established that socioeconomic status is associated with mental and physical health as well as brain development, with emerging data suggesting that these relationships begin in utero. However, less is known about how prenatal socioeconomic environments interact with the gestational environment to affect neonatal brain volume. Methods: Maternal cortisol output measured at each trimester of pregnancy and neonatal brain structure were assessed in 241 mother-infant dyads. We examined associations between the trajectory of maternal cortisol output across pregnancy and volumes of cortisol receptor–rich regions of the brain, including the amygdala, hippocampus, medial prefrontal cortex, and caudate. Given the known effects of poverty on infant brain structure, socioeconomic disadvantage was included as a moderating variable. Results: Neonatal amygdala volume was predicted by an interaction between maternal cortisol output across pregnancy and socioeconomic disadvantage (standardized β = −0.31, p <.001), controlling for postmenstrual age at scan, infant sex, and total gray matter volume. Notably, amygdala volumes were positively associated with maternal cortisol for infants with maternal disadvantage scores 1 standard deviation below the mean (i.e., less disadvantage) (simple slope = 123.36, p <.01), while the association was negative in infants with maternal disadvantage 1 standard deviation above the mean (i.e., more disadvantage) (simple slope = −82.70, p =.02). Individuals with disadvantage scores at the mean showed no association, and there were no significant interactions in the other brain regions examined. Conclusions: These data suggest that fetal development of the amygdala is differentially affected by maternal cortisol production at varying levels of socioeconomic advantage. © 2023 The Authors

Author Keywords
Amygdala;  Cortisol;  Development;  Infancy;  Neonatal MRI;  Socioeconomic status

Funding details
National Institutes of HealthNIHR01 MH113883, T32 MH100019
Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine in St. LouisIDDRCP50 HD103525

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Dissociation of Cognitive Effort–Based Decision Making and Its Associations With Symptoms, Cognition, and Everyday Life Function Across Schizophrenia, Bipolar Disorder, and Depression
(2023) Biological Psychiatry, . 

Barch, D.M.^a b c , Culbreth, A.J.^d , Ben Zeev, D.^e , Campbell, A.^f , Nepal, S.^f , Moran, E.K.^a

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore, MD, United States
^e Department of Psychiatry, University of Washington, Seattle, WA, United States
^f Department of Computer Science, Dartmouth College, Hanover, NH, United States

Abstract
Background: Anhedonia and amotivation are symptoms of many different mental health disorders that are frequently associated with functional disability, but it is not clear whether the same processes contribute to motivational impairments across disorders. This study focused on one possible factor, the willingness to exert cognitive effort, referred to as cognitive effort–cost decision making. Methods: We examined performance on the deck choice task as a measure of cognitive effort–cost decision making, in which people choose to complete an easy task for a small monetary reward or a harder task for larger rewards, in 5 groups: healthy control (n = 80), schizophrenia/schizoaffective disorder (n = 50), bipolar disorder with psychosis (n = 58), current major depression (n = 60), and past major depression (n = 51). We examined cognitive effort–cost decision making in relation to clinician and self-reported motivation symptoms, working memory and cognitive control performance, and life function measured by ecological momentary assessment and passive sensing. Results: We found a significant diagnostic group × reward interaction (F8,588 = 4.37, p &lt;.001, ηp2 = 0.056). Compared with the healthy control group, the schizophrenia/schizoaffective and bipolar disorder groups, but not the current or past major depressive disorder groups, showed a reduced willingness to exert effort at the higher reward values. In the schizophrenia/schizoaffective and bipolar disorder groups, but not the major depressive disorder groups, reduced willingness to exert cognitive effort for higher rewards was associated with greater clinician-rated motivation impairments, worse working memory and cognitive control performance, and less engagement in goal-directed activities measured by ecological momentary assessment. Conclusions: These findings suggest that the mechanisms contributing to motivational impairments differ among individuals with psychosis spectrum disorders versus depression. © 2023 Society of Biological Psychiatry

Author Keywords
Anhedonia;  Depression;  Ecological momentary assessment;  Effort;  Function;  Motivation;  Psychosis

Funding details
National Institute of Mental HealthNIMHK23126986, R01MH066031
National Institute on Drug AbuseNIDA
Boehringer IngelheimBI

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Examining Increasing Racial Inequities in Opioid Overdose Deaths: a Spatiotemporal Analysis of Black and White Decedents in St. Louis, Missouri, 2011–2021
(2023) Journal of Urban Health, . 

Banks, D.E.^a , Scroggins, S.^b c , Paschke, M.E.^a , Shacham, E.^b c , Nance, M.^a , Cavazos-Rehg, P.^d , Winograd, R.P.^a e

^a Department of Psychological Sciences, University of Missouri—St. Louis, One University Blvd., 325 Stadler Hall, St. Louis, MO, United States
^b College for Public Health & Social Justice, Saint Louis University, St. Louis, United States
^c Taylor Geospatial Institute, St. Louis, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, United States
^e Missouri Institute of Mental Health, University of Missouri—St. Louis, St. Louis, United States

Abstract
The third wave of the opioid overdose crisis—defined by the proliferation of illicit fentanyl and its analogs—has not only led to record numbers of overdose deaths but also to unprecedented racial inequities in overdose deaths impacting Black Americans. Despite this racialized shift in opioid availability, little research has examined how the spatial epidemiology of opioid overdose death has also shifted. The current study examines the differential geography of OOD by race and time (i.e., pre-fentanyl versus fentanyl era) in St. Louis, Missouri. Data included decedent records from the local medical examiners suspected to involve opioid overdose (N = 4420). Analyses included calculating spatial descriptive analyses and conducting hotspot analyses (i.e., Gettis-Ord Gi*) stratified by race (Black versus White) and time (2011–2015 versus 2016–2021). Results indicated that fentanyl era overdose deaths were more densely clustered than pre-fentanyl era deaths, particularly those among Black decedents. Although hotspots of overdose death were racially distinct pre-fentanyl, they substantially overlapped in the fentanyl era, with both Black and White deaths clustering in predominantly Black neighborhoods. Racial differences were observed in substances involved in cause of death and other overdose characteristics. The third wave of the opioid crisis appears to involve a geographic shift from areas where White individuals live to those where Black individuals live. Findings demonstrate racial differences in the epidemiology of overdose deaths that point to built environment determinants for future examination. Policy interventions targeting high-deprivation communities are needed to reduce the burden of opioid overdose on Black communities. © 2023, The New York Academy of Medicine.

Author Keywords
Fentanyl;  Geographic information systems;  Opioids;  Overdose;  Racial disparities

Funding details
National Center for Advancing Translational SciencesNCATSKL2 TR002346

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Persistence of auditory modulation of wind-induced escape behavior in crickets
(2023) Frontiers in Physiology, 14, art. no. 1153913, . 

Lu, A.^a , Fukutomi, M.^b , Shidara, H.^c d , Ogawa, H.^c

^a Graduate School of Life Science, Hokkaido University, Sapporo, Japan
^b Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Biological Sciences, Faculty of Science, Hokkaido University, Sapporo, Japan
^d Department of Biochemistry, Graduate School of Medicine, Mie University, Tsu, Japan

Abstract
Animals, including insects, change their innate escape behavior triggered by a specific threat stimulus depending on the environmental context to survive adaptively the predators’ attack. This indicates that additional inputs from sensory organs of different modalities indicating surrounding conditions could affect the neuronal circuit responsible for the escape behavior. Field crickets, Gryllus bimaculatus, exhibit an oriented running or jumping escape in response to short air puff detected by the abdominal mechanosensory organ called cerci. Crickets also receive a high-frequency acoustic stimulus by their tympanal organs on their frontal legs, which suggests approaching bats as a predator. We have reported that the crickets modulate their wind-elicited escape running in the moving direction when they are exposed to an acoustic stimulus preceded by the air puff. However, it remains unclear how long the effects of auditory inputs indicating surrounding contexts last after the sound is terminated. In this study, we applied a short pulse (200 ms) of 15-kHz pure tone to the crickets in various intervals before the air-puff stimulus. The sound given 200 or 1000 ms before the air puff biased the wind-elicited escape running backward, like the previous studies using the longer and overlapped sound. But the sounds that started 2000 ms before and simultaneously with the air puff had little effect. In addition, the jumping probability was higher only when the delay of air puff to the sound was 1000 ms. These results suggest that the cricket could retain the auditory memory for at least one second and alter the motion choice and direction of the wind-elicited escape behavior. Copyright © 2023 Lu, Fukutomi, Shidara and Ogawa.

Author Keywords
behavioral choice;  contextual memory;  cricket (Gryllus bimaculatus);  crossmodal interactions;  escape behavior;  multisensory integration

Funding details
Japan Society for the Promotion of ScienceKAKEN
Ministry of Education, Culture, Sports, Science and TechnologyMEXT16H06544, 21H05295, 21K06259

Document Type: Article
Publication Stage: Final
Source: Scopus

Social familiarity and reinforcement value: a behavioral-economic analysis of demand for social interaction with cagemate and non-cagemate female rats
(2023) Frontiers in Psychology, 14, art. no. 1158365, . 

Schulingkamp, R.^a , Wan, H.^a b , Hackenberg, T.D.^a

^a Department of Psychology, Reed College, Portland, OR, United States
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Rats were studied in social reinforcement procedures in which lever presses opened a door separating two adjacent spaces, permitting access to social interaction with a partner rat. The number of lever presses required for social interaction was systematically increased across blocks of sessions according to fixed-ratio schedules, generating demand functions at three different social reinforcement durations: 10 s, 30 s, and 60 s. The social partner rats were cagemates in one phase, and non-cagemates in a second phase. The rate at which social interactions were produced declined with the fixed-ratio price, and was well described by an exponential model that has been successfully employed with a range of social and non-social reinforcers. None of the main parameters of the model varied systematically with social interaction duration or with the social familiarity of the partner rat. On the whole, the results provide further evidence of the reinforcing value of social interaction, and its functional parallels with non-social reinforcers. Copyright © 2023 Schulingkamp, Wan and Hackenberg.

Author Keywords
demand analysis;  operant methods;  rats;  social familiarity;  social reinforcement

Funding details
Reed College

Document Type: Article
Publication Stage: Final
Source: Scopus

Neonatal Intensive Care Unit Latent Profiles of Maternal Distress: Associations With 5-Year Maternal and Child Mental Health Outcomes
(2023) Journal of the American Academy of Child and Adolescent Psychiatry, . 

Njoroge, W.F.M.^a b c d , Gerstein, E.D.^e , Lean, R.E.^f , Paul, R.^f , Smyser, C.D.^f , Rogers, C.E.^f

^a Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States
^b Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
^c Policy Lab, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
^d Lifespan Brain Institute, Children’s Hospital of Philadelphia and Penn Medicine, Philadelphia, Pennsylvania, United States
^e University of Missouri–St. Louis, St. Louis County, Missouri, United States
^f Washington University School of Medicine, St. Louis, Missouri, United States

Abstract
Objective: To examine profiles of distress of mothers of preterm infants in the neonatal intensive care unit (NICU) and relate profiles to maternal and child outcomes at child age 5 years. Method: A racially and economically diverse sample of mothers (n = 94; 39% African American, 52% White) of preterm infants (≤30 weeks of gestation) completed validated questionnaires assessing depression, anxiety (state and trait), NICU stress, and life stress at NICU discharge of their infant. Mothers reported on their own and their children’s symptomatology at child age 5. A latent profile analysis was conducted to categorize maternal symptomatology. Results: Latent profile analysis yielded 4 distinct maternal profiles: low symptomatology, high NICU stress, high depression and anxiety, and high state anxiety. Social determinants of health factors including age, education, neighborhood deprivation, and infant clinical risk distinguished the profiles. Mothers in the high depression and anxiety profile reported more anxiety and life stress at follow-up and reported their children experienced more anxious/depressed symptoms. Conclusion: Existing literature has gaps related to examining multiple dimensions of NICU distress and understanding how patterns of mood/affective symptoms, life stressors, and related social determinants of health factors vary across mothers. In this study, one specific profile of maternal NICU distress demonstrated enduring risks for poorer maternal and child mental health outcomes. This new knowledge underscores sources of disparate health outcomes for mothers of preterm infants and the infants themselves. Universal screening is needed to identify at-risk dyads for poor health outcomes in need of individualized interventions that address both maternal and child well-being. Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. © 2023 American Academy of Child and Adolescent Psychiatry

Author Keywords
anxiety;  depression;  NICU;  postpartum;  stress

Funding details
National Institutes of HealthNIHK01MH122735, K02 NS089852, K23 MH105179, KL2 TR000450, P50 HD103525, R01 HD057098, R01 MH113570, UL1 TR000448
Dana FoundationDF
Cerebral Palsy International Research FoundationCPIRF
Child Neurology FoundationCNF
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Identifying genetic loci and phenomic associations of substance use traits: A multi-trait analysis of GWAS (MTAG) study
(2023) Addiction, . 

Xu, H.^a , Toikumo, S.^a b , Crist, R.C.^a b , Glogowska, K.^a , Jinwala, Z.^a , Deak, J.D.^c d , Justice, A.C.^d e f , Gelernter, J.^c d , Johnson, E.C.^g , Kranzler, H.R.^a b , Kember, R.L.^a b

^a Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^b Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, United States
^c Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
^d Veterans Affairs Connecticut Healthcare Center, West Haven, CT, United States
^e Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
^f Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, United States
^g Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background and Aims: Genome-wide association studies (GWAS) of opioid use disorder (OUD) and cannabis use disorder (CUD) have lagged behind those of alcohol use disorder (AUD) and smoking, where many more loci have been identified. We sought to identify novel loci for substance use traits (SUTs) in both African- (AFR) and European- (EUR) ancestry individuals to enhance our understanding of the traits’ genetic architecture. Design: We used multi-trait analysis of GWAS (MTAG) to analyze four SUTs in EUR subjects (OUD, CUD, AUD and smoking initiation [SMKinitiation]), and three SUTs in AFR subjects (OUD, AUD and smoking trajectory [SMKtrajectory]). We conducted gene-set and protein–protein interaction analyses and calculated polygenic risk scores (PRS) in two independent samples. Setting: This study was conducted in the United States. Participants: A total of 5692 EUR and 4918 AFR individuals in the Yale-Penn sample and 29 054 EUR and 10 265 AFR individuals in the Penn Medicine BioBank sample. Findings: MTAG identified genome-wide significant (GWS) single nucleotide polymorphisms (SNPs) for all four traits in EUR: 41 SNPs in 36 loci for OUD; 74 SNPs in 60 loci for CUD; 63 SNPs in 52 loci for AUD; and 183 SNPs in 144 loci for SMKinitiation. MTAG also identified GWS SNPs in AFR: 2 SNPs in 2 loci for OUD; 3 SNPs in 3 loci for AUD; and 1 SNP in 1 locus for SMKtrajectory. In the Yale-Penn sample, the MTAG-derived PRS consistently yielded more significant associations with both the corresponding substance use disorder diagnosis and multiple related phenotypes than the GWAS-derived PRS. Conclusions: Multi-trait analysis of genome-wide association studies boosted the number of loci found for substance use traits, identifying genes not previously linked to any substance, and increased the power of polygenic risk scores. Multi-trait analysis of genome-wide association studies can be used to identify novel associations for substance use, especially those for which the samples are smaller than those for historically legal substances. © 2023 Society for the Study of Addiction.

Author Keywords
alcohol use disorder;  cannabis use disorder;  GWAS;  opioid use disorder;  polygenic risk scores;  smoking initiation

Funding details
I01 BX004820, I01 CX001734
National Institutes of HealthNIHUL1TR001878
National Institute on Drug AbuseNIDAK01DA051759, P30 DA046345
National Institute on Alcohol Abuse and AlcoholismNIAAA813913, K01 AA028292, R01 AA026364, T32 AA028259
National Center for Advancing Translational SciencesNCATS
Enzon Pharmaceuticals
Perelman School of Medicine, University of Pennsylvania
American Society of Clinical PsychopharmacologyASCP

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

REV-ERB activation as a novel pharmacological approach for treating inflammatory pain
(2023) Frontiers in Pharmacology, 14, art. no. 1171931, . 

Makhija, S.^a , Griffett, J.D.^a , Veerakanellore, G.B.^b c , Burris, T.P.^d , Elgendy, B.^b c , Griffett, K.^a

^a Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
^b Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences & Pharmacy, St. Louis, MO, United States
^c Department of Pharmaceutical and Administrative Sciences, University of Health Sciences & Pharmacy, St. Louis, MO, United States
^d University of Florida Genetics Institute, Gainesville, FL, United States

Abstract
Pain is a complex problem affecting millions of people worldwide. The current therapies to reduce pain are limited as many treatment options inadequately address the causes of pain, lead to tolerance of the drug, or have adverse effects including abuse potential. While there are many causes of pain, one underlying mechanism to the pathogenesis and maintenance of pain conditions is chronic inflammation driven by the NLRP3 inflammasome. Several inflammasome inhibitors are currently under investigation however have the potential to suppress the functioning of the innate immune system, which may cause unwanted affects in patients. Here, we show that the nuclear receptor REV-ERB can suppress the activation of the inflammasome when pharmacologically activated with small molecule agonists. Additionally, REV-ERB activation appears to have analgesic potential in a model of acute inflammatory pain, likely as a result of inflammasome suppression. Copyright © 2023 Makhija, Griffett, Veerakanellore, Burris, Elgendy and Griffett.

Author Keywords
inflammasome;  inflammation;  NLRP3;  pain;  REV-ERB;  SR9009;  STL1267

Document Type: Article
Publication Stage: Final
Source: Scopus

Factors influencing engagement in in-person and remotely delivered lifestyle interventions for young adults with serious mental illness: A qualitative study
(2023) Early Intervention in Psychiatry, . 

Browne, J.^a b c , Naslund, J.A.^d , Salwen-Deremer, J.K.^e f , Sarcione, C.^e , Cabassa, L.J.^g , Aschbrenner, K.A.^e

^a Geriatric Research, Education and Clinical Center, Durham VA Health Care System, Durham, NC, United States
^b Research Service, VA Providence Health Care System, Providence, RI, United States
^c Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States
^d Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, United States
^e Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
^f Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
^g Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Aim: Young adults (ages 18–35) are underrepresented in lifestyle interventions for people with serious mental illness (SMI), such as schizophrenia, bipolar disorder, and severe depression, and little is known about factors influencing their engagement in these programmes. This qualitative study examined factors affecting engagement amongst young adults with SMI who were enrolled in a lifestyle intervention trial at community mental health centres. Methods: Seventeen young adults with SMI participated in this qualitative study. Participants were drawn from a 12-month randomized controlled trial (n = 150) comparing an in-person group lifestyle intervention augmented with mobile health technology (PeerFIT) to one-on-one personalized remote health coaching (BEAT) using purposive sampling. The 17 participants completed semi-structured qualitative interviews at post-intervention to explore their perceived benefits of the intervention and factors impacting engagement. We used a team-based descriptive qualitative approach to code transcripts and identify themes in the data. Results: Participants across both interventions reported experiencing improved ability to engage in health behaviour change. Participants described managing psychosocial stressors and family and other responsibilities that limited their ability to attend in-person PeerFIT sessions. The remote and flexible BEAT remote health coaching intervention appeared to facilitate engagement even in the context of challenging life circumstances. Conclusions: Remotely delivered lifestyle interventions can facilitate engagement amongst young adults with SMI navigating social stressors. © 2023 John Wiley & Sons Australia, Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Author Keywords
bipolar disorder;  depression;  digital health;  exercise;  nutrition;  schizophrenia

Funding details
National Institute of Mental HealthNIMHR01 MH‐110965
Rehabilitation Research and Development ServiceRR&DIK1RX003904, P50MH115843

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer’s disease
(2023) Alzheimer’s and Dementia, . 

Panyard, D.J.^a , McKetney, J.^b c , Deming, Y.K.^a d e , Morrow, A.R.^a , Ennis, G.E.^d , Jonaitis, E.M.^d f , Van Hulle, C.A.^d e , Yang, C.^g h i , Sung, Y.J.^g h i , Ali, M.^g h i , Kollmorgen, G.^j , Suridjan, I.^k , Bayfield, A.^j , Bendlin, B.B.^d e f l , Zetterberg, H.^{m n o p q} , Blennow, K.^m n , Cruchaga, C.^g h i , Carlsson, C.M.^d e f l , Johnson, S.C.^d e f l , Asthana, S.^d e l , Coon, J.J.^b c r s , Engelman, C.D.^a

^a Department of Population Health Sciences, University of Wisconsin–Madison, Madison, WI, United States
^b National Center for Quantitative Biology of Complex Systems, University of Wisconsin–Madison, Madison, WI, United States
^c Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, WI, United States
^d Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin–Madison, Madison, WI, United States
^e Department of Medicine, University of Wisconsin–Madison, Madison, WI, United States
^f Wisconsin Alzheimer’s Institute, University of Wisconsin–Madison, Madison, WI, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^j Roche Diagnostics GmbH, Penzberg, Germany
^k Roche Diagnostics International Ltd, Rotkreuz, Switzerland
^l William S. Middleton Memorial Veterans Hospital, Madison, WI, United States
^m Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
ⁿ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^o Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
^p UK Dementia Research Institute at UCL, London, United Kingdom
^q Hong Kong Center for Neurodegenerative Diseases, Hong Kong
^r Morgridge Institute for Research, Madison, WI, United States
^s Department of Chemistry, University of Wisconsin–Madison, Madison, WI, United States

Abstract
INTRODUCTION: A hallmark of Alzheimer’s disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTS: We identified 61 proteins significantly associated with the AT category (P &lt; 5.46 × 10−5) and 636 significant protein-biomarker associations (P &lt; 6.07 × 10−6). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine–phosphorylated tau association. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
acylcarnitines;  Alzheimer’s disease;  amyloid;  biomarkers;  carbon metabolism;  glucose metabolism;  metabolism;  metabolomics;  multiomics;  neurodegeneration;  neuroinflammation;  proteomics;  tau

Funding details
5T32HL83806, T32LM012413
715986
1R01AG068398‐01, 1RF1AG074007, JPND2019‐466‐236, R01AG044546, R01AG058501, R01AG064614, R01AG064877, RF1AG053303, U01AG058922
P30AG017266
2019‐0228
720931
National Institutes of HealthNIHP30AG062715, P41GM108538, P50AG033514, R01AG021155, R01AG037639, R01AG054047, R01AG27161
National Institute on AgingNIAT32AG000213
U.S. National Library of MedicineNLM
Alzheimer’s AssociationAA2019‐AARF‐643973
Wisconsin Alumni Research FoundationWARF
Alzheimer’s Drug Discovery FoundationADDF201809‐2016862
National Center for Advancing Translational SciencesNCATSUL1TR000427
University of Wisconsin-MadisonUWP2CHD047873
Familjen Erling-Perssons Stiftelse
Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin-MadisonVCRGE, UW
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZIP01AG003991, P30AG066444
Cerveau Technologies
European Research CouncilERC681712
VetenskapsrådetVR2018‐02532
Horizon 2020860197
Alzheimerfonden2017‐0243, 742881
UK Dementia Research InstituteUK DRI2017‐00915, 201809‐2016615
Olav Thon Stiftelsen

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

The relationship of trait-like compassion with epigenetic aging: The population-based prospective Young Finns Study
(2023) Frontiers in Psychiatry, 14, art. no. 1018797, . 

Dobewall, H.^a b , Keltikangas-Järvinen, L.^c , Marttila, S.^d e , Mishra, P.P.^d f , Saarinen, A.^c , Cloninger, C.R.^g , Zwir, I.^g h , Kähönen, M.ⁱ , Hurme, M.^j , Raitakari, O.^k l m , Lehtimäki, T.^d f , Hintsanen, M.^a

^a Faculty of Education, VISE Research Unit, Faculty of Education and Psychology, University of Oulu, Oulu, Finland
^b Finnish Institute for Health and Welfare, Helsinki, Finland
^c Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
^d Molecular Epidemiology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^e Gerontology Research Center, Tampere University, Tampere, Finland
^f Fimlab Laboratories and Finnish Cardiovascular Research Center – Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Computer Science, University of Granada, Granada, Spain
ⁱ Department of Clinical Physiology, Tampere University Hospital, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^j Department of Microbiology and Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^k Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
^l Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
^m Centre for Population Health Research, University of Turku, Turku University Hospital, Turku, Finland

Abstract
Introduction: Helping others within and beyond the family has been related to living a healthy and long life. Compassion is a prosocial personality trait characterized by concern for another person who is suffering and the motivation to help. The current study examines whether epigenetic aging is a potential biological mechanism that explains the link between prosociality and longevity. Methods: We used data from the Young Finns Study that follows six birth-cohorts from age 3–18 to 19–49. Trait-like compassion for others was measured with the Temperament and Character Inventory in the years 1997 and 2001. Epigenetic age acceleration and telomere length were measured with five DNA methylation (DNAm) indicators (DNAmAgeHorvath, IEAA_Hannum, EEAA_Hannum, DNAmPhenoAge, and DNAmTL) based on blood drawn in 2011. We controlled for sex, socioeconomic status in childhood and adulthood, and body-mass index. Results and discussion: An association between higher compassion in 1997 and a less accelerated DNAmPhenoAge, which builds on previous work on phenotypic aging, approached statistical significance in a sex-adjusted model (n = 1,030; b = −0.34; p = 0.050). Compassion in 1997 predicted less accelerated epigenetic aging over and above the control variables (n = 843; b = −0.47; p = 0.016). There was no relationship between compassion in 2001 (n = 1108/910) and any of the other four studied epigenetic aging indicators. High compassion for others might indeed influence whether an individual’s biological age is lower than their chronological age. The conducted robustness checks partially support this conclusion, yet cannot rule out that there might be a broader prosocial trait behind the findings. The observed associations are interesting but should be interpreted as weak requiring replication. Copyright © 2023 Dobewall, Keltikangas-Järvinen, Marttila, Mishra, Saarinen, Cloninger, Zwir, Kähönen, Hurme, Raitakari, Lehtimäki and Hintsanen.

Author Keywords
compassion;  DNA methylation;  DNAmPhenoAge;  epigenetic aging;  longevity;  prosocial personality;  temperament and character inventory

Funding details
Yrjö Jahnssonin Säätiö
H2020 European Research CouncilERC; es:CEI; fr:CER; pl:ERBN
University HospitalsUH
Horizon Pharmaceuticals
Fondazione Diabete Ricerca
Harrington Discovery Institute, University HospitalsHDIX51001
European Research CouncilERC742927
Academy of FinlandAKA117787, 121584, 124282, 126925, 129378, 134309, 286284, 308676, 322098, 41071
Suomen KulttuurirahastoSKR
Juho Vainion Säätiö
Signe ja Ane Gyllenbergin Säätiö
Emil Aaltosen Säätiö
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Tampereen Tuberkuloosisäätiö
Horizon 2020755320, 848146
Diabetesliitto
Paavo Nurmen Säätiö
Tays
Turun Yliopistollinen KeskussairaalaAUCS
Suomen kliinisen kemian yhdistysFSCC

Document Type: Article
Publication Stage: Final
Source: Scopus

Comparing Tau PET Visual Interpretation with Tau PET Quantification, Cerebrospinal Fluid Biomarkers, and Longitudinal Clinical Assessment
(2023) Journal of Alzheimer’s Disease: JAD, 93 (2), pp. 765-777. 

Chen, C.D.^a , Ponisio, M.R.^a , Lang, J.A.^a , Flores, S.^a , Schindler, S.E.^b , Fagan, A.M.^b , Morris, J.C.^b , Benzinger, T.L.S.^a

^a Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: 18F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer’s disease (AD). However, manufacturer’s guidelines for visual interpretation of 18F-flortaucipir PET differ from how 18F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. OBJECTIVE: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n = 189, 23 were cognitively impaired). METHODS: Participants had tau PET, Aβ PET, MRI, and clinical and cognitive evaluation within 18 months (n = 189); the majority (n = 144) also underwent lumbar puncture. Two radiologists followed manufacturer’s guidelines for 18F-flortaucipir PET visual interpretation. RESULTS: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. CONCLUSION: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals.

Author Keywords
Alzheimer’s disease;  cerebrospinal fluid;  positron emission tomography;  tauopathies

Document Type: Article
Publication Stage: Final
Source: Scopus

Exogenous exposures shape genetic predisposition to lipids, Alzheimer’s, and coronary heart disease in the MLXIPL gene locus
(2023) Aging, 15 (9), pp. 3249-3272. 

Loika, Y.^a , Loiko, E.^a , Feng, F.^a , Stallard, E.^a , Yashin, A.I.^a , Arbeev, K.^a , Kuipers, A.L.^b , Feitosa, M.F.^c , Province, M.A.^c , Kulminski, A.M.^a

^a Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, United States
^b Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15260, United States
^c Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Associations of single nucleotide polymorphisms (SNPs) of the MLXIPL lipid gene with Alzheimer’s (AD) and coronary heart disease (CHD) and potentially causal mediation effects of their risk factors, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), were examined in two samples of European ancestry from the US (22,712 individuals 587/2,608 AD/CHD cases) and the UK Biobank (UKB) (232,341 individuals; 809/15,269 AD/CHD cases). Our results suggest that these associations can be regulated by several biological mechanisms and shaped by exogenous exposures. Two patterns of associations (represented by rs17145750 and rs6967028) were identified. Minor alleles of rs17145750 and rs6967028 demonstrated primary (secondary) association with high TG (lower HDL-C) and high HDL-C (lower TG) levels, respectively. The primary association explained ~50% of the secondary one suggesting partly independent mechanisms of TG and HDL-C regulation. The magnitude of the association of rs17145750 with HDL-C was significantly higher in the US vs. UKB sample and likely related to differences in exogenous exposures in the two countries. rs17145750 demonstrated a significant detrimental indirect effect through TG on AD risk in the UKB only (βIE = 0.015, pIE = 1.9 × 10−3), which suggests protective effects of high TG levels against AD, likely shaped by exogenous exposures. Also, rs17145750 demonstrated significant protective indirect effects through TG and HDL-C in the associations with CHD in both samples. In contrast, rs6967028 demonstrated an adverse mediation effect through HDL-C on CHD risk in the US sample only (βIE = 0.019, pIE = 8.6 × 10−4). This trade-off suggests different roles of triglyceride mediated mechanisms in the pathogenesis of AD and CHD © 2023 Loika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Author Keywords
Alzheimer’s disease;  coronary heart disease;  lipids;  MLXIPL;  triglycerides

Funding details
National Institute on AgingNIA

Document Type: Article
Publication Stage: Final
Source: Scopus