WashU weekly Neuroscience publications: August 18, 2024

Multi-omic analysis of Huntington’s disease reveals a compensatory astrocyte state
(2024) Nature Communications, 15 (1), art. no. 6742, . 

Paryani, F.^a , Kwon, J.-S.^b , Ng, C.W.^c , Jakubiak, K.^d , Madden, N.^d , Ofori, K.^d , Tang, A.^d , Lu, H.^d , Xia, S.^d , Li, J.^d , Mahajan, A.^d , Davidson, S.M.^e , Basile, A.O.^f , McHugh, C.^f , Vonsattel, J.P.^d , Hickman, R.^d , Zody, M.C.^f , Housman, D.E.^c , Goldman, J.E.^d g , Yoo, A.S.^b , Menon, V.^a g , Al-Dalahmah, O.^d g

^a Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^b Department of Developmental Biology Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, United States
^d Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, United States
^e Northwestern Feinberg School of Medicine, Northwestern University, Evanston, IL, United States
^f New York Genome Center, New York, NY, United States
^g Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, NY, United States

Abstract
The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington’s disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, one protoplasmic astrocyte state showed high levels of metallothioneins and was correlated with the selective vulnerability of distinct striatal neuronal populations. When modeled in vitro, this state improved the viability of HD-patient-derived spiny projection neurons. Our findings uncover key roles of astrocytic states in protecting against neurodegeneration in HD. © The Author(s) 2024.

Funding details
Hereditary Disease FoundationHDF
American Brain Tumor AssociationABTA
Huntington’s Disease Society of AmericaHDSA
Niagara UniversityNUP30AG066462
Niagara UniversityNU
Nihon Kohden AmericaR21 AG075754
Nihon Kohden America

Document Type: Article
Publication Stage: Final
Source: Scopus

Inter-Ocular Fixation Instability of Amblyopia: Relationship to Visual Acuity, Strabismus, Nystagmus, Stereopsis, Vergence, and Age
(2024) American Journal of Ophthalmology, 267, pp. 230-248. 

Ghasia, F.^a , Tychsen, L.^b

^a From the Neurosciences and Ocular Motility Laboratory (F.G.), Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States
^b Department of Ophthalmology and Visual Sciences (L.T.), St Louis Children’s Hospital at Washington University School of Medicine, St. Louis, MO, United States

Abstract
PURPOSE: Amblyopia damages visual sensory and ocular motor functions. One manifestation of the damage is abnormal fixational eye movements. Tiny fixation movements are normal; however, when these exceed a normal range, the behavior is labeled “fixation instability” (FI). Here we compare FI between normal and amblyopic subjects, and evaluate the relationship between FI and severity of amblyopia, strabismus angle, nystagmus, stereopsis, vergence, and subject age. METHODS: Fixation eye movements were recorded using infrared video-oculography from 47 controls (15.3 ± 12.2 years of age) and 104 amblyopic subjects (13.3 ± 11.2 years of age) during binocular and monocular viewing. FI and vergence instability were quantified as the bivariate contour ellipse area (BCEA). We also calculated the ratio of FI between the 2 eyes: right eye/left eye for controls, amblyopic eye/fellow eye for amblyopes. Multiple regression analysis evaluated how FI related to a range of visuo-motor measures. RESULTS: During binocular viewing, the FI of fellow and amblyopic eye, vergence instability, and inter-ocular FI ratios were least in anisometropic and most in mixed amblyopia (P < .05). Each correlated positively with the strabismus angle (P < .01). During monocular viewing, subjects with deeper amblyopia (P < .01) and larger strabismus angles (P < .05) had higher inter-ocular FI ratios. In all, 27% of anisometropic and >65% of strabismic/mixed amblyopes had nystagmus. Younger age and nystagmus increased FI and vergence instability (P < .05) but did not affect the inter-ocular FI ratios (P > .05). CONCLUSIONS: Quantitative recording of perturbed eye movements in children reveal a major functional deficit linked to amblyopia. Imprecise fixation, measured as inter-ocular FI ratios, may be used as a robust marker for amblyopia and strabismus severity. NOTE: Publication of this article is sponsored by the American Ophthalmological Society. © 2024 Elsevier Inc.

Funding details
American Center for Reproductive Medicine, Cleveland ClinicACRM
Department of Biomedical Engineering, Case Western Reserve UniversityBME
Hartwell Foundation
Research to Prevent BlindnessRPB
Knights Templar Eye FoundationKTEF
Cleveland Eye Bank FoundationCEBF
Cleveland ClinicCC

Document Type: Article
Publication Stage: Final
Source: Scopus

Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial
(2024) Pediatric Neurology, 159, pp. 62-71. 

Farach, L.S., MD^a , Richard, M.A., PhD^b , Wulsin, A.C., MD, PhD^c , Bebin, E.M., MD^d , Krueger, D.A., MD, PhD^c , Sahin, M.^e f s s , Porter, B.E., MD, PhD^g , McPherson, T.O., PhD^h , Peters, J.M.^e f s s , O’Kelley, S.^i s s , O’Kelley, S.^j , Rajaraman, R.^k s , Rajaraman, R.^l , McClintock, W.M.^m s , Koenig, M.K., MD^a , McClintock, W.M.ⁿ , Werner, K.^o s , Nolan, D.A., MD^p , Wong, M.^q s , Cutter, G.^r s , Northrup, H.^a s , Au, K.S., PhD^a , Bebin, E.M.^s , Krueger, D.^s , Flamini, R.^s , Sergott, R.C.^s , McPherson, T.^s , Peri, K.^s , Krefting, J.^s , Porter, B.^s , Taub, K.^s , Litt, B.^s , Wu, J.^s , Lagory, D.^s , Korf, B.^s , Messiaen, L.^s , Biasini, F.^s , Byars, A.^s , Roberds, S.L.^s , Rushing, G.^s , Griffith, M.^s , Davis, P.^s , Hansen, E.^s , Arcasoy, E.^s , Phillips, J.^s , Solidum, R.^s , Gulsrud, A.^s , Solis, N.^s , Randle, S.^s , Patrick, K.^s , Lee-Eng, J.^s , Frost, M.D.^s , Branson, J.^s , Ellis, S.^s , White, D.^s , Novak, O.^s , Fasciola, A.^s , Lorenzi, J.^s , Layer, M.^s , Thomas, A.^s , Chanbers, E.^s , Berl, M.^s , Elling, N.^s , Kassoff, B.^s , Hardie, K.^s , Nolan, D.^s , DeBastos, A.^s , Batchelder, C.^s , Koening, M.K.^s , Au, K.S.^s , Pearson, D.^s , Mansour, R.^s , Farach, L.^s , Salazar, E.^s , PREVeNT Study Group^t

^a Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children’s Memorial Hermann Hospital, Houston, Texas, United States
^b Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
^c Division of Neurology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
^d Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States
^e Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, Massachusetts, United States
^f Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
^g Department of Neurology, Stanford University, Stanford, California, United States
^h Department of Biostatistics and Bioinformatics, Emory University, Georgia, Atlanta, Georgia
ⁱ Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, United States
^j Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
^k Department of Pediatrics and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, United States
^l Division Pediatric Neurology and Epilepsy, Department of Neurology, Seattle Children’s Hospital, Seattle, WA, United States
^m Division of Neurology, Department of Pediatrics, Children’s National Medical Center, Washington, District of Columbia, United States
ⁿ Minnesota Epilepsy Group, P.A., Roseville, Minnesota, United States
^o Department of Pediatrics, Duke University, Durham, North Carolina, United States
^p Beaumont Florence and Richard McBrien Pediatric Neuroscience Center, Beaumont Hospital, Royal Oak, MI, United States
^q Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri, United States
^r Department of Biostatistics, University of Alabama at BirminghamAlabama, United States

Abstract
Background: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE. Methods: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models. Results: Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes. Conclusions: Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management. © 2024 Elsevier Inc.

Author Keywords
Drug-resistant epilepsy;  Epilepsy;  Genotype;  Phenotype;  Tuberous sclerosis complex (TSC);  Vigabatrin

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluating speech latencies during structured psychiatric interviews as an automated objective measure of psychomotor slowing(2024) Psychiatry Research, 340, art. no. 116104, . 

Cohen, A.S.^a b c , Rodriguez, Z.^a b , Opler, M.^c d , Kirkpatrick, B.^c e , Milanovic, S.^f , Piacentino, D.^f , Szabo, S.T.^f , Tomioka, S.^f , Ogirala, A.^f , Koblan, K.S.^f , Siegel, J.S.^f g , Hopkins, S.^f

^a Louisiana State University, Department of Psychology, United States
^b Louisiana State University, Center for Computation and Technology, United States
^c Quantic Innovation, Inc, United States
^d WCG, Inc, United States
^e Psychiatric Research Institute, University of Arkansas for Medical Sciences, United States
^f Sumitomo Pharmaceuticals, Inc, United States
^g Washington University in St. Louis, Department of Psychiatry, United States

Abstract
We sought to derive an objective measure of psychomotor slowing from speech analytics during a psychiatric interview to avoid potential burden of dedicated neurophysiological testing. Speech latency, which reflects response time between speakers, shows promise from the literature. Speech data was obtained from 274 subjects with a diagnosis of bipolar I depression enrolled in a randomized, doubleblind, 6-week phase 2 clinical trial. Audio recordings of structured Montgomery–Åsberg Depression Rating Scale (MADRS) interviews at 6 time points were examined (k = 1,352). We evaluated speech latencies, and other aspects of speech, for temporal stability, convergent validity, sensitivity/responsivity to clinical change, and generalization across seven socio-linguistically diverse countries. Speech latency was minimally associated with demographic features, and explained nearly a third of the variance in depression (categorically defined). Speech latency significantly decreased as depression symptoms improved over time, explaining nearly 20 % of variance in depression remission. Classification for differentiating people with versus without concurrent depression was high (AUCs > 0.85) both cross-sectionally and longitudinally. Results replicated across countries. Other speech features offered modest incremental contribution. Neurophysiological speech parameters with face validity can be derived from psychiatric interviews without the added patient burden of additional testing. © 2024

Author Keywords
Biomarker;  Depression;  Digital phenotyping;  Interview;  Language;  Latency;  Psychomotor;  Speech

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluating the interaction between hemorrhagic transformation and cerebral edema on functional outcome after ischemic stroke
(2024) Journal of Stroke and Cerebrovascular Diseases, 33 (10), art. no. 107913, . 

Avula, A.^a , Bui, Q.^a , Kumar, A.^a , Chen, Y.^a , Hamzehloo, A.^a , Cifarelli, J.^a , Heitsch, L.^a b , Slowik, A.^c , Strbian, D.^d , Lee, J.-M.^a , Dhar, R.^a

^a Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S Euclid Avenue, St. Louis, MO, United States
^b Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
^d Department of Neurology, Helsinki University Hospital, Helsinki, Finland

Abstract
Background: Hemorrhagic transformation (HT) and cerebral edema (CED) are both major complications following ischemic stroke, but few studies have evaluated their overlap. We evaluated the frequency and predictors of CED/HT overlap and whether their co-occurrence impacts functional outcome more than each in isolation. Methods: 892 stroke patients enrolled in a prospective study had follow-up CT imaging evaluated for HT and CED; the latter was quantified using the ratio of hemispheric CSF volumes (with hemispheric CSF ratio < 0.90 used as the CED threshold). The interaction between HT and CED on functional outcome (using modified Rankin Scale at 3 months) was compared to that for each condition separately. Results: Among the 275 (31%) who developed HT, 233 (85%) manifested hemispheric CSF ratio < 0.9 (CED/HT), with this overlap group representing half of the 475 with measurable CED. Higher baseline NIHSS scores and larger infarct volumes were observed in the CED/HT group compared with those with CED or HT alone. Functional outcome was worse in those with CED/HT [median mRS 3 (IQR 2-5)] than those with CED [median 2 (IQR 1-4)] or HT alone [median 1 (IQR 0-2), p < 0.0001]. Overlap of CED/HT independently predicted worse outcome [OR 1.89 (95% CI: 1.12-3.18), p = 0.02] while HT did not; however, CED/HT was no longer associated with worse outcome after adjusting for severity of CED [adjusted OR 0.35 (95% CI: 0.23, 0.51) per 0.21 lower hemispheric CSF ratio, p < 0.001]. Conclusions: Most stroke patients with HT also have measurable CED. The co-occurrence of CED and HT occurs in larger and more severe strokes and is associated with worse functional outcome, although this is driven by greater severity of stroke-related edema in those with HT. © 2024

Author Keywords
Cerebral edema;  Functional outcome;  Hemorrhagic transformation;  Overlap of HT and CED

Funding details
National Institutes of HealthNIHR01NS085419, R01NS121218, K23NS099440, K23NS099487, U24NS107230
National Institutes of HealthNIH

Document Type: Article
Publication Stage: Final
Source: Scopus

Brief Report: Veterans Aging Cohort Study Index 2.0 Shows Improved Discrimination of Neurocognitive Impairment and Frailty in People with HIV
(2024) Journal of Acquired Immune Deficiency Syndromes, 97 (1), pp. 63-67. 

Yan, C.Y.^a , Cooley, S.A.^a , Ances, B.M.^a b c

^a Department of Neurology, Washington University in Saint Louis, St. Louis, MO, United States
^b Department of Radiology, Washington University in Saint Louis, St. Louis, MO, United States
^c Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, United States

Abstract
Objective:To examine whether the revised Veterans Aging Cohort Study (VACS2.0) index [including serum albumin, body mass index, and white blood cell count] had stronger correlations with cognitive function, brain volume, and frailty in persons with HIV (PWHs) ≥50 years compared with the VACS1.0.Design and methods:Neuropsychological performance (NP) Z-scores (learning, retention, executive functioning, psychomotor function/processing speed, language, and global cognition), and neuroimaging measures (brain volumetrics) were analyzed in PWHs (n = 162). A subset of the sample (n = 159) was defined as either frail (n = 18) or nonfrail (n = 141) according to the Fried phenotype criteria. Brain volumes, NP scores, and frailty subgroups were analyzed with VACS scores, albumin, body mass index, and white blood cell count using Pearson significance tests and independent T tests.Results:Higher VACS scores significantly correlated with lower brain volumes. Higher VACS2.0 scores were associated with lower NP in the executive functioning and psychomotor function/processing speed domains and were primarily driven by albumin. VACS1.0 scores did not correlate with cognition Z-scores. There was no relationship between frailty status and VACS1.0. PWHs who were frail had significantly greater VACS2.0 scores than nonfrail PWHs.Conclusions:The addition of albumin to the VACS index improved its correlations with NP and frailty in PWHs. While low albumin levels may contribute to cognitive decline or frailty, the reverse causality should also be considered. These findings suggest that the VACS2.0 index (especially albumin) is a valuable measure for clinicians to improve outcomes in PWHs. © 2024 Wolters Kluwer Health, Inc.

Author Keywords
albumin;  frailty;  HIV;  neuropsychology;  VACS

Document Type: Article
Publication Stage: Final
Source: Scopus

Intergenerational Educational Mobility and Cognitive Trajectories among Middle-Aged and Older Chinese People: An Application of Growth Mixture and Mobility Contrast Models in Longitudinal Analysis
(2024) Journals of Gerontology – Series B Psychological Sciences and Social Sciences, 79 (9), art. no. gbae125, . 

Shi, S.^a , Chen, Y.-C.^a b , Gugushvili, A.^c , Yip, P.S.F.^a d

^a Department of Social Work and Social Administration, The University of Hong Kong, Hong Kong
^b Social Policy Institute, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Sociology and Human Geography, University of Oslo, Oslo, Norway
^d Hong Kong Jockey Club Centre for Suicide Research and Prevention, The University of Hong Kong, Hong Kong

Abstract
Objectives: Due to statistical challenges in disentangling the mobility effect (i.e., intergenerational educational mobility) from the position effect (i.e., parental and person’s own education), the impact of intergenerational educational mobility on cognitive function remains unclear. We employed a novel approach to identify the mobility effect and investigate the net impact of intergenerational educational mobility on heterogeneous patterns of cognition among middle-aged and older adults in China. Methods: Participants aged 45 and older were recruited from the China Health and Retirement Longitudinal Study, a population-based prospective cohort study between 2011 and 2018. We identified cognitive trajectories using the growth mixture model (GMM) and subsequently employed the mobility contrast model (MCM) to examine the effects of intergenerational educational mobility on cognitive patterns stratified by gender. Results: Almost two thirds of respondents experienced intergenerational educational mobility, and 55% experienced upward mobility. Men had a higher rate of upward mobility than women. Three population-based cognitive patterns were identified: the low cognitive function with decline group (28%), the moderate cognitive function group (47%), and the high cognitive function group (26%). MCM analysis revealed that both upward and downward intergenerational educational mobility negatively affected cognitive trajectory patterns, extending beyond the influence of individuals’ current and parental education. Discussion: In future research, the impact of mobility can be studied in longitudinal data sets by combining the GMM and MCM approaches. The net negative effect of intergenerational educational mobility on cognitive trajectory patterns indicates that it should be recognized as an independent predictor of cognitive decline. © The Author(s) 2024.

Author Keywords
China;  Cognitive function trajectory;  Growth mixture model;  Life course;  Mobility contrast model

Document Type: Article
Publication Stage: Final
Source: Scopus

Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study
(2024) The Lancet Neurology, 23 (9), pp. 901-912. Cited 1 time.

Van den Berg, L.H.^a , Rothstein, J.D.^b , Shaw, P.J.^c d , Babu, S.^e , Benatar, M.^f , Bucelli, R.C.^g , Genge, A.^h , Glass, J.D.ⁱ , Hardiman, O.^j , Libri, V.^k , Mobach, T.^l , Oskarsson, B.^m , Pattee, G.L.^n o , Ravits, J.^p , Shaw, C.E.^q , Weber, M.^r , Zinman, L.^s , Jafar-nejad, P.^t , Rigo, F.^t , Lin, L.^u , Ferguson, T.A.^u , Gotter, A.L.^u , Graham, D.^u , Monine, M.^u , Inra, J.^u , Sinks, S.^u , Eraly, S.^u , Garafalo, S.^u , Fradette, S.^u

^a UMC Utrecht Brain Center, Department of Neurology, UMC Utrecht, Utrecht, Netherlands
^b Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
^c Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
^d National Institute for Health and Care Research Sheffield Biomedical Research Centre and Clinical Research Facility, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
^e Sean M Healey and AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^f Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States
^g Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^h Montreal Neurological Institute and Hospital, Montreal, Canada
ⁱ Department of Neurology, Emory University, Atlanta, GA, United States
^j School of Medicine, Trinity College, Dublin, Ireland
^k University College London Institute of Neurology and National Institute for Health and Care Research (NIHR) University College London Hospitals (UCLH) Clinical Research Facility and Biomedical Research Centre, London, United Kingdom
^l Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
^m Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
ⁿ Bryan Physicians Network, Lincoln, NE, United States
^o Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, United States
^p Department of Neurosciences, University of California San Diego Health, San Diego, CA, United States
^q UK Dementia Research Institute, King’s College London, London, United Kingdom
^r Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St Gallen, Switzerland
^s Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
^t Ionis Pharmaceuticals, Carlsbad, CA, United States
^u Biogen, Cambridge, MA, United States

Abstract
Background: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. Methods: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1–6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1–3 and about 6 months for cohorts 4–6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed. Findings: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator. Interpretation: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS. Funding: Biogen. © 2024 Elsevier Ltd

Funding details
Biogen

Document Type: Article
Publication Stage: Final
Source: Scopus

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer’s disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)
(2024) The Lancet Neurology, 23 (9), pp. 913-924. Cited 1 time.

Schultz, S.A.^a b , Liu, L.^c d , Schultz, A.P.^a b , Fitzpatrick, C.D.^a b , Levin, R.^a b , Bellier, J.-P.^c d , Shirzadi, Z.^a b c , Joseph-Mathurin, N.^e , Chen, C.D.^e , Benzinger, T.L.S.^e , Day, G.S.^k , Farlow, M.R.^l , Gordon, B.A.^e , Hassenstab, J.J.^f , Jack, C.R., Jr^m , Jucker, M.ⁿ , Karch, C.M.^g , Lee, J.-H.^o , Levin, J.^p q r , Perrin, R.J.^g h , Schofield, P.R.^s t , Xiong, C.ⁱ , Johnson, K.A.^a b , McDade, E.^j , Bateman, R.J.^j , Sperling, R.A.^a b c , Selkoe, D.J.^b c d , Chhatwal, J.P.^a b c d , Aguillon, D.^u , Allegri, R.F.^u , Aschenbrenner, A.J.^u , Baker, B.^u , Barthelemy, N.^u , Bechara, J.A.^u , Berman, S.B.^u , Brooks, W.S.^u , Cash, D.M.^u , Chen, A.^u , Chrem Mendez, P.^u , Courtney, L.^u , Cruchaga, C.^u , Daniels, A.J.^u , Fagan, A.M.^u , Flores, S.^u , Fox, N.C.^u , Franklin, E.^u , Goate, A.M.^u , Graber-Sultan, S.^u , Graff-Radford, N.R.^u , Gremminger, E.^u , Herries, E.^u , Hofmann, A.^u , Holtzman, D.M.^u , Hornbeck, R.^u , Huey, E.D.^u , Ibanez, L.^u , Ikeuchi, T.^u , Ikonomovic, S.^u , Jackson, K.^u , Jarman, S.^u , Jerome, G.^u , Johnson, E.C.B.^u , Kasuga, K.^u , Keefe, S.^u , Koudelis, D.^u , Kuder-Buletta, E.^u , Laske, C.^u , Leon, Y.M.^u , Levey, A.I.^u , Li, Y.^u , Llibre-Guerra, J.J.^u , Lopera, F.^u , Lu, R.^u , Marsh, J.^u , Martins, R.^u , Massoumzadeh, P.^u , Masters, C.^u , McCullough, A.^u , McKay, N.^u , Minton, M.^u , Mori, H.^u , Morris, J.C.^u , Nadkarni, N.K.^u , Nicklaus, J.^u , Niimi, Y.^u , Noble, J.M.^u , Obermueller, U.^u , Picarello, D.M.^u , Pulizos, C.^u , Ramirez, L.^u , Renton, A.E.^u , Ringman, J.^u , Rizzo, J.^u , Roedenbeck, Y.^u , Roh, J.H.^u , Rosa-Neto, P.^u , Ryan, N.S.^u , Sabaredzovic, E.^u , Salloway, S.^u , Sanchez-Valle, R.^u , Scott, J.^u , Seyfried, N.T.^u , Simmons, A.^u , Smith, J.^u , Smith, H.^u , Stauber, J.^u , Stout, S.^u , Supnet-Bell, C.^u , Surace, E.^u , Vazquez, S.^u , Vöglein, J.^u , Wang, G.^u , Wang, Q.^u , Xu, X.^u , Xu, J.^u , Dominantly Inherited Alzheimer Network^v

^a Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^b Department of Neurology, Medical School, Harvard University, Boston, MA, United States
^c Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
^d Ann Romney Center for Neurologic Diseases, Boston, MA, United States
^e Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, United States
^f Department of Psychology, Washington University, St Louis, MO, United States
^g Department of Psychiatry, Washington University, St Louis, MO, United States
^h Department of Pathology and Immunology, Washington University, St Louis, MO, United States
ⁱ Division of Biostatistics, Washington University, St Louis, MO, United States
^j Department of Neurology, Washington University, St Louis, MO, United States
^k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^l Indiana Alzheimer’s Disease Research Center, Indianapolis, IN, United States
^m Department of Neurology, Mayo Clinic, Rochester, MN, United States
ⁿ German Center for Neurodegenerative Diseases, Tübingen, Germany
^o Department of Neurology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
^p German Center for Neurodegenerative Diseases, Munich, Germany
^q Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany
^r Munich Cluster for Systems Neurology, Munich, Germany
^s Neuroscience Research Australia, Randwick, NSW, Australia
^t School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia

Abstract
Background: Genetic variants that cause autosomal dominant Alzheimer’s disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer’s disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production. Methods: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)–PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)–PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume. Findings: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p&lt;0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (–0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB–PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p&lt;0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). Interpretation: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer’s disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. Funding: US National Institute on Aging, Alzheimer’s Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III. © 2024 Elsevier Ltd

Funding details
National Institute of Child Health and Human DevelopmentNICHD
Barrow Neurological InstituteBNI
Instituto de Salud Carlos IIIISCIII
Korea Research Institute of Chemical TechnologyKRICT
Center for Performance ResearchCPR
German Network for Motor Neuron DiseasesMND-NET
Ministry of Health and WelfareMOHW
National Institute on AgingNIA
Japan Agency for Medical Research and DevelopmentAMEDJP23dk0207066, JP22dk0207049
Japan Agency for Medical Research and DevelopmentAMED
Ministry of Science and ICT, South KoreaMSITHI21C0066
Ministry of Science and ICT, South KoreaMSIT
Alzheimer’s AssociationAASG-20–690363-DIAN
Alzheimer’s AssociationAA

Document Type: Article
Publication Stage: Final
Source: Scopus

Parvalbumin expression does not account for discrete electrophysiological profiles of glutamatergic ventral pallidal subpopulations
(2024) Addiction Neuroscience, 12, art. no. 100170, . 

Graham, R.D.^a , Fang, L.Z.^a , Tooley, J.R.^a b , Kalyanaraman, V.^a , Stander, M.C.^a , Sapkota, D.^e f , Lynch, M.R.^a d , Dougherty, J.D.^b c f , Copits, B.A.^a b , Creed, M.C.^a b

^a Department of Anesthesiology, Washington University in St. Louis, United States
^b Graduate program in neuroscience, Division of Biological and Biomedical Sciences, United States
^c Department of Psychiatry, Washington University in St. Louis, United States
^d NINDS Neuroscience Postbaccalaureate Program, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Biological Sciences, University of Texas at Dallas, United States
^f Department of Genetics, Washington University in St. Louis, United States

Abstract
The ventral pallidum (VP) has emerged as a critical node in the mesolimbic reward system. Modulating the VP can impact the subjective valuation of rewards, reward motivation, and reward seeking under conflict, making it an attractive target for clinical neuromodulation therapies that manage substance use disorders. To understand how to rationally modulate the VP, we need a better understanding of the electrophysiological properties of VP neurons and the molecular and biophysical determinants of these properties. Here, we used patch-clamp electrophysiology to characterize the intrinsic properties of glutamatergic VP (VPGlu) neurons and observed two distinct electrophysiological profiles: VPGlu neurons that undergo depolarization block in response to progressively increasing current injection amplitudes and those that were resistant to depolarization block. To explore the mechanisms that could contribute to these distinct profiles, we used targeted ribosome affinity purification to identify ion channel subunits and regulatory proteins by isolating actively transcribed mRNA selectively from VPGlu neurons. We then used this transcriptomic information to implement a Markov Chain Monte Carlo method to parameterize a large population of biophysically distinct multicompartment models of VPGlu neurons conforming to either subpopulation. Based on prior literature suggesting parvalbumin (PV) is expressed in a subset of VPGlu neurons, and that PV expression governs the firing properties of those neurons, we tested the hypothesis that PV expression accounted for differences in subgroups, by increasing the maximal firing frequency and conferring resistance to depolarization block. In contrast, our model determined that PV expression at physiological levels had no effect on maximum firing rate. However, supraphysiological expression levels of PV appeared to induce a depolarization block in previously depolarization block-resistant neuron models, suggesting that other intracellular calcium-binding proteins could play a role in determining the firing phenotype of VPGlu neurons. We corroborated this result with single-cell patch-clamp RT-PCR, which confirmed that PV expression did not distinguish the two electrophysiologically distinct subpopulations. Together, these findings establish that VPGlu neurons are composed of biophysically distinct subpopulations that have not been appreciated in prior studies interrogating the function of this population. With the advent of novel tools for cell-type specific pharmacology and targeted neurostimulation, this understanding will be critical for developing strategies to rationally modulate VPGlu cells to treat disorders characterized by maladaptive reward seeking. © 2024 The Author(s)

Author Keywords
Electrophysiology;  Ion channels;  Markov chain Monte-Carlo;  Neuron modeling;  Translating ribosome affinity purification

Funding details
Joint Genome InstituteJGI
National Institutes of HealthNIH
Genome Technology Access CenterGTAC
National Center for Research ResourcesNCRR
Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of PennsylvaniaIDOM
Foundation for Barnes-Jewish HospitalFBJH4642, 3770
#P30 CA91842
National Institute on Drug AbuseNIDAR01DA058755, R01DA049924, R01DA056829
R25NS130965
St. Louis Children’s HospitalSLCHCDI-CORE-2019-813, CDI-CORE-2015-505
University of WashingtonUWT32DA007261, P30DK020579

Document Type: Article
Publication Stage: Final
Source: Scopus

The consequences of AI training on human decision-making
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (33), pp. e2408731121. 

Treiman, L.S.^a , Ho, C.-J.^a b , Kool, W.^a c

^a Division of Computational & Data Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Division of Computer Science & Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^c Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
AI is now an integral part of everyday decision-making, assisting us in both routine and high-stakes choices. These AI models often learn from human behavior, assuming this training data is unbiased. However, we report five studies that show that people change their behavior to instill desired routines into AI, indicating this assumption is invalid. To show this behavioral shift, we recruited participants to play the ultimatum game, where they were asked to decide whether to accept proposals of monetary splits made by either other human participants or AI. Some participants were informed their choices would be used to train an AI proposer, while others did not receive this information. Across five experiments, we found that people modified their behavior to train AI to make fair proposals, regardless of whether they could directly benefit from the AI training. After completing this task once, participants were invited to complete this task again but were told their responses would not be used for AI training. People who had previously trained AI persisted with this behavioral shift, indicating that the new behavioral routine had become habitual. This work demonstrates that using human behavior as training data has more consequences than previously thought since it can engender AI to perpetuate human biases and cause people to form habits that deviate from how they would normally act. Therefore, this work underscores a problem for AI algorithms that aim to learn unbiased representations of human preferences.

Author Keywords
AI training;  decision-making;  fairness;  habit formation;  ultimatum game

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain region-specific action of ketamine as a rapid antidepressant
(2024) Science (New York, N.Y.), 385 (6709), p. eado7010. 

Chen, M.^a b , Ma, S.^b c , Liu, H.^a b , Dong, Y.^b , Tang, J.^b , Ni, Z.^b , Tan, Y.^b , Duan, C.^d , Li, H.^b , Huang, H.^c , Li, Y.^e , Cao, X.^f , Lingle, C.J.^g , Yang, Y.^b , Hu, H.^a b c h

^a Department of Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
^b Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou, 311121, China
^c Fourth Affiliated Hospital of School of Medicine, International School of Medicine, International Institutes of Medicine, Zhejiang University School of Medicine, Zhejiang University, China
^d Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan UniversityShanghai 200433, China
^e State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, School of Life Sciences, Peking UniversityBeijing 100871, China
^f Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Science, East China Normal UniversityShanghai 200062, China
^g Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^h Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, 311121, China

Abstract
Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine’s antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine’s antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.

Document Type: Article
Publication Stage: Final
Source: Scopus

Stroke Severity, Caregiver Feedback, and Cognition in the REGARDS-CARES Study
(2024) Journal of the American Heart Association, 13 (15), p. e033375. 

Blake, J.A.^a , Long, D.L.^b , Knight, A.J.^c , Goodin, B.R.^d , Crowe, M.^a , Judd, S.E.^b , Rhodes, J.D.^b , Roth, D.L.^e , Clay, O.J.^a f

^a Department of Psychology University of Alabama at Birmingham Birmingham AL
^b Department of Biostatistics University of Alabama at Birmingham Birmingham AL
^c Department of Neurology University of Alabama at Birmingham Birmingham AL
^d Department of Anesthesiology Washington University in St. Louis St. Louis MO
^e Center on Aging and Health Johns Hopkins School of Medicine Baltimore MD
^f Alzheimer’s Disease Research Center University of Alabama at Birmingham Birmingham AL

Abstract
BACKGROUND: Cognitive impairment after stroke is common and is present in up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of 2 stroke severity ratings and a caregiver-report of poststroke functioning with longitudinal cognitive outcomes. METHODS AND RESULTS: One hundred fifty-seven caregivers and stroke survivor dyads participated in the CARES (Caring for Adults Recovering From the Effects of Stroke) project, an ancillary study of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) national cohort study. The Glasgow Outcome Scale and modified Rankin Scale scores collected at hospitalization discharge were included as 2 primary predictors of cognitive impairment. The number of caregiver-reported problems and impairments at 9 months following stroke were included as a third predictor. Cognition was measured using a biennial telephone battery and included the domains of learning, memory, and executive functioning. Multiple cognitive assessments were analyzed up to 5 years poststroke, controlling for prestroke cognition and demographic variables of the stroke survivor. Separate mixed models showed significant main effects of the Glasgow Outcome Scale (b=0.3380 [95% CI, 0.14-0.5]; P=0.0009), modified Rankin Scale (b=-0.2119 [95% CI, -0.32 to -0.10]; P=0.0002), and caregiver-reported problems (b=-0.0671 [95% CI, -0.09 to -0.04]; P<0.0001) on longitudinal cognitive scores. In a combined model including all 3 predictors, only caregiver-reported problems significantly predicted cognition (b=-0.0480 [95% CI, -0.08 to -0.03]; P<0.0001). CONCLUSIONS: These findings emphasize the importance of caregiver feedback in predicting cognitive consequences of stroke.

Author Keywords
cognition;  prognosis;  prospective studies;  stroke care;  stroke severity

Document Type: Article
Publication Stage: Final
Source: Scopus

A Protocol for the Inclusion of Minoritized Persons in Alzheimer Disease Research From the ADNI3 Diversity Taskforce
(2024) JAMA network open, 7 (8), p. e2427073. 

Okonkwo, O.C.^a , Rivera Mindt, M.^b c , Ashford, M.T.^d e , Conti, C.^d e , Strong, J.^a , Raman, R.^f , Donohue, M.C.^f , Nosheny, R.L.^e g , Flenniken, D.^d e , Miller, M.J.^d e , Diaz, A.^d e , Soto, A.M.^c , Ances, B.M.^h , Beigi, M.R.ⁱ , Doraiswamy, P.M.^j , Duara, R.^k l m , Farlow, M.R.ⁿ , Grossman, H.T.^o , Mintzer, J.E.^p , Reist, C.^q r s , Rogalski, E.J.^t , Sabbagh, M.N.^u , Salloway, S.^v , Schneider, L.S.^w , Shah, R.C.^x , Petersen, R.C.^y , Aisen, P.S.^f , Weiner, M.W.^{d e g z aa ab} , Alzheimer’s Disease Neuroimaging Initiative^ac

^a Department of Medicine and Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, United States
^b Department of Psychology, Latin American Latinx Studies Institute, African and African American Studies, Fordham University, Bronx, NY, United States
^c Department of Neurology, Icahn School of Medicine at Mount SinaiNY, United States
^d Northern California Institute for Research and Education, Department of Veterans Affairs Medical Center, San Francisco, Mexico
^e VA Advanced Imaging Research Center, San Francisco Veteran’s Administration Medical Center, San Francisco, CA, United States
^f Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, Mexico
^g Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, Mexico
^h Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri
ⁱ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Mexico
^j Departments of Psychiatry and Medicine, Duke University School of Medicine, Durham, NC, United States
^k Wein Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami BeachFL, Puerto Rico
^l Herbert Wertheim College of Medicine, Florida International University, Miami, United States
^m Alzheimer’s Disease Research Center, University of Florida College of Medicine, Gainesville, United States
ⁿ Department of Neurology, Indiana University Health, Indianapolis, United States
^o Alzheimer Disease Research Center, Mount Sinai School of MedicineNY, United States
^p Medical University of South Carolina, Ralph H. Johnson VA Healthcare Center, Charleston, United States
^q MindX Sciences Inc, Indianapolis, IN, United States
^r Science 37 Inc, Durham, NC, United States
^s Department of Psychiatry, University of California Irvine, Long Beach
^t Department of Neurology, University of Chicago, Chicago, IL, United States
^u Alzheimer’s and Memory Disorders Division, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
^v Memory and Aging Program, Butler Hospital, Alpert Medical School, Brown University, Providence, RI, United States
^w Department of Psychiatry and Behavioral Sciences, Department of Neurology, Alzheimer’s Disease Research Center, Keck School of Medicine of USC, Los Angeles, CA, United States
^x Department of Family and Preventive Medicine and the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^y Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, United States
^z Department of Radiology and Biomedical Imaging, University of California, San Francisco, Mexico
^aa Department of Medicine, University of California, San Francisco, Mexico
^ab Department of Neurology, University of California, San Francisco, Mexico

Abstract
Importance: Black or African American (hereinafter, Black) and Hispanic or Latino/a/x (hereinafter, Latinx) adults are disproportionally affected by Alzheimer disease, but most research studies do not enroll adequate numbers of both of these populations. The Alzheimer’s Disease Neuroimaging Initiative-3 (ADNI3) launched a diversity taskforce to pilot a multipronged effort to increase the study inclusion of Black and Latinx older adults. Objective: To describe and evaluate the culturally informed and community-engaged inclusion efforts to increase the screening and enrollment of Black and Latinx older adults in ADNI3. Design, Setting, and Participants: This cross-sectional study used baseline data from a longitudinal, multisite, observational study conducted from January 15, 2021, to July 12, 2022, with no follow-up. The study was conducted at 13 ADNI3 sites in the US. Participants included individuals aged 55 to 90 years without cognitive impairment and those with mild cognitive impairment or Alzheimer disease. Exposures: Efforts included (1) launch of an external advisory board, (2) changes to the study protocol, (3) updates to the digital prescreener, (4) selection and deployment of 13 community-engaged research study sites, (5) development and deployment of local and centralized outreach efforts, and (6) development of a community-science partnership board. Main Outcomes and Measures: Screening and enrollment numbers from centralized and local outreach efforts, digital advertisement metrics, and digital prescreener completion. Results: A total of 91 participants enrolled in the trial via centralized and local outreach efforts, of which 22 (24.2%) identified as Latinx and 55 (60.4%) identified as Black (median [IQR] age, 65.6 [IQR, 61.5-72.5] years; 62 women [68.1%]). This represented a 267.6% increase in the monthly rate of enrollment (before: 1.11 per month; during: 4.08 per month) of underrepresented populations. For the centralized effort, social media advertisements were run between June 1, 2021, and July 31, 2022, which resulted in 2079 completed digital prescreeners, of which 1289 met criteria for subsequent site-level screening. Local efforts were run between June 1, 2021, to July 31, 2022. A total of 151 participants underwent site-level screening (100 from local efforts, 41 from centralized efforts, 10 from other sources). Conclusions and Relevance: In this cross-sectional study of pilot inclusion efforts, a culturally informed, community-engaged approach increased the inclusion of Black and Latinx participants in an Alzheimer disease cohort study.

Document Type: Article
Publication Stage: Final
Source: Scopus

Active mutual conjoint estimation of multiple contrast sensitivity functions
(2024) Journal of Vision, 24 (8), p. 6. 

Marticorena, D.C.P.^a b , Wong, Q.W.^a , Browning, J.^c , Wilbur, K.^c , Davey, P.G.^d e , Seitz, A.R.^f , Gardner, J.R.^g h , Barbour, D.L.^a

^a Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
^b dominic.m@wustl.edu
^c Department of Computer Science and Engineering, Washington University, St. Louis, MO, United States
^d College of Optometry, Western University of Health Sciences, Pomona, CA, United States
^e contact@pinakin-gunvant.com
^f Department of Psychology, Northeastern University, Boston, MA, United States
^g Department of Computer and Information Science, University of Pennsylvania, Philadelphia, PA, United States
^h jacobrg@seas.upenn.edu

Abstract
Recent advances in nonparametric contrast sensitivity function (CSF) estimation have yielded a new tradeoff between accuracy and efficiency not available to classical parametric estimators. An additional advantage of this new framework is the ability to independently tune multiple aspects of the estimator to seek further improvements. Machine learning CSF estimation with Gaussian processes allows for design optimization in the kernel, acquisition function, and underlying task representation, to name a few. This article describes a novel kernel for CSF estimation that is more flexible than a kernel based on strictly functional forms. Despite being more flexible, it can result in a more efficient estimator. Further, trial selection for data acquisition that is generalized beyond pure information gain can also improve estimator quality. Finally, introducing latent variable representations underlying general CSF shapes can enable simultaneous estimation of multiple CSFs, such as from different eyes, eccentricities, or luminances. The conditions under which the new procedures perform better than previous nonparametric estimation procedures are presented and quantified.

Document Type: Article
Publication Stage: Final
Source: Scopus

Traumatic Brain Injury, Seizures, and Cognitive Impairment Among Older Adults
(2024) JAMA network open, 7 (8), p. e2426590. 

Zhu, Y.^a , Williams, J.^b , Beyene, K.^c , Trani, J.-F.^d e f g , Babulal, G.M.^b e f h

^a School of Social Work, Adelphi University, Garden City, NY, United States
^b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in St Louis, St Louis, MO, United States
^d National Conservatory of Arts and Crafts, Paris, France
^e Institute of Public Health, Washington University School of Medicine, St Louis, MO, United States
^f Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
^g Brown School of Social Work, Washington University in St Louis, St Louis, MO, United States
^h Department of Clinical Research and Leadership, George Washington University School of Medicine and Health SciencesWA, United States

Abstract
Importance: Traumatic brain injury (TBI), seizures, and dementia increase with age. There is a gap in understanding the associations of TBI, seizures, and medications such as antiseizure and antipsychotics with the progression of cognitive impairment across racial and ethnic groups. Objective: To investigate the association of TBI and seizures with the risk of cognitive impairment among cognitively normal older adults and the role of medications in moderating the association. Design, Setting, and Participants: This multicenter cohort study was a secondary analysis of the Uniform Data Set collected between June 1, 2005, and June 30, 2020, from the National Alzheimer’s Coordination Center. Statistical analysis was performed from February 1 to April 3, 2024. Data were collected from participants from 36 Alzheimer’s Disease Research Centers in the US who were 65 years or older at baseline, cognitively normal at baseline (Clinical Dementia Rating of 0 and no impairment based on a presumptive etiologic diagnosis of AD), and had complete information on race and ethnicity, age, sex, educational level, and apolipoprotein E genotype. Exposure: Health history of TBI, seizures, or both conditions. Main Outcomes and Measures: Progression to cognitive impairment measured by a Clinical Dementia Rating greater than 0. Results: Among the cohort of 7180 older adults (median age, 74 years [range, 65-102 years]; 4729 women [65.9%]), 1036 were African American or Black (14.4%), 21 were American Indian or Alaska Native (0.3%), 143 were Asian (2.0%), 332 were Hispanic (4.6%), and 5648 were non-Hispanic White (78.7%); the median educational level was 16.0 years (range, 1.0-29.0 years). After adjustment for selection basis using propensity score weighting, seizure was associated with a 40% higher risk of cognitive impairment (hazard ratio [HR], 1.40; 95% CI, 1.19-1.65), TBI with a 25% higher risk of cognitive impairment (HR, 1.25; 95% CI, 1.17-1.34), and both seizure and TBI were associated with a 57% higher risk (HR, 1.57; 95% CI, 1.23-2.01). The interaction models indicated that Hispanic participants with TBI and seizures had a higher risk of cognitive impairment compared with other racial and ethnic groups. The use of antiseizure medications (HR, 1.23; 95% CI, 0.99-1.53), antidepressants (HR, 1.32; 95% CI, 1.17-1.50), and antipsychotics (HR, 2.15; 95% CI, 1.18-3.89) was associated with a higher risk of cognitive impairment, while anxiolytic, sedative, or hypnotic use (HR, 0.88; 95% CI, 0.83-0.94) was associated with a lower risk. Conclusions and Relevance: This study highlights the importance of addressing TBI and seizures as risk factors for cognitive impairment among older adults. Addressing the broader social determinants of health and bridging the health divide across various racial and ethnic groups are essential for the comprehensive management and prevention of dementia.

Document Type: Article
Publication Stage: Final
Source: Scopus

Is Mild Really Mild?: Generating Longitudinal Profiles of Stroke Survivor Impairment and Impact Using Unsupervised Machine Learning
(2024) Applied Sciences (Switzerland), 14 (15), art. no. 6800, . 

Adikari, A.^a , Nawaratne, R.^a , De Silva, D.^a , Carey, D.L.^b , Walsh, A.^c d , Baum, C.^c e , Davis, S.^f , Donnan, G.A.^f , Alahakoon, D.^a , Carey, L.M.^c d

^a Centre for Data Analytics and Cognition, La Trobe University, Melbourne, VIC 3086, Australia
^b Sports Analytics, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC 3086, Australia
^c Occupational Therapy, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne, VIC 3086, Australia
^d Neurorehabilitation and Recovery, The Florey Institute, Melbourne, VIC 3084, Australia
^e Occupational Therapy, School of Medicine, Washington University, St. Louis, MO 63110, United States
^f Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3052, Australia

Abstract
The National Institute of Health Stroke Scale (NIHSS) is used worldwide to classify stroke severity as ‘mild’, ‘moderate’, or ‘severe’ based on neurological impairment. Yet, stroke survivors argue that the classification of ‘mild’ does not represent the holistic experience and impact of stroke on their daily lives. In this observational cohort study, we aimed to identify different types of impairment profiles among stroke survivors classified as ‘mild’. We used survivors of mild stroke’ data from the START longitudinal stroke cohort (n = 73), with measures related to sensorimotor, cognition, depression, functional disability, physical activity, work, and social adjustment over 12 months. Given the multisource, multigranular, and unlabeled nature of the data, we utilized a structure-adapting, unsupervised machine learning approach, the growing self-organizing map (GSOM) algorithm, to generate distinct clinical profiles. These diverse impairment profiles revealed that survivors of mild stroke experience varying degrees of impairment and impact (cognitive, depression, physical activity, work/social adjustment) at different time points, despite the uniformity implied by their NIHSS-classified ‘mild’ stroke. This emphasizes the necessity of creating a holistic and more comprehensive representation of survivors of mild stroke’ needs over the first year after stroke to improve rehabilitation and poststroke care. © 2024 by the authors.

Author Keywords
artificial intelligence;  mild stroke;  patient profiling;  personalized healthcare;  unsupervised learning

Funding details
La Trobe Law School, La Trobe University
Commonwealth Scientific and Industrial Research OrganisationCSIRO
Melanoma Centre of Research Excellence1113352, 1077898, 1153236
Melanoma Centre of Research Excellence
National Health and Medical Research CouncilNHMRC2004443
National Health and Medical Research CouncilNHMRC
James N. Kirby FoundationJNKF220020413
James N. Kirby FoundationJNKF

Document Type: Article
Publication Stage: Final
Source: Scopus

NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma
(2024) Neuro-Oncology, 26 (8), pp. 1496-1508. 

Anastasaki, C.^a , Chatterjee, J.^a , Koleske, J.P.^a , Gao, Y.^a , Bozeman, S.L.^a , Kernan, C.M.^a , Marco Y Marquez, L.I.^a , Chen, J.-K.^a , Kelly, C.E.^b , Blair, C.J.^b , Dietzen, D.J.^b , Kesterson, R.A.^c , Gutmann, D.H.^a

^a Departments of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^b Department of Pathology & Immunology, Washington University, School of Medicine, St. Louis, MO, United States
^c Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States

Abstract
Background: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. Methods: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. Results: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. Conclusions: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG. © 2024 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Author Keywords
lamotrigine;  midkine;  neuronal excitability;  NF1;  optic glioma

Funding details
WITH Foundation
Gilbert Family FoundationGFF
Molecular Engineering Materials Center, University of WashingtonMEM-C
Erasmus MC Vriendenfonds
National Institutes of HealthNIHR35NS097211, R50CA233164
National Institutes of HealthNIH
P30-CA091842
National Eye InstituteNEIP30EY002687
National Eye InstituteNEI
National Cancer InstituteNCI1R01CA261939
National Cancer InstituteNCI

Document Type: Article
Publication Stage: Final
Source: Scopus

The Effects of Satisfaction With Different Domains of Life on General Life Satisfaction Vary Between Individuals (but We Cannot Tell You Why)
(2024) Collabra: Psychology, 10 (1), art. no. 121238, . 

Rohrer, J.^a , Seifert, I.S.^a , Arslan, R.C.^a , Sun, J.^b , Schmukle, S.C.^a

^a Wilhelm Wundt Institute for Psychology, Leipzig University, Leipzig, Germany
^b Department of Psychological & Brain Sciences, Washington University in St. LouisMO, United States

Abstract
People care about different domains of life (e.g., their health, social life, work) to varying degrees. It thus seems plausible that how satisfied they are with those domains matters for their general life satisfaction to varying degrees. This idea has been investigated in the importance-weighting literature with at best mixed results, but variations of it can be found across different fields of psychology and include claims that values, personality, and age moderate the extent to which different life domains affect life satisfaction. In this study, we investigated the effects of satisfaction with 14 different life domains on general life satisfaction in a study of 439 individuals who provided up to 15 diary entries, resulting in a total of 6,071 observations. All domains had positive effects on average, with the largest effects for satisfaction with leisure time usage (b = 0.19, bstd = 0.25 relative to the within-person variability) and relationship satisfaction (b = 0.16, bstd = 0.17). Beyond these averages, there was robust interindividual variability; the standard deviation of the individual-level effects was of a similar magnitude as the average effect (and sometimes even larger). But when exploring correlations between these individual-level effects with third variables (e.g., self-reported importance of the respective domain, gender and age, Big Five personality traits), no convincing overall patterns arose. This may at least in part result from the high uncertainty with which individual-level effects were estimated, with reliabilities of ~.30, and the resulting low statistical power. © 2024 University of California Press. All rights reserved.

Author Keywords
diary study;  domain satisfaction;  importance weighting;  life satisfaction

Funding details
Universität Leipzig

Document Type: Article
Publication Stage: Final
Source: Scopus

Lacosamide and Levetiracetam Are Not Toxic to the Developing Mouse Brain
(2024) Annals of Neurology, . 

Noguchi, K.K.^a , Palmer, C.W.^a , Fuhler, N.A.^a , Neblock, E.^a , Fotedar, M.^a , Ikonomidou, C.^b

^a Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States
^b Department of Neurology, University of Wisconsin, School of Medicine, Madison, WI, United States

Abstract
Many antiseizure medications cause apoptotic cell death in developing brains. The newer antiseizure medication lacosamide is increasingly used in neonates and infants. Neurotoxicity of lacosamide and its combination with levetiracetam was studied in neonatal mice. Animals received single or repeat injections of saline, phenobarbital (75mg/kg), lacosamide (20–40mg/kg), levetiracetam (100mg/kg), lacosamide (40mg/kg) + levetiracetam (100mg/kg) and euthanized at 6 to 30 hours. Cells undergoing apoptosis were increased in the brains of phenobarbital-treated animals. Densities of apoptotic profiles following lacosamide and levetiracetam treatment did not differ from saline-treated controls. Findings suggest that lacosamide, levetiracetam and their combination do not cause apoptosis in developing mouse brains. ANN NEUROL 2024. © 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Funding details
Dr. Cyrus and Myrtle Katzen Cancer Research Center, George Washington University
Institute for Clinical and Translational Research, University of Wisconsin, MadisonUW ICTR
Nihon Kohden America
Department of Neurology, University of Pittsburgh
P50‐HD103525

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

Extended nnU-Net for Brain Metastasis Detection and Segmentation in Contrast-Enhanced Magnetic Resonance Imaging With a Large Multi-Institutional Data Set
(2024) International Journal of Radiation Oncology Biology Physics, . 

Yoo, Y.^a , Gibson, E.^a , Zhao, G.^a , Re, T.J.^a , Parmar, H.^b , Das, J.^a , Wang, H.^c , Kim, M.M.^d , Shen, C.^e , Lee, Y.^f , Kondziolka, D.^g , Ibrahim, M.^b , Lian, J.^e , Jain, R.^h , Zhu, T.ⁱ , Comaniciu, D.^a , Balter, J.M.^d , Cao, Y.^d

^a Siemens Healthineers, Digital Technology and Innovation, Princeton, New Jersey, United States
^b Department of Radiology, University of Michigan, Ann Arbor, MI, United States
^c Department of Radiation Oncology, New York University, New York, New York, United States
^d Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
^e Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, United States
^f Department of Radiology, University of North Carolina, Chapel Hill, NC, United States
^g Center for Advanced Radiosurgery, New York University, New York, New York, United States
^h Department of Radiology, New York University, New York, New York, United States
ⁱ Department of Radiation Oncology, Washington University, St. Louis, Missouri, United States

Abstract
Purpose: The purpose of this study was to investigate an extended self-adapting nnU-Net framework for detecting and segmenting brain metastases (BM) on magnetic resonance imaging (MRI). Methods and Materials: Six different nnU-Net systems with adaptive data sampling, adaptive Dice loss, or different patch/batch sizes were trained and tested for detecting and segmenting intraparenchymal BM with a size ≥2 mm on 3 Dimensional (3D) post-Gd T1-weighted MRI volumes using 2092 patients from 7 institutions (1712, 195, and 185 patients for training, validation, and testing, respectively). Gross tumor volumes of BM delineated by physicians for stereotactic radiosurgery were collected retrospectively and curated at each institute. Additional centralized data curation was carried out to create gross tumor volumes of uncontoured BM by 2 radiologists to improve the accuracy of ground truth. The training data set was augmented with synthetic BMs of 1025 MRI volumes using a 3D generative pipeline. BM detection was evaluated by lesion-level sensitivity and false-positive (FP) rate. BM segmentation was assessed by lesion-level Dice similarity coefficient, 95-percentile Hausdorff distance, and average Hausdorff distance (HD). The performances were assessed across different BM sizes. Additional testing was performed using a second data set of 206 patients. Results: Of the 6 nnU-Net systems, the nnU-Net with adaptive Dice loss achieved the best detection and segmentation performance on the first testing data set. At an FP rate of 0.65 ± 1.17, overall sensitivity was 0.904 for all sizes of BM, 0.966 for BM ≥0.1 cm3, and 0.824 for BM &lt;0.1 cm3. Mean values of Dice similarity coefficient, 95-percentile Hausdorff distance, and average HD of all detected BMs were 0.758, 1.45, and 0.23 mm, respectively. Performances on the second testing data set achieved a sensitivity of 0.907 at an FP rate of 0.57 ± 0.85 for all BM sizes, and an average HD of 0.33 mm for all detected BM. Conclusions: Our proposed extension of the self-configuring nnU-Net framework substantially improved small BM detection sensitivity while maintaining a controlled FP rate. Clinical utility of the extended nnU-Net model for assisting early BM detection and stereotactic radiosurgery planning will be investigated. © 2024 Elsevier Inc.

Funding details
Amazon Web ServicesAWS
Nihon Kohden AmericaR01 CA262182-01
Nihon Kohden America

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

Evaluation of inpatient and emergency department healthcare resource utilization and costs pre-and post-nusinersen for the treatment of spinal muscular atrophy using United States claims
(2024) Journal of Comparative Effectiveness Research, 13 (7), art. no. e230187, . 

Zhu, C.^a , Zaidman, C.^b , Youn, B.^a , Paradis, A.D.^a , Raynaud, S.^a , Neville, B.A.^a , Johnson, N.B.^a

^a Biogen, Cambridge, MA 02142, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Aim: Nusinersen, administered by intrathecal injection at a dose of 12 mg, is indicated across all ages for the treatment of spinal muscular atrophy (SMA). Evidence on real-world healthcare resource use (HRU) and costs among patients taking nusinersen remains limited. This study aimed to evaluate real-world HRU and costs associated with nusinersen use through US claims databases. Patients &amp; methods: Using the Merative™ MarketScanR○ Research Databases, patients with SMA receiving nusinersen were identified from commercial (January 2017 to June 2020) and Medicaid claims (January 2017 to December 2019). Those likely to have complete information on the date of nusinersen initiation and continuous enrollment 12 months pre-and post-index (first record of nusinersen treatment) were retained. Number and costs (US$ 2020) of inpatient admissions and emergency department (ED) visits, unrelated to nusinersen administration, were evaluated for 12 months pre-and post-nusinersen initiation and stratified by age: pediatric (&lt;18 years) and adult (≥18 years). Results: Overall, 103 individuals treated with nusinersen were retained: 59 were pediatric (mean age [range]: 9 [1–17] years), and 44 were adults (30 [18–63] years). Inpatient admissions decreased by 41% for pediatrics and 67% for adults in the 12 months post-treatment versus the 12 months pre-treatment. Average inpatient admission costs per patient for the pediatric cohort decreased by 63% ($22,903 vs $8466) and by 79% ($13,997 vs $2899) for the adult cohort when comparing the 12 months pre-index with the 12 months post-index period. Total ED visits and ED visit costs decreased by 8% and 35%, respectively, for the overall cohort over the 12-month period pre-and post-index. Conclusion: Using US claims databases, nusinersen treatment in pediatric and adult patients was associated with reductions in HRU and costs over a 12-month period post-treatment initiation relative to the pre-treatment period. Plain language summary: What is this article about/what is the aim of the research?: Spinal muscular atrophy (SMA) is an inherited disease affecting mainly infants and children, but it can also present in adults. This condition damages nerve cells and muscles that control key activities, such as sitting, walking, speaking, swallowing and breathing. Nusinersen was the first drug approved in the US to help manage SMA. It is administered by injection with a thin needle into a space in the lower back, below the end of the spinal cord, through a medical procedure known as a “lumbar puncture”. There is very little information on the medical management for people with SMA receiving nusinersen. Using insurance claims processed in the US, this study assessed trends in hospital stays, in emergency department (ED) visits and in related medical costs before and after nusinersen use. What were the results?: Comparing the 12 months before nusinersen treatment with the 12 months following treatment, the number of hospital stays was 41% lower for children and 67% lower for adults after treatment. The average cost per person associated with hospital stays was 63% lower for children and 79% lower for adults. The number of days spent at the hospital was also reduced for all ages following nusinersen treatment. The number of ED visits and the resulting costs were 8% and 35% lower, respectively, for the overall cohort. What do these results mean?: Overall, nusinersen treatment lessens the burden of disease among people with SMA in the US by lowering the rate of hospital stays and ED visits, and by reducing associated costs. © 2024 The Authors.

Author Keywords
commercial and Medicaid claims;  healthcare resource utilization;  medical cost offsets;  nusinersen;  patient-level claims;  spinal muscular atrophy

Funding details
Biogen
Novartis Gene Therapies

Document Type: Article
Publication Stage: Final
Source: Scopus

Evidence for Environmental Risk Factors and Cumulative Stress Linking Racial/Ethnic Identity and Psychotic-Like Experiences in ABCD Study Data
(2024) Journal of the American Academy of Child and Adolescent Psychiatry, . Cited 1 time.

Petti, E.^a , Schiffman, J.^a , Oh, H.^b , Karcher, N.R.^c

^a University of California, Irvine, California, United States
^b University of Southern California Suzanne Dworak-Peck School of Social Work, Los Angeles, California, United States
^c Washington University School of Medicine, St. Louis, Missouri, United States

Abstract
Objective: Previous work has found increased endorsement of psychotic-like experiences (PLEs) among marginalized racial and ethnic groups. According to social determinants frameworks, marginalized groups are at increased risk for exposure to socio-environmental risk factors, including systemic factors (eg, poverty and poor housing conditions) and social stressors (eg, discrimination). We examine the extent to which environmental risk factors and stress account for associations between racial/ethnic groups with PLEs. Method: Analyses included 11,876 young adolescents 9 to 10 years of age from the Adolescent Brain Cognitive Development (ABCD) study. Mediation models assessed whether stress at 1-year follow-up indirectly linked baseline environmental risk to later distressing PLEs at 2-year follow-up. Serial mediation models examined whether environmental risk and stress indirectly accounted for variation among racial/ethnic groups in self-reported distressing PLEs. Results: Through principal component and mediation analyses, we found evidence that the link between environmental risk (eg, poverty and exposure to crime) and distressing PLEs was mediated by stress. There was also evidence that higher endorsement of distressing PLEs within the Black and Hispanic groups was serially mediated by greater environmental risk and greater stress. Conclusion: The analyses provide evidence that the associations between marginalized racial and ethnic identities with the endorsement of PLEs partially reflects the sequelae of systemic socio-environmental factors. Findings suggest the potential for intervening upon environmental risk factors to target the reduction of cumulative stress over time, which may in turn buffer against the development of PLEs. Plain Language Summary: Using longitudinal data from 11,876 young adolescents aged 9-10 from the Adolescent Brain Cognitive Development (ABCD) study, this study examined environmental (e.g., poverty) and stress-related factors (e.g., experiences of discrimination, childhood adversity) that are associated with psychotic-like experiences, and whether these factors explain racial/ethnic differences in psychotic-like experiences. The authors found evidence that the association between these environmental risk factors and psychotic-like experiences is partially explained by cumulative stress, and that differences in psychotic-like experiences across racial/ethnic groups were accounted for by both environmental risk factors and stress. Results highlight that systemic factors may explain higher levels of psychotic-like experiences among historically marginalized racial/ethnic groups. Findings suggest the potential for intervening upon modifiable risk factors to buffer against stress, and in turn, the development of psychotic-like experiences over time. Diversity Inclusion Statement: We worked to ensure sex and gender balance 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 sex and gender balance in our author group. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. © 2024 American Academy of Child and Adolescent Psychiatry

Author Keywords
environment;  ethnicity;  psychotic-like experiences;  race;  stress

Funding details
M00B2600258, U01MH124639, R01MH112612, R34 MH126063, R01MH1200901A1
Together Women RiseCV-5692169
National Institutes of HealthNIHU01DA041174, U01DA041148, U01DA041022, U01DA041025, U01DA041120, U01DA041028, U24DA041123, U01DA041048, U01DA041089, U01DA041093, U01DA041117, U01DA041156, U01DA041134, U01DA041106, U24DA041147
1H79SM084536-01, HHS00095-01
National Institute of Mental HealthNIMHK23MH121792-01

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

Use of Electroconvulsive Therapy in Children and Adolescents with Catatonia – A Case Series
(2024) Journal of ECT, . 

Pal, R., Cheng, T., Eddington, S., Subramanian, S., Wenzinger, M., Cristancho, P.

Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background Electroconvulsive therapy (ECT) is highly efficacious in catatonia yet remains underutilized in pediatric patients. Practice guidelines recommend bilateral placement in cases with urgent need for response such as catatonia. Because of significantly lower cognitive burden and efficacy (compared to bilateral), right unilateral placement (RUL) is preferred for major depression. Increasing literature shows RUL is effective for catatonia in adults, but its use in catatonic youth is largely unknown. Objectives The aims of the study are to describe naturalistic outcomes of ECT in pediatric patients with catatonia and to discuss ECT parameter considerations. Methods This is a retrospective chart review of patients under 18-years of age at Saint Louis Children’s Hospital with diagnosis of catatonia who received ECT from 2019 to November 2023. All cases received ECT per clinical protocol. Catatonic symptoms were monitored using the Busch Francis Catatonia Scale. Institutional review board approved the study. Results Twelve inpatients with debilitating catatonia and a failed benzodiazepine trial underwent ECT. Ten of these 12 patients initiated RUL placement, one received bifrontal, and another bilateral. All patients achieved resolution of catatonia: 6 patients with RUL alone and 4 who started with RUL later switched to bilateral due to nonresponse. The patient receiving bifrontal switched to bilateral due to nonresponse. Patients with malignant catatonia preferentially responded to bilateral placement. Patients experienced expected side effects from ECT. Conclusions RUL ECT was effective for catatonia in pediatric patients and can be considered as initial placement. A switch to bilateral can be considered in nonresponse, similar to current approach for major depression. For malignant catatonia, bilateral placement remains preferential. © Copyright 2024 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
benzodiazepines;  catatonia;  ECT;  electroconvulsive therapy;  pediatrics

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

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment
(2024) JAMA Neurology, pp. E1-E11. 

Janelidze, S.^a , Barthélemy, N.R.^b c , Salvadó, G.^a , Schindler, S.E.^b c d , Palmqvist, S.^a e , Mattsson-Carlgren, N.^a f g , Braunstein, J.B.^h , Ovod, V.^b c , Bollinger, J.G.^b c , He, Y.^b c , Li, Y.^b c , Raji, C.A.ⁱ , Morris, J.C.^b , Holtzman, D.M.^j , Ashton, N.J.^k l m n , Blennow, K.^k o p , Stomrud, E.^a e , Bateman, R.J.^b c , Hansson, O.^a e

^a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
^b Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^c The Tracy Family SILQ Center, St Louis, MO, United States
^d The Knight ADRC, Washington University School of Medicine, St Louis, MO, United States
^e Memory Clinic, Skåne University Hospital, Malmö, Sweden
^f Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
^g Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
^h C2N Diagnostics, St Louis, MO, United States
ⁱ Department of Radiology and Neurology, Washington University in St Louis, St Louis, MO, United States
^j Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University in St Louis, St Louis, MO, United States
^k Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
^l Wallenberg Centre for Molecular Medicine, University of Gothenburg, Gothenburg, Sweden
^m King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute, Clinical Neuroscience Institute, London, United Kingdom
ⁿ NIHR Biomedical Research Centre for Mental Health, Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, United Kingdom
^o Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
^p Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden

Abstract
Importance: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ. Objective: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline. Design, Setting, and Participants: This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024. Exposures: Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Main Outcomes and Measures: Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology. Results: This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve =0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aβ42/40: β = -2.14; 95% CI, -2.79 to -1.49; P <.001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aβ42/40: β = -0.31; 95% CI, -0.44 to -0.18; P <.001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P =.002; Aβ42/40: β = -0.74; 95% CI, -1.26 to -0.22; P =.006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = -0.0003; 95% CI, -0.0004 to -0.0001; P =.01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P <.001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Conclusions and Relevance: Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials. © 2024 American Medical Association. All rights reserved.

Funding details
GE Healthcare
Henrietta B. and Frederick H. Bugher Foundation
Horizon 2020 Framework ProgrammeH2020
Harald och Greta Jeanssons Stiftelse
FLÄK Research School, Lunds UniversityFLÄK
GHR FoundationGHR
Sahlgrenska University Hospitals Research Foundations2020-O000028
Sahlgrenska University Hospitals Research Foundations
Alzheimer’s SocietyZEN24-1069572, SG-23-1061717
Alzheimer’s Society
Banner Alzheimer’s FoundationFRS-0003
Banner Alzheimer’s Foundation
European Research CouncilERCADG-101096455
European Research CouncilERC
EU Joint Programme – Neurodegenerative Disease ResearchJPND2019-03401
EU Joint Programme – Neurodegenerative Disease ResearchJPND
Helse Vest Regionalt Helseføretak2022-1259
Helse Vest Regionalt Helseføretak
Marie-Claire Cronstedts Stiftelse101061836, -22-972612
Marie-Claire Cronstedts Stiftelse
Swedish Cancer FoundationFO2023-0163, FO2021-0293, AF-994229, AF-980907, AF-980942
Swedish Cancer Foundation
National Institute on AgingNIAR01AG083740, R01AG070941, P30 AG066444, P01AG003991, P01AG026276
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDFGC-201711-2013978
Alzheimer’s Drug Discovery FoundationADDF
WASP/DDLS22-066
Sweden-Japan FoundationSJF1412/22
Sweden-Japan FoundationSJF
Nihon SuperiorCA2016636, R44 AG059489
Nihon Superior
Knut och Alice Wallenbergs Stiftelse2022-0231
Knut och Alice Wallenbergs Stiftelse
Swedish Foundation for MS Research2022-00775, 2018-02052, ERAPERMED2021-184, 2021-02219
Swedish Foundation for MS Research
Swedish Brain PowerSBP2022-Projekt0080, 2022-Projekt0107
Swedish Brain PowerSBP

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

Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care
(2024) JAMA, . Cited 2 times.

Palmqvist, S.^a b , Tideman, P.^a b , Mattsson-Carlgren, N.^a c d , Schindler, S.E.^e , Smith, R.^a b , Ossenkoppele, R.^a f g , Calling, S.^h i , West, T.^j , Monane, M.^j , Verghese, P.B.^j , Braunstein, J.B.^j , Blennow, K.^k l m , Janelidze, S.^a , Stomrud, E.^a b , Salvadó, G.^a , Hansson, O.^a b

^a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
^b Memory Clinic, Skåne University Hospital, Malmö, Sweden
^c Neurology Clinic, Skåne University Hospital, Lund, Sweden
^d Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
^e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^f Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
^g Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands
^h Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
ⁱ University Clinic Primary Care, Skåne, Sweden
^j C2N Diagnostics LLC, St Louis, MO, United States
^k Paris Brain Institute, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
^l Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
^m Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden

Abstract
Importance: An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD. Objective: To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values. Design, Setting, and Participants: There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n = 307) and a secondary care cohort (n = 300); 1 plasma sample per patient was analyzed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n = 208) and in the secondary care cohort (n = 398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection. Exposure: Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-β 42 and amyloid-β 40 (Aβ42:Aβ40) plasma ratio (the amyloid probability score 2 [APS2]). Main Outcomes and Measures: The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aβ42:Aβ40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated. Results: The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology. When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%]). Conclusions and Relevance: The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care. © 2024 American Medical Association. All rights reserved.

Funding details
GE Healthcare
Alzheimer’s Society
Knut och Alice Wallenbergs Stiftelse
Sweden-Japan FoundationSJF
Cure Alzheimer’s FundCAF
Swedish Brain PowerSBP101061836
Swedish Brain PowerSBP
GHR FoundationGHRADG-101096455
GHR FoundationGHR
Swedish Cancer FoundationFO2023-0163, FO2021-0293, FO2022-0204, 1412/22, FRS-0003, FRS-0004
Swedish Cancer Foundation
EU Joint Programme – Neurodegenerative Disease ResearchJPND2022-1259, 2022-Projekt0080, 2022-Projekt0107, 22-066
EU Joint Programme – Neurodegenerative Disease ResearchJPND
European Research CouncilERC2022-00775, 2021-02219, 2018-02052
European Research CouncilERC
National Institute on AgingNIASG-23-1061717, ZEN24-1069572
National Institute on AgingNIA
FLÄK Research School, Lunds UniversityFLÄKAF-981132, AF-994229, AF-980907, AF-980942
FLÄK Research School, Lunds UniversityFLÄK
Stiftelsen Konung Gustaf V:s Jubileumsfond2020-O000028
Stiftelsen Konung Gustaf V:s Jubileumsfond
Horizon 2020 Framework ProgrammeH2020AARF-22-972612
Horizon 2020 Framework ProgrammeH2020
Swedish Foundation for MS Research2021-184, 2022-0231
Swedish Foundation for MS Research
Sahlgrenska University Hospitals Research Foundations2019-03401
Sahlgrenska University Hospitals Research Foundations

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

Neighborhood Resources Associated with Psychological Trajectories and Neural Reactivity to Reward after Trauma
(2024) JAMA Psychiatry, . 

Webb, E.K.^a b , Stevens, J.S.^c , Ely, T.D.^c , Lebois, L.A.M.^a b , Van Rooij, S.J.H.^c , Bruce, S.E.^d , House, S.L.^e , Beaudoin, F.L.^f g , An, X.^h , Neylan, T.C.ⁱ , Clifford, G.D.^j k , Linnstaedt, S.D.^h , Germine, L.T.^a l m , Bollen, K.A.^n o , Rauch, S.L.^a l p , Haran, J.P.^q , Storrow, A.B.^r , Lewandowski, C.^s , Musey, P.I., Jr^t , Hendry, P.L.^u , Sheikh, S.^u , Jones, C.W.^v , Punches, B.E.^w x , Swor, R.A.^y , Murty, V.P.^z , Hudak, L.A.^aa , Pascual, J.L.^ab ac , Seamon, M.J.^ac ad , Datner, E.M.^ae af , Pearson, C.^ag , Peak, D.A.^ah , Domeier, R.M.^ai , Rathlev, N.K.^aj , O’Neil, B.J.^ak , Sergot, P.^al , Sanchez, L.D.^am an , Joormann, J.^ao , Pizzagalli, D.A.^a b , Harte, S.E.^ap aq , Kessler, R.C.^ar , Koenen, K.C.^as , Ressler, K.J.^a b , McLean, S.A.^at au , Harnett, N.G.^a b

^a Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^b Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, United States
^c Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
^d Department of Psychological Sciences, University of Missouri-St Louis, St Louis, United States
^e Department of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
^f Department of Epidemiology, Brown University, Providence, RI, United States
^g Department of Emergency Medicine, Brown University, Providence, RI, United States
^h Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, United States
ⁱ Department of Psychiatry and Neurology, University of California San Francisco, San Francisco, United States
^j Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, gA, United States
^k Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, United States
^l Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
^m The Many Brains Project, Belmont, MA, United States
ⁿ Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, United States
^o Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, United States
^p Department of Psychiatry, McLean Hospital, Belmont, MA, United States
^q Department of Emergency Medicine, University of Massachusetts, Chan Medical School, Worcester, United States
^r Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^s Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
^t Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, United States
^u Department of Emergency Medicine, University of Florida College of Medicine Ͽ Jacksonville, Jacksonville, United States
^v Department of Emergency Medicine, Cooper Medical School, Rowan University, Camden, NJ, United States
^w Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, United States
^x Ohio State University, College of Nursing, Columbus, United States
^y Department of Emergency Medicine, Oakland University, William Beaumont School of Medicine, Rochester, MI, United States
^z Department of Psychology, Temple University, Philadelphia, PA, United States
^aa Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
^ab Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, United States
^ac Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^ad Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, United States
^ae Department of Emergency Medicine, Jefferson Einstein Hospital, Jefferson Health, Philadelphia, PA, United States
^af Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
^ag Department of Emergency Medicine, Wayne State University, Ascension St John Hospital, Detroit, MI, United States
^ah Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
^ai Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, United States
^aj Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, United States
^ak Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
^al Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, TX, United States
^am Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^an Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
^ao Department of Psychology, Yale University, New Haven, CT, United States
^ap Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, United States
^aq Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, United States
^ar Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^as Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
^at Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States
^au Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States

Abstract
Importance: Research on resilience after trauma has often focused on individual-level factors (eg, ability to cope with adversity) and overlooked influential neighborhood-level factors that may help mitigate the development of posttraumatic stress disorder (PTSD). Objective: To investigate whether an interaction between residential greenspace and self-reported individual resources was associated with a resilient PTSD trajectory (ie, low/no symptoms) and to test if the association between greenspace and PTSD trajectory was mediated by neural reactivity to reward. Design, Setting, and Participants: As part of a longitudinal cohort study, trauma survivors were recruited from emergency departments across the US. Two weeks after trauma, a subset of participants underwent functional magnetic resonance imaging during a monetary reward task. Study data were analyzed from January to November 2023. Exposures: Residential greenspace within a 100-m buffer of each participant’s home address was derived from satellite imagery and quantified using the Normalized Difference Vegetation Index and perceived individual resources measured by the Connor-Davidson Resilience Scale (CD-RISC). Main Outcome and Measures: PTSD symptom severity measured at 2 weeks, 8 weeks, 3 months, and 6 months after trauma. Neural responses to monetary reward in reward-related regions (ie, amygdala, nucleus accumbens, orbitofrontal cortex) was a secondary outcome. Covariates included both geocoded (eg, area deprivation index) and self-reported characteristics (eg, childhood maltreatment, income). Results: In 2597 trauma survivors (mean [SD] age, 36.5 [13.4] years; 1637 female [63%]; 1304 non-Hispanic Black [50.2%], 289 Hispanic [11.1%], 901 non-Hispanic White [34.7%], 93 non-Hispanic other race [3.6%], and 10 missing/unreported [0.4%]), 6 PTSD trajectories (resilient, nonremitting high, nonremitting moderate, slow recovery, rapid recovery, delayed) were identified through latent-class mixed-effect modeling. Multinominal logistic regressions revealed that for individuals with higher CD-RISC scores, greenspace was associated with a greater likelihood of assignment in a resilient trajectory compared with nonremitting high (Wald z test = -3.92; P &lt;.001), nonremitting moderate (Wald z test = -2.24; P =.03), or slow recovery (Wald z test = -2.27; P =.02) classes. Greenspace was also associated with greater neural reactivity to reward in the amygdala (n = 288; t277= 2.83; adjusted P value = 0.02); however, reward reactivity did not differ by PTSD trajectory. Conclusions and Relevance: In this cohort study, greenspace and self-reported individual resources were significantly associated with PTSD trajectories. These findings suggest that factors at multiple ecological levels may contribute to the likelihood of resiliency to PTSD after trauma. © 2024 American Medical Association. All rights reserved.

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

Predictors of Response to Cognitive Behavioral Therapy in Patients with Tinnitus
(2024) JAMA Otolaryngology – Head and Neck Surgery, art. no. 100659, . 

Mueller, L.^a b , Kallogjeri, D.^a e , Frumkin, M.R.^c , Dizdar, K.^a , Shin, J.^c , Rodebaugh, T.^d , Piccirillo, J.F.^a e

^a Department of Otolaryngology-Head and Neck Surgery, Washington University in St Louis School of Medicine, St Louis, MO, United States
^b School of Medicine, Tulane University, New Orleans, LA, United States
^c Department of Psychological and Brain Sciences, Washington University in St Louis School of Medicine, St Louis, MO, United States
^d Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, United States
^e JAMA Otolaryngology-Head and Neck Surgery, United States

Abstract
Importance: Clinical guidelines recommend cognitive behavioral therapy (CBT) as a treatment for tinnitus. However, patient response to CBT is variable, and currently, there are no known predictors of response to CBT treatment for tinnitus. Objective: To identify the clinical predictors of patient response to CBT for treatment of tinnitus. Design, Setting, and Participants: This was a secondary cohort analysis of a single-arm clinical study including adults with chronic bothersome tinnitus recruited from Washington University School of Medicine in St Louis (Missouri) from September 2019 to February 2023. Participants completed an 8-week group CBT program with a licensed clinical psychologist. Each week consisted of 2.5 hours of CBT, amounting to 20 hours of total CBT participation, primarily delivered through a virtual platform. Conjunctive consolidation was used to create a predictive classification system for response to CBT based on tinnitus bother and anxiety levels. Main Outcome and Measure: Response to CBT was predefined as a 13-point or greater decrease in the Tinnitus Functional Index (TFI) survey score. Results: The study sample included 88 adult patients (median [IQR] age, 59 [49-66] years; 47 [53%] females and 41 [47%] males) with chronic bothersome tinnitus, of whom 53 (60%) had at least 13-point decrease in TFI and were considered to be responders. In univariable and multivariable logistic regression analyses, high to moderate anxiety level and severe tinnitus bother were associated with treatment response (adjusted odds ratio: anxiety, 3.33; 95% CI, 0.90-12.30; tinnitus bother, 12.08; 95% CI, 1.48-98.35). The clinical stratification system showed good predictive and discriminative ability (χ2for linear trend = 20.0; C statistic = 0.75; 95% CI, 0.65-0.85). Conclusions and Relevance: The findings of this study show that assessment of bother and anxiety levels in patients with tinnitus may be useful for identifying those who are more likely to respond to CBT. Before incorporation into clinical practice, future research should externally validate this finding in a separate population. © 2024 American Medical Association. All rights reserved.

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