WashU weekly Neuroscience publications

Large posttraumatic stress disorder improvement and antidepressant medication adherence
(2020) Journal of Affective Disorders, 260, pp. 119-123. 

Salas, J.^{a b} , Scherrer, J.F.^{a b} , Tuerk, P.^c , van den Berk-Clark, C.^a , Chard, K.M.^d , Schneider, F.D.^e , Schnurr, P.P.^f , Friedman, M.J.^f , Norman, S.B.^g , Cohen, B.E.^h , Lustman, P.^{i j}

^a Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
^b Harry S. Truman Veterans Administration Medical Center, Columbia, MO, United States
^c Sheila C. Johnson Center for Clinical Services, Department of Human Services, University of Virginia, Charlottesville, VA, United States
^d Trauma Recovery Center Cincinnati VAMC and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States
^e Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
^f National Center for PTSD and Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
^g National Center for PTSD, VA Center of Excellence for Stress and Mental Health and Department of Psychiatry, University of California San Diego, United States
^h Department of Medicine, University of California San Francisco School of Medicine and San Francisco VAMC, San Francisco, CA, United States
ⁱ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^j The Bell Street Clinic Opioid Treatment Program, Mental Health Service, VA St. Louis Health Care System, St. Louis, MO, United States

Abstract
Background: Patients with vs. without posttraumatic stress disorder (PTSD) are more likely to have poor antidepressant medication (ADM) adherence but it is unclear if improved PTSD is associated with ADM adherence. We determined if clinically meaningful PTSD symptom reduction was associated with ADM adherence. Methods: Electronic health record data (2008–2015) was obtained from 742 Veterans Health Affairs (VHA) patients using PTSD specialty clinics with a PTSD diagnosis and PTSD checklist (PCL) score ≥50. The last PCL in the exposure year after the first PCL≥50 was used to identify patients with a clinically meaningful PCL decrease (≥20 point) versus those without (< 20 point). Patients had a depression diagnosis in the 12-months before the exposure year and received an ADM in the exposure year. Proportion of days covered ≥80% in exposure year defined adherence. Confounding was controlled using propensity scores and inverse probability of treatment weighting. Results: Patients were 42.2 ± 13.1 years of age, 63.9% white and 18.9% had a clinically meaningful PCL decrease. After controlling for confounding variables, patients with vs. without a clinically meaningful PCL decrease were significantly more likely to be adherent (OR = 1.78; 95% CI:1.16–2.73). However, adherence remained low in both patients with and without meaningful PCL decrease (53.5% vs. 39.3%). Limitations: The sample was limited to VHA patients. Patients may not have taken medication as prescribed. Conclusions: Large reductions in PTSD symptoms are associated with ADM adherence. Prior literature suggests ADM adherence improves depression symptoms. Thus, PTSD symptom reduction may lead to better depression outcomes. © 2019 Elsevier B.V.

Author Keywords
Antidepressant medication adherence;  Depression;  PTSD symptoms

Document Type: Article
Publication Stage: Final
Source: Scopus

A mechanism for synaptic copy between neural circuits
(2019) Neural Computation, 31 (10), pp. 1964-1984. 

Shao, Y.^a , Wang, B.^{a b} , Sornborger, A.T.^c , Tao, L.^d

^a Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, School of Life Sciences, Peking University, Beijing, 100871, China
^b Washington University, St. Louis, MO 63130, United States
^c Information Sciences, Los Alamos National Laboratory, Los Alamos, NM 87545, United States
^d Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, School of Life Sciences, and Center for Quantitative Biology, Peking University, Beijing, 100871, China

Abstract
Cortical oscillations are central to information transfer in neural systems. Significant evidence supports the idea that coincident spike input can allow the neural threshold to be overcome and spikes to be propagated downstream in a circuit. Thus, an observation of oscillations in neural circuits would be an indication that repeated synchronous spiking may be enabling information transfer. However, for memory transfer, in which synaptic weights must be being transferred from one neural circuit (region) to another, what is the mechanism? Here, we present a synaptic transfer mechanism whose structure provides some understanding of the phenomena that have been implicated in memory transfer, including nested oscillations at various frequencies. The circuit is based on the principle of pulse-gated, graded information transfer between neural populations. © 2019 Massachusetts Institute of Technology.

Document Type: Letter
Publication Stage: Final
Source: Scopus

Correlation Between Brain Tissue Damage and Inertial Cavitation Dose Quantified Using Passive Cavitation Imaging
(2019) Ultrasound in Medicine and Biology, 45 (10), pp. 2758-2766. 

Xu, S.^{a b} , Ye, D.^c , Wan, L.^b , Shentu, Y.^b , Yue, Y.^b , Wan, M.^a , Chen, H.^{b d}

^a The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Mechanical Engineering and Material Science, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Focused ultrasound (FUS)-induced cavitation-mediated brain therapies have become emerging therapeutic modalities for neurologic diseases. Cavitation monitoring is essential to ensure the safety of all cavitation-mediated therapeutic techniques as inertial cavitation can be associated with tissue damage. The objective of this study was to reveal the correlation between the inertial cavitation dose, quantified by passive cavitation imaging (PCI), and brain tissue histologic-level damage induced by FUS in combination with microbubbles. An ultrasound image-guided FUS system consisting of a single-element FUS transducer (1.5 MHz) and a co-axially aligned 128-element linear ultrasound imaging array was used to perform FUS treatment of mice. Mice were sonicated by FUS with different peak negative pressures (0.5 MPa, 1.1 MPa, 4.0 MPa and 6.5 MPa) in the presence of systemically injected microbubbles. The acoustic emissions from the FUS-activated microbubbles were passively detected by the imaging array. The pre-beamformed channel data were acquired and processed offline using the frequency-domain delay, sum and integration algorithm to generate inertial cavitation maps. All the mice were sacrificed after the FUS treatment, and their brains were harvested and processed for hematoxylin and eosin staining. The obtained inertial cavitation maps revealed the dynamic changes of microbubble behaviors during FUS treatment at different pressure levels. It was found that the inertial cavitation dose quantified based on PCI had a linear correlation with the scale of histologic-level tissue damage. Findings from this study suggested that PCI can be used to predict histologic-level tissue damage associated with the FUS-induced cavitation. © 2019 World Federation for Ultrasound in Medicine & Biology

Author Keywords
Brain therapies;  Cavitation;  Focused ultrasound;  Passive cavitation imaging;  Tissue damage

Document Type: Article
Publication Stage: Final
Source: Scopus

Unemployment and the relationship between borderline personality pathology and health
(2019) Journal of Research in Personality, 82, art. no. 103863, . 

Cruitt, P.J., Oltmanns, T.F.

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

Abstract
Evidence suggests that employment may buffer against the negative health outcomes associated with borderline personality disorder (BPD). The purpose of the current analyses was to examine unemployment and the BPD-health relationship prospectively. Participants were 1536 older adults in a longitudinal study of health and aging, with repeated measures of physical health, depressive symptoms, and life satisfaction. We measured BPD features using multiple sources at baseline, and used principal components analysis to obtain latent scores. Multilevel models indicated that unemployment experiences did not moderate the prospective relationship between BPD features and physical health or life satisfaction, but did strengthen the positive relationship between BPD features and depressive symptoms. These findings provide insight into mechanisms of recovery for individuals with BPD. © 2019 Elsevier Inc.

Author Keywords
Borderline personality disorder;  Depressive symptoms;  Life satisfaction;  Physical health;  Unemployment

Document Type: Article
Publication Stage: Final
Source: Scopus

Trial of SAGE-217 in Patients with Major Depressive Disorder
(2019) The New England Journal of Medicine, 381 (10), pp. 903-911. 

Gunduz-Bruce, H., Silber, C., Kaul, I., Rothschild, A.J., Riesenberg, R., Sankoh, A.J., Li, H., Lasser, R., Zorumski, C.F., Rubinow, D.R., Paul, S.M., Jonas, J., Doherty, J.J., Kanes, S.J.

From Sage Therapeutics, Cambridge (H.G.-B., C.S., A.J.S., H.L., R.L., S.M.P., J.J., J.J.D., S.J.K.), Kaul Consulting, Concord (I.K.), and the University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester (A.J.R.) – all in Massachusetts; the Atlanta Center for Medical Research, Atlanta (R.R.); Washington University School of Medicine, St. Louis (C.F.Z., S.M.P.); and the University of North Carolina School of Medicine, Chapel Hill (D.R.R.)

Abstract
BACKGROUND: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.). Copyright © 2019 Massachusetts Medical Society.

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurofibromatosis 2 in children presenting during the first decade of life
(2019) Neurology, 93 (10), pp. e964-e967. 

Gaudioso, C., Listernick, R., Fisher, M.J., Campen, C.J., Paz, A., Gutmann, D.H.

From the Department of Neurology (C.G., D.H.G.), Washington University School of Medicine, St. Louis, MO; Ann & Robert H. Lurie Children’s Hospital of Chicago (R.L.), Feinberg School of Medicine, Northwestern University, IL; Division of Oncology (M.J.F., A.P.), Children’s Hospital of Philadelphia, PA; and Department of Neurology (C.J.C.), Stanford University, Palo Alto, CA

Abstract
OBJECTIVE: To educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children. METHODS: A retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed. RESULTS: The average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%). CONCLUSIONS: Although uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management. © 2019 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Rapid and active stabilization of visual cortical firing rates across light-dark transitions
(2019) Proceedings of the National Academy of Sciences of the United States of America, 116 (36), pp. 18068-18077. 

Pacheco, A.T.^a , Tilden, E.I.^{a d} , Grutzner, S.M.^{a e} , Lane, B.J.^a , Wu, Y.^b , Hengen, K.B.^a , Gjorgjieva, J.^{b c} , Turrigiano, G.G.^a

^a Department of Biology, Brandeis University, Waltham, MA 02453, United States
^b Computation in Neural Circuits Group, Max Planck Institute for Brain Research, Frankfurt, 60438, Germany
^c School of Life Sciences, Technical University of Munich, Freising, 85354, Germany
^d Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
^e Department of Biology, Stanford University, Stanford, CA 94305, United States

Abstract
The dynamics of neuronal firing during natural vision are poorly understood. Surprisingly, mean firing rates of neurons in primary visual cortex (V1) of freely behaving rodents are similar during prolonged periods of light and darkness, but it is unknown whether this reflects a slow adaptation to changes in natural visual input or insensitivity to rapid changes in visual drive. Here, we use chronic electrophysiology in freely behaving rats to follow individual V1 neurons across many dark-light (D-L) and light-dark (L-D) transitions. We show that, even on rapid timescales (1 s to 10 min), neuronal activity was only weakly modulated by transitions that coincided with the expected 12-/12-h L-D cycle. In contrast, a larger subset of V1 neurons consistently responded to unexpected L-D and D-L transitions, and disruption of the regular L-D cycle with 60 h of complete darkness induced a robust increase in V1 firing on reintroduction of visual input. Thus, V1 neurons fire at similar rates in the presence or absence of natural stimuli, and significant changes in activity arise only transiently in response to unexpected changes in the visual environment. Furthermore, although mean rates were similar in light and darkness, pairwise correlations were significantly stronger during natural vision, suggesting that information about natural scenes in V1 may be more strongly reflected in correlations than individual firing rates. Together, our findings show that V1 firing rates are rapidly and actively stabilized during expected changes in visual input and are remarkably stable at both short and long timescales. © 2019 National Academy of Sciences. All rights reserved.

Author Keywords
Firing-rate stability;  Rodent vision;  Visual cortex;  Visual experience

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Sex differences in the genetic predictors of Alzheimer’s pathology
(2019) Brain : a Journal of Neurology, 142 (9), pp. 2581-2589. 

Dumitrescu, L.^{a b} , Barnes, L.L.^c , Thambisetty, M.^d , Beecham, G.^{e f} , Kunkle, B.^f , Bush, W.S.^g , Gifford, K.A.^a , Chibnik, L.B.^{h i} , Mukherjee, S.^j , De Jager, P.L.^{k l} , Kukull, W.^m , Crane, P.K.^j , Resnick, S.M.^d , Keene, C.D.ⁿ , Montine, T.J.^o , Schellenberg, G.D.^p , Deming, Y.^q , Chao, M.J.^r , Huentelman, M.^s , Martin, E.R.^{e f} , Hamilton-Nelson, K.^f , Shaw, L.M.^p , Trojanowski, J.Q.^p , Peskind, E.R.^t , Cruchaga, C.^q , Pericak-Vance, M.A.^f , Goate, A.M.^r , Cox, N.J.^b , Haines, J.L.^g , Zetterberg, H.^{u v w x} , Blennow, K.^{u v} , Larson, E.B.^{j y} , Johnson, S.C.^z , Albert, M.^aa , Bennett, D.A.^c , Schneider, J.A.^c , Jefferson, A.L.^a , Hohman, T.J.^{a b} , Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative^ab

^a Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, United States
^b Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^c Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^d Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
^e John T MacDonald Foundation Department of Human Genetics, University of Miami, Miami, FL, United States
^f John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, United States
^g Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States
^h Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
ⁱ Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^j Department of Medicine, University of Washington, Seattle, WA, United States
^k Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA
^l Cell Circuits Program, Broad Institute, Cambridge MA, United States
^m Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, United States
ⁿ Department of Pathology, University of Washington, Seattle, WA, United States
^o Department of Pathology, Stanford University, Stanford, CA, United States
^p Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^q Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^r Ronald M Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
^s Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
^t Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
^u Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
^v Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^w Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
^x UK Dementia Research Institute at UCL, London, United Kingdom
^y Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States
^z Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^aa Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer’s disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
Alzheimer’s disease;  beta-amyloid;  genome-wide association study;  neuropathology;  tau

Document Type: Article
Publication Stage: Final
Source: Scopus

Time’s up healthcare: The role of mental health
(2019) American Journal of Psychiatry, 176 (9), pp. 687-689. 

Gold, J.A.^a , Bernstein, C.A.^b , Cyrus, K.D.^c , Fitelson, E.^d , Lieberman, A.^e , Mangurian, C.^e

^a Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, United States
^b Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, New York, United States
^c Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
^d Department of Psychiatry, Columbia University, New York, United States
^e Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States

Document Type: Note
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Maternal depression and child development: Clues to causal mechanisms from potential confounders
(2019) American Journal of Psychiatry, 176 (9), pp. 680-682. 

Barch, D.M.^{a b c} , Rogers, C.^{b d}

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, Washington University School of Medicine, St. Louis, United States
^b Departments of Psychiatry, Washington University School of Medicine, St. Louis, United States
^c Departments of Radiology, Washington University School of Medicine, St. Louis, United States
^d Departments of Pediatrics, Washington University School of Medicine in, St. Louis, United States

Document Type: Editorial
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Rapid Recovery With Plasma Exchange in Acute Motor Axonal Neuropathy With Reversible Conduction Failure
(2019) Journal of Clinical Neuromuscular Disease, 21 (1), pp. 35-41. 

Burford, M.^{a b} , Chou, C.A.^a , Sommerville, R.B.^a , Bucelli, R.C.^a

^a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States

Abstract
Characterization of Guillain-Barré syndrome (GBS) subtypes has become increasingly complicated with the recognition of paranodal dysfunction and reversible conduction failure (RCF) in acute motor axonal neuropathy. We describe 2 cases of seronegative acute motor axonal neuropathy with RCF with a rapid onset of severe quadriplegia. Treatment with plasma exchange was associated with rapid clinical and electrophysiological response on serial examinations. Increased recognition of RCF may lead to improved characterization of GBS subtypes and may play a role in determining future treatment options in GBS.

Document Type: Article
Publication Stage: Final
Source: Scopus

Blood Pressure and Outcome After Mechanical Thrombectomy With Successful Revascularization
(2019) Stroke, 50 (9), pp. 2448-2454. 

Anadani, M.^{a b} , Orabi, M.Y.^a , Alawieh, A.^c , Goyal, N.^d , Alexandrov, A.V.^d , Petersen, N.^e , Kodali, S.^{b e} , Maier, I.L.^f , Psychogios, M.-N.^g , Swisher, C.B.^h , Inamullah, O.^h , Kansagra, A.P.ⁱ , Giles, J.A.^b , Wolfe, S.Q.^j , Singh, J.^k , Gory, B.^l , De Marini, P.^l , Kan, P.^m , Nascimento, F.A.ⁿ , Freire, L.I.^o , Pandhi, A.^d , Mitchell, H.^d , Kim, J.-T.^p , Fargen, K.M.^j , Al Kasab, S.^a , Liman, J.^f , Rahman, S.^{h l} , Allen, M.^r , Richard, S.^q , Spiotta, A.M.^c

^a From the Department of Neurology, Medical University of South Carolina, Switzerland
^b Department of Neurology, Washington University School of Medicine, Saint Louis, United States
^c Department of Neurosurgery, Medical University of South Carolina, Switzerland
^d Department of Neurology, University of Tennessee Health Science Center, A.V.A, A.P, India
^e Department of Neurology, Yale University School of Medicine, CT (N.P, New Haven
^f Department of Neurology, University Medical Center Göttingen, Germany (I.M
^g Department of Neuroradiology, University Medical Center Göttingen, Germany (M.P)
^h Department of Neurology, Duke University Hospital, S.R, Durham, Canada
ⁱ Department of Radiology, Washington University School of Medicine, Saint Louis, United States
^j Department of Neurosurgery, Wake Forest University, Winston-Salem, Italy
^k Department of Radiology, Wake Forest University, Winston-Salem, Italy
^l Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nancy, P.D.M.
^m Department of Neurosurgery, Baylor College of Medicine, Houston, Canada
ⁿ Department of Neurology, Baylor College of Medicine, Houston, Canada
^o Department of Neurology, Leeds General Infirmary, University of Leeds, United Kingdom (L.I.F)
^p Department of Neurology (J-T. K), Chonnam National University Hospital Gwangju, South Korea
^q Department of Neurology, Stroke Unit, CIC-P 1433, INSERM U1116, University Hospital of Nancy

Abstract
Background and Purpose- Successful reperfusion can be achieved in more than two-thirds of patients treated with mechanical thrombectomy. Therefore, it is important to understand the effect of blood pressure (BP) on clinical outcomes after successful reperfusion. In this study, we investigated the relationship between BP on admission and during the first 24 hours after successful reperfusion with clinical outcomes. Methods- This was a multicenter study from 10 comprehensive stroke centers. To ensure homogeneity of the studied cohort, we included only patients with anterior circulation who achieved successful recanalization at the end of procedure. Clinical outcomes included 90-day modified Rankin Scale, symptomatic intracerebral hemorrhage (sICH), mortality, and hemicraniectomy. Results- A total of 1245 patients were included in the study. Mean age was 69±14 years, and 51% of patients were female. Forty-nine percent of patients had good functional outcome at 90-days, and 4.7% suffered sICH. Admission systolic BP (SBP), mean SBP, maximum SBP, SBP SD, and SBP range were associated with higher risk of sICH. In addition, patients in the higher mean SBP groups had higher rates of sICH. Similar results were found for hemicraniectomy. With respect to functional outcome, mean SBP, maximum SBP, and SBP range were inversely associated with the good outcome (modified Rankin Scale score, 0-2). However, the difference in SBP parameters between the poor and good outcome groups was modest. Conclusions- Higher BP within the first 24 hours after successful mechanical thrombectomy was associated with a higher likelihood of sICH, mortality, and requiring hemicraniectomy.

Author Keywords
blood pressure;  cerebral hemorrhage;  hemorrhage;  reperfusion;  stroke;  thrombectomy

Document Type: Article
Publication Stage: Final
Source: Scopus

T2-Weighted-Fluid-Attenuated Inversion Recovery Hyperintensity on Magnetic Resonance Imaging Is Associated With Aggressive Symptoms in Patients With Dural Arteriovenous Fistulas
(2019) Stroke, 50 (9), pp. 2565-2567. 

Patel, B.^a , Chatterjee, A.^b , Petr, O.^c , Collins, H.^b , Lanzino, G.^c , Derdeyn, C.P.^d , Zipfel, G.J.^a

^a From the Department of Neurological Surgery, Washington University School of Medicine, St. Louis, United States
^b Department of Radiology, Medical University of South Carolina, Switzerland
^c Department of Neurological Surgery, College of Medicine, Mayo Clinic, Rochester, United Kingdom
^d Department of Radiology, Carver College of Medicine, University of Iowa (C.P.D.)

Abstract
Background and Purpose- Several angiographic factors of dural arteriovenous fistulas (dAVFs) are associated with aggressive presentation and poor natural history. We examined the association of magnetic resonance imaging T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) hyperintensity with aggressive presentation. Methods- A cohort of dAVF patients from 2 centers was retrospectively examined. T2/FLAIR hyperintensity was determined by blinded, de-identified review and compared with angiographic grade and presenting symptoms. Results- T2/FLAIR hyperintensity was only identified in dAVF patients with cortical venous drainage (CVD). Among patients with CVD, those with T2/FLAIR hyperintensity were more likely to present with aggressive symptoms (20/23, 87.0%) than those without (6/21, 28.5%), P<0.001. All cured dAVFs with symptom resolution and available post-treatment imaging had resolution of T2/FLAIR hyperintensity. Conclusions- T2/FLAIR hyperintensity strongly correlates with aggressive presentation and CVD in dAVF patients, and may identify a subset that would benefit from early treatment.

Author Keywords
cerebrovascular disorders;  cohort studies;  humans;  magnetic resonance imaging;  vascular malformations

Document Type: Article
Publication Stage: Final
Source: Scopus

Auditory Evoked Responses in Older Adults With Normal Hearing, Untreated, and Treated Age-Related Hearing Loss
(2019) Ear and Hearing, 40 (5), pp. 1106-1116. 

McClannahan, K.S.^{a b} , Backer, K.C.^c , Tremblay, K.L.^b

^a Department of Psychological and Brain Sciences, Washington University, St Louis, WA, United States
^b Department of Speech and Hearing Sciences, University of WashingtonWA, United States
^c Department of Cognitive and Information Sciences, University of California, Merced, CA, United States

Abstract
OBJECTIVES: The goal of this study was to identify the effects of auditory deprivation (age-related hearing loss) and auditory stimulation (history of hearing aid use) on the neural registration of sound across two stimulus presentation conditions: (1) equal sound pressure level and (2) equal sensation level. DESIGN: We used a between-groups design, involving three groups of 14 older adults (n = 42; 62 to 84 years): (1) clinically defined normal hearing (≤25 dB from 250 to 8000 Hz, bilaterally), (2) bilateral mild-moderate/moderately severe sensorineural hearing loss who have never used hearing aids, and (3) bilateral mild-moderate/moderately severe sensorineural hearing loss who have worn bilateral hearing aids for at least the past 2 years. RESULTS: There were significant delays in the auditory P1-N1-P2 complex in older adults with hearing loss compared with their normal hearing peers when using equal sound pressure levels for all participants. However, when the degree and configuration of hearing loss were accounted for through the presentation of equal sensation level stimuli, no latency delays were observed. These results suggest that stimulus audibility modulates P1-N1-P2 morphology and should be controlled for when defining deprivation and stimulus-related neuroplasticity in people with hearing loss. Moreover, a history of auditory stimulation, in the form of hearing aid use, does not appreciably alter the neural registration of unaided auditory evoked brain activity when quantified by the P1-N1-P2. CONCLUSIONS: When comparing auditory cortical responses in older adults with and without hearing loss, stimulus audibility, and not hearing loss-related neurophysiological changes, results in delayed response latency for those with age-related hearing loss. Future studies should carefully consider stimulus presentation levels when drawing conclusions about deprivation- and stimulation-related neuroplasticity. Additionally, auditory stimulation, in the form of a history of hearing aid use, does not significantly affect the neural registration of sound when quantified using the P1-N1-P2-evoked response.

Document Type: Article
Publication Stage: Final
Source: Scopus

TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death
(2019) Cancer Medicine, 8 (11), pp. 5232-5241. 

Qin, W.^{a b} , Godec, A.^a , Zhang, X.^a , Zhu, C.^a , Shao, J.^{a c} , Tao, Y.^d , Bu, X.^b , Hirbe, A.C.^{a c}

^a Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
^b School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
^c Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO, United States
^d Cancer Center Biostatistics Shared Resource, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 (TYK2) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis. Methods: Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout cells were established using shRNA and CRISPR/Cas9 systems, respectively. Results: We have demonstrated that TYK2 was highly expressed in the majority of human MPNSTs examined. Additionally, we demonstrated that knockdown of Tyk2/TYK2 in murine and human MPNST cells significantly increased cell death in vitro. These effects were accompanied by a decrease in the levels of activated Stats and Bcl-2 as well as an increase in the levels of Cleaved Caspase-3. In addition, Tyk2-KD cells demonstrated impaired growth in subcutaneous and metastasis models in vivo. Conclusion: Taken together, these data illustrate the importance of TYK2 in MPNST pathogenesis and suggest that the TYK2 pathway may be a potential therapeutic target for these deadly cancers. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Author Keywords
cancer;  MPNST;  sarcoma;  TYK2

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Age differences in emotion regulation strategy use, variability, and flexibility: An experience sampling approach
(2019) Developmental Psychology, 55 (9), pp. 1951-1964. 

Benson, L.^a , English, T.^b , Conroy, D.E.^c , Pincus, A.L.^d , Gerstorf, D.^e , Ram, N.^a

^a Department of Human Development and Family Studies, Pennsylvania State University, Australia
^b Department of Psychological and Brain Sciences, Washington University in St. Louis
^c Department of Kinesiology, Pennsylvania State University, Australia
^d Department of Psychology, Pennsylvania State University, Australia
^e Department of Psychology, Humboldt University Berlin, Germany

Abstract
Life span developmental theories suggest that as individuals age, they accumulate knowledge about how to deploy emotion regulation (ER) strategies effectively and learn how to match their ER strategy use with changes in situational demands. Using an event-contingent experience sampling design wherein 150 adults Age 18 to 89 years reported on 64,213 social interactions (M = 427.41, SD = 145.66) during 9 weeks of daily life, this study examines (a) age-related differences in individuals’ usual ER strategy use (reappraisal, suppression) during everyday social interactions, (b) age-related differences in how much individuals’ use of these two strategies varies across social situations-ER variability, and (c) age-related differences in the extent to which ER strategy use covaries with relational (close vs. nonclose others) and emotional (happy, sad) contextual features of those social situations-ER flexibility. In line with a small body of prior work, usual ER strategy use did not differ across adulthood and ER variability was lower at older ages. Results from multilevel models of intraindividual covariation suggested that individuals flexibly matched their ER strategy implementation to changes in emotional context-especially when interacting with close others. The results also provided evidence that the intraindividual covariation between relational context and use of suppression was weaker at older ages. Beyond these specific findings, this study demonstrated the utility of experience sampling designs, event-contingent reports, and the measurement/modeling of intraindividual variation and covariation for study of emotional development across the life span. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Document Type: Article
Publication Stage: Final
Source: Scopus

Indicators for nonroutine discharge following cervical deformity-corrective surgery: Radiographic, surgical, and patient-related factors
(2019) Clinical Neurosurgery, 85 (3), art. no. nyz016, pp. E509-E519. 

Bortz, C.A.^a , Passias, P.G.^a , Segreto, F.^a , Horn, S.R.^a , Lafage, V.^b , Smith, J.S.^c , Line, B.^d , Mundis, G.M.^e , Kebaish, K.M.^f , Kelly, M.P.^g , Protopsaltis, T.^a , Sciubba, D.M.^h , Soroceanu, A.ⁱ , Klineberg, E.O.^j , Burton, D.C.^k , Hart, R.A.^l , Schwab, F.J.^b , Bess, S.^m , Shaffrey, C.I.^c , Ames, C.P.ⁿ

^a Department of Orthopedics, NYU Langone Orthopedic Hospital New York, 301 East 17th St, New York, NY 10003, United States
^b Department of Orthopedics, Hospital for Special Surgery, New York, NY, United States
^c Department of Neurosurgery, University of Virginia, Charlottesville, VA, United States
^d International Spine Study Group, Denver, CO, United States
^e San Diego Center for Spinal Disorders, San Diego, CA, United States
^f Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^g Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States
^h Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
ⁱ Department of Orthopaedic Surgery, University of Calgary, Calgary, AB, Canada
^j Department of Orthopedic Surgery, University of California, Davis, CA, United States
^k Department of Orthopedic Surgery, University of Kansas Medical Center, Kansas City, KS, United States
^l Department of Orthopaedic Surgery, Swedish Neuroscience Institute, Seattle, WA, United States
^m Rocky Mountain Scoliosis and Spine, Denver, CO, United States
ⁿ Department of Neurological Surgery, University of California, San Francisco, CA, United States

Abstract
BACKGROUND: Nonroutine discharge, including discharge to inpatient rehab and skilled nursing facilities, is associated with increased cost-of-care. Given the rising prevalence of cervical deformity (CD)-corrective surgery and the necessity of value-based healthcare, it is important to identify indicators for nonroutine discharge. OBJECTIVE: To identify factors associated with nonroutine discharge after CD-corrective surgery using a statistical learning algorithm. METHODS: A retrospective review of patients ≥18 yr with discharge and baseline (BL) radiographic data. Conditional inference decision trees identified factors associated with nonroutine discharge and cut-off points at which factors were significantly associated with discharge status. A conditional variable importance table used nonreplacement sampling set of 10 000 conditional inference trees to identify influential patient/surgical factors. The binary logistic regression indicated odds of nonroutine discharge for patients with influential factors at significant cut-off points. RESULTS: Of 138 patients (61 yr, 63% female) undergoing surgery for CD (8 ± 5 levels; 49% posterior approach, 16% anterior, and 35% combined), 29% experienced nonroutine discharge. BL cervical/upper-cervical malalignment showed the strongest relationship with nonroutine discharge: C1 slope ≥ 14°, C2 slope ≥ 57°, TS-CL ≥ 57°. Patient-related factors associated with nonroutine discharge included BL gait impairment, age ≥ 59 yr and apex of CD primary driver ≥ C7. The only surgical factor associated with nonroutine discharge was fusion ≥ 8 levels. There was no relationship between nonhome discharge and reoperation within 6 mo or 1 yr (both P >. 05) of index procedure. Despite no differences in BL EQ-5D (P =. 946), nonroutine discharge patients had inferior 1-yr postoperative EQ-5D scores (P =. 044). CONCLUSION: Severe preoperative cervical malalignment was strongly associated with nonroutine discharge following CD-corrective surgery. Age, deformity driver, and ≥ 8 level fusions were also associated with nonroutine discharge and should be taken into account to improve patient counseling and health care resource allocation. © Copyright 2019 by the Congress of Neurological Surgeons.

Author Keywords
CD;  Cervical deformity;  Discharge;  Outcomes;  Rehabilitation;  Skilled nursing facility;  Surgery

Document Type: Article
Publication Stage: Final
Source: Scopus

Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease
(2019) Science Translational Medicine, 11 (507), art. no. aav6221, . 

Ewers, M.^a , Franzmeier, N.^a , Suárez-Calvet, M.^{b c d e p} , Morenas-Rodriguez, E.^{b f} , Caballero, M.A.A.^a , Kleinberger, G.^{b g h} , Piccio, L.^{i j k} , Cruchaga, C.^{j l} , Deming, Y.^{j l} , Dichgans, M.^{a c g} , Trojanowski, J.Q.^m , Shaw, L.M.ⁿ , Weiner, M.W.^o , Haass, C.^{b c g} , Alzheimer’s Disease Neuroimaging Initiative^q

^a Institute for Stroke and Dementia Research, University Hospital Munich, LMU, Munich, Germany
^b Department of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
^c German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
^d Barcelonaeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Catalonia, Spain
^e Department of Neurology, Hospital del Mar, Barcelona, Catalonia, Spain
^f Department of Neurology, Institut d’Investigacions Biomèdiques, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
^g Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^h ISAR Bioscience GmbH, Planegg, 82152, Germany
ⁱ Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^j Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO, United States
^k Brain and Mind Centre, University of Sydney, Sydney, Australia
^l Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
^m Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ⁿ Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^o University of California at San Francisco, San Francisco, CA, United States
^p BarcelonaBeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Catalonia, Spain

Abstract
Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer’s disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF A1-42 (amyloid -peptide 1 to 42; A+) and CSF p-tau181 (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF A1-42 and CSF p-tau181 (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau181 concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF A1-42 and CSF p-tau181. These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD. © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Telomere alterations in neurofibromatosis type 1-associated solid tumors
(2019) Acta Neuropathologica Communications, 7 (1), p. 139. 

Rodriguez, F.J.^{a b c} , Graham, M.K.^d , Brosnan-Cashman, J.A.^d , Barber, J.R.^e , Davis, C.^d , Vizcaino, M.A.^d , Palsgrove, D.N.^{d f} , Giannini, C.^g , Pekmezci, M.^h , Dahiya, S.ⁱ , Gokden, M.^j , Noë, M.^d , Wood, L.D.^{d f} , Pratilas, C.A.^f , Morris, C.D.^k , Belzberg, A.^l , Blakeley, J.^{f m} , Heaphy, C.M.^d

^a Departments of Pathology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD 21231, United States
^b Departments of Ophthalmology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD 21231, United States
^c Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD 21231, United States
^d Departments of Pathology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD 21231, United States
^e Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
^f Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD 21231, United States
^g Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^h Department of Pathology, University of California San Francisco, San Francisco, CA, United States
ⁱ Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
^j University of Arkansas, Little Rock, AR, United States
^k Department of Orthopedics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^l Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^m Departments of Neurology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD 21231, United States

Abstract
The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.

Author Keywords
Alternative lengthening of telomeres;  ATRX;  Glioma;  MPNST;  NF1

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Validation of a clinical-genetics score to predict hemorrhagic transformations after rtPA
(2019) Neurology, 93 (9), pp. e851-e863. 

Carrera, C., Cullell, N., Torres-Águila, N., Muiño, E., Bustamante, A., Dávalos, A., López-Cancio, E., Ribó, M., Molina, C.A., Giralt-Steinhauer, E., Soriano-Tárraga, C., Mola-Caminal, M., Jiménez-Conde, J., Roquer, J., Vives-Bauza, C., Navarro, R.D., Obach, V., Arenillas, J.F., Segura, T., Serrano-Heras, G., Martí-Fàbregas, J., Freijo, M., Cabezas, J.A., Tatlisumak, T., Heitsch, L., Ibañez, L., Cruchaga, C., Lee, J.-M., Strbian, D., Montaner, J., Fernández-Cadenas, I., Spanish Stroke Genetic Consortium

From the Neurovascular Research Laboratory (C.C., A.B.), Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona; Stroke Pharmacogenomics and Genetics (N.C., N.-T.A.) and Stroke Genomics and Genetics (E.M.), Fundació Docència i Recerca Mútua Terrassa; Department of Neuroscience (A.D.), Hospital Germans Trias i Pujol; Stroke Unit (E.L.-C.), Hospital Universitario Central de Asturias; Stroke Unit (M.R., C.A.M.), Hospital Universitari Vall d’Hebron; Stroke Unit, Hospital Universitari Vall d’Hebron; Department of Neurology (E.G.-S., C.S.-T., M.M.-C., J.J.-C., J.R.), Neurovascular Research Group, IMIM-Hospital del Mar; Neurobiology Laboratory (C.V.-B.), Institut d’Investigacio Sanitaria de Palma; Department of Neurology (R.D.N.), Hospital Universitari Son Espases; Department of Neurology (V.O.), Hospital Clínic i Provincial de Barcelona; Department of Neurology (J.F.A.), Hospital Clínico Universitario, University of Valladolid; Department of Neurology (T.S.) and Experimental Research Unit (G.S.-H.), Hospital Universitario de Albacete; Department of Neurology (J.M.-F.), Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau; Department of Neurology (M.F.), Hospital de Basurto; Department of Neurology (J.A.C.), Virgen del Rocío & Macarena Hospitals, IBIS, Spain; Department of Clinical Neuroscience/Neurology (T.T.), Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Sweden; Division of Emergency Medicine (L.H.), Department of Psychiatry (L.I., C.C.), and Department of Neurology (J.-M.L.), Washington University School of Medicine, St. Louis, MO

Abstract
OBJECTIVE: To validate the Genot-PA score, a clinical-genetic logistic regression score that stratifies the thrombolytic therapy safety, in a new cohort of patients with stroke. METHODS: We enrolled 1,482 recombinant tissue plasminogen activator (rtPA)-treated patients with stroke in Spain and Finland from 2003 to 2016. Cohorts were analyzed on the basis of ethnicity and therapy: Spanish patients treated with IV rtPA within 4.5 hours of onset (cohort A and B) or rtPA in combination with mechanical thrombectomy within 6 hours of onset (cohort C) and Finnish participants treated with IV rtPA within 4.5 hours of onset (cohort D). The Genot-PA score was calculated, and hemorrhagic transformation (HT) and parenchymal hematoma (PH) risks were determined for each score stratum. RESULTS: Genot-PA score was tested in 1,324 (cohort A, n = 726; B, n = 334; C, n = 54; and D, n = 210) patients who had enough information to complete the score. Of these, 213 (16.1%) participants developed HT and 85 (6.4%) developed PH. In cohorts A, B, and D, HT occurrence was predicted by the score (p = 2.02 × 10-6, p = 0.023, p = 0.033); PH prediction was associated in cohorts A through C (p = 0.012, p = 0.034, p = 5.32 × 10-4). Increased frequency of PH events from the lowest to the highest risk group was found (cohort A 4%-15.7%, cohort B 1.5%-18.2%, cohort C 0%-100%). The best odds ratio for PH prediction in the highest-risk group was obtained in cohort A (odds ratio 5.16, 95% confidence interval 1.46-18.08, p = 0.009). CONCLUSION: The Genot-PA score predicts HT in patients with stroke treated with IV rtPA. Moreover, in an exploratory study, the score was associated with PH risk in mechanical thrombectomy-treated patients. © 2019 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Human GNPTAB stuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum
(2019) Proceedings of the National Academy of Sciences of the United States of America, 116 (35), pp. 17515-17524. 

Han, T.-U.^a , Root, J.^a , Reyes, L.D.^b , Huchinson, E.B.^b , Du Hoffmann, J.^c , Lee, W.-S.^d , Barnes, T.D.^e , Drayna, D.^a

^a Section on Genetics of Communication Disorders, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, United States
^b Section on Quantitative Medical Imaging, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, United States
^c Section on Behavioral Neuroscience, Rodent Behavioral Core, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, United States
^d Department of Internal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^e Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Stuttering is a common neurodevelopmental disorder that has been associated with mutations in genes involved in intracellular trafficking. However, the cellular mechanisms leading to stuttering remain unknown. Engineering a mutation in N-acetylglucosamine-1- phosphate transferase subunits α and β (GNPTAB) found in humans who stutter into the mouse Gnptab gene resulted in deficits in the flow of ultrasonic vocalizations similar to speech deficits of humans who stutter. Here we show that other human stuttering mutations introduced into this mouse gene, Gnptab Ser321Gly and Ala455Ser, produce the same vocalization deficit in 8-day-old pup isolation calls and do not affect other nonvocal behaviors. Immunohistochemistry showed a marked decrease in staining of astrocytes, particularly in the corpus callosum of the Gnptab Ser321Gly homozygote mice compared to wild-type littermates, while the staining of cerebellar Purkinje cells, oligodendrocytes, microglial cells, and dopaminergic neurons was not significantly different. Diffusion tensor imaging also detected deficits in the corpus callosum of the Gnptab Ser321Gly mice. Using a range of cell type-specific Cre-drivers and a Gnptab conditional knockout line, we found that only astrocyte-specific Gnptab-deficient mice displayed a similar vocalization deficit. These data suggest that vocalization defects in mice carrying human stuttering mutations in Gnptab derive from abnormalities in astrocytes, particularly in the corpus callosum, and provide support for hypotheses that focus on deficits in interhemispheric communication in stuttering. © 2019 National Academy of Sciences. All rights reserved.

Author Keywords
Astrocytes;  Cre-drivers;  Mouse vocalization;  Stuttering;  White matter

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Person-Environment Fit Approach to Trajectories of Cognitive Function Among Older Adults Who Live Alone: Intersection of Life-Course SES Disadvantage and Senior Housing
(2019) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 74 (6), pp. e1-e12. 

Park, S.^a , Kwon, E.^b , Kim, B.^c , Han, Y.^d

^a Brown School of Social Work, Washington University in Saint LouisMO, United States
^b Department of Social Work, St. Cloud State UniversityMN, United States
^c Department of Social Work, University of New Hampshire, Durham, Canada
^d Department of Social Welfare, Seoul National University, Seoul, South Korea

Abstract
OBJECTIVES: Drawing from life course and environmental perspectives, we examined the trajectory of cognitive function and how senior housing moderates the effects of life-course socioeconomic status (SES) disadvantage among older people living alone over time. METHOD: Six waves of the Health and Retirement Study (HRS) were used with multilevel growth modeling to analyze developmental patterns of cognitive function over time and how various forms of life-course SES disadvantage affect cognitive function depending on senior housing residency status. RESULTS: At baseline, we found a positive role of senior housing in four subgroups: SES disadvantage in childhood only, unstable mobility pattern (disadvantage in childhood and old age only), downward mobility (no disadvantage in childhood, but in later two life stages), and cumulative disadvantage (all three life stages). Over time, the positive role of senior housing for the unstable and the most vulnerable group persisted. DISCUSSION: Our findings provide a much-needed practical and theoretical underpinning for environmental policy-making efforts regarding vulnerable elders who live alone. © The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Environmental gerontology;  Housing;  Later-year cognitive function;  Life-course perspective;  Living alone

Document Type: Article
Publication Stage: Final
Source: Scopus

Sensorimotor Coding of Vermal Granule Neurons in the Developing Mammalian Cerebellum
(2019) The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 39 (34), pp. 6626-6643. 

Markwalter, K.H.^{a b} , Yang, Y.^a , Holy, T.E.^c , Bonni, A.^d

^a Department of Neuroscience, Sweden
^b MD-PhD Program, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neuroscience, Sweden
^d Department of Neuroscience, Sweden

Abstract
The vermal cerebellum is a hub of sensorimotor integration critical for postural control and locomotion, but the nature and developmental organization of afferent information to this region have remained poorly understood in vivo Here, we use in vivo two-photon calcium imaging of the vermal cerebellum in awake behaving male and female mice to record granule neuron responses to diverse sensorimotor cues targeting visual, auditory, somatosensory, and motor domains. Use of an activity-independent marker revealed that approximately half (54%) of vermal granule neurons were activated during these recordings. A multikernel linear model distinguished the relative influences of external stimuli and co-occurring movements on neural responses, indicating that, among the subset of activated granule neurons, locomotion (44%-56%) and facial air puffs (50%) were more commonly and reliably encoded than visual (31%-32%) and auditory (19%-28%) stimuli. Strikingly, we also uncover populations of granule neurons that respond differentially to voluntary and forced locomotion, whereas other granule neurons in the same region respond similarly to locomotion in both conditions. Finally, by combining two-photon calcium imaging with birth date labeling of granule neurons via in vivo electroporation, we find that early- and late-born granule neurons convey similarly diverse sensorimotor information to spatially distinct regions of the molecular layer. Collectively, our findings elucidate the nature and developmental organization of sensorimotor information in vermal granule neurons of the developing mammalian brain.SIGNIFICANCE STATEMENT Cerebellar granule neurons comprise over half the neurons in the brain, and their coding properties have been the subject of theoretical and experimental interest for over a half-century. In this study, we directly test long-held theories about encoding of sensorimotor stimuli in the cerebellum and compare the in vivo coding properties of early- and late-born granule neurons. Strikingly, we identify populations of granule neurons that differentially encode voluntary and forced locomotion and find that, although the birth order of granule neurons specifies the positioning of their parallel fiber axons, both early- and late-born granule neurons convey a functionally diverse sensorimotor code. These findings constitute important conceptual advances in understanding the principles underlying cerebellar circuit development and function. Copyright © 2019 the authors.

Author Keywords
calcium imaging;  cerebellar development;  cerebellar granule neuron;  sensorimotor encoding;  two-photon imaging

Document Type: Article
Publication Stage: Final
Source: Scopus

Metacontrol of decision-making strategies in human aging
(2019) eLife, 8, . 

Bolenz, F.^a , Kool, W.^{b c} , Reiter, A.M.^{a d e} , Eppinger, B.^{a f g}

^a Chair of Lifespan Developmental Neuroscience, Faculty of Psychology, Technische Universität Dresden, Dresden, Germany
^b Department of Psychology, Harvard University, Cambridge, United States
^c Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, United States
^d Wellcome Centre for Human Neuroimaging, University College London, London, United Kingdom
^e Max Planck UCL Centre for Computational Psychiatry and Ageing Research, London, United Kingdom
^f Department of Psychology, Concordia University, Montreal, Canada
^g PERFORM centre, Concordia University, Montreal, Canada

Abstract
Humans employ different strategies when making decisions. Previous research has reported reduced reliance on model-based strategies with aging, but it remains unclear whether this is due to cognitive or motivational factors. Moreover, it is not clear how aging affects the metacontrol of decision making, that is the dynamic adaptation of decision-making strategies to varying situational demands. In this cross-sectional study, we tested younger and older adults in a sequential decision-making task that dissociates model-free and model-based strategies. In contrast to previous research, model-based strategies led to higher payoffs. Moreover, we manipulated the costs and benefits of model-based strategies by varying reward magnitude and the stability of the task structure. Compared to younger adults, older adults showed reduced model-based decision making and less adaptation of decision-making strategies. Our findings suggest that aging affects the metacontrol of decision-making strategies and that reduced model-based strategies in older adults are due to limited cognitive abilities. © 2019, Bolenz et al.

Author Keywords
decision making;  human;  lifespan development;  model-based;  model-free;  neuroscience;  reinforcement learning;  reward

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Biophysically interpretable inference of single neuron dynamics
(2019) Journal of Computational Neuroscience, 47 (1), pp. 61-76. 

Narayanan, V., Li, J.-S., Ching, S.N.

Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Identification of key ionic channel contributors to the overall dynamics of a neuron is an important problem in experimental neuroscience. Such a problem is challenging since even in the best cases, identification relies on noisy recordings of membrane potential only, and strict inversion to the constituent channel dynamics is mathematically ill-posed. In this work, we develop a biophysically interpretable, learning-based strategy for data-driven inference of neuronal dynamics. In particular, we propose two optimization frameworks to learn and approximate neural dynamics from an observed voltage trajectory. In both the proposed strategies, the membrane potential dynamics are approximated as a weighted sum of ionic currents. In the first strategy, the ionic currents are represented using voltage dependent channel conductances and membrane potential in a parametric form, while in the second strategy, the currents are represented as a linear combination of generic basis functions. A library of channel activation/inactivation and time-constant curves describing prototypical channel kinetics are used to provide estimates of the channel variables to approximate the ionic currents. Finally, a linear optimization problem is solved to infer the weights/scaling variables in the membrane-potential dynamics. In the first strategy, the weights can be used to recover the channel conductances, and the reversal potentials while in the second strategy, using the estimated weights, active channels can be inferred and the trajectory of the gating variables are recovered, allowing for biophysically salient inference. Our results suggest that the complex nonlinear behavior of the neural dynamics over a range of temporal scales can be efficiently inferred in a data-driven manner from noisy membrane potential recordings. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Conductance based model;  Identification;  Learning

Document Type: Article
Publication Stage: Final
Source: Scopus

Obstructive sleep apnoea, positive airway pressure treatment and postoperative delirium: Protocol for a retrospective observational study
(2019) BMJ Open, 9 (8), art. no. e026649, . 

King, C.R.^a , Escallier, K.E.^a , Ju, Y.-E.S.^b , Lin, N.^{c d} , Palanca, B.J.^a , McKinnon, S.L.^a , Avidan, M.S.^a

^a Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, MI, United States
^b Neurology, Washington University in Saint Louis School of Medicine, Saint Louis, MI, United States
^c Mathematics, Washington University in Saint Louis, St. Louis, MI, United States
^d Division of Biostatistics, Washington Univiersity in Saint Louis, St. Louis, MI, United States

Abstract
Introduction Obstructive sleep apnoea (OSA) is common among older surgical patients, and delirium is a frequent and serious postoperative complication. Emerging evidence suggests that OSA increases the risk for postoperative delirium. We hypothesise that OSA is an independent risk factor for postoperative delirium, and that in patients with OSA, perioperative adherence to positive airway pressure (PAP) therapy decreases the incidence of postoperative delirium and its sequelae. The proposed retrospective cohort analysis study will use existing datasets to: (i) describe and compare the incidence of postoperative delirium in surgical patients based on OSA diagnosis and treatment with PAP; (ii) assess whether preoperatively untreated OSA is independently associated with postoperative delirium; and (iii) explore whether preoperatively untreated OSA is independently associated with worse postoperative quality of life (QoL). The findings of this study will inform on the potential utility and approach of an interventional trial aimed at preventing postoperative delirium in patients with diagnosed and undiagnosed OSA. Methods and analysis Observational data from existing electronic databases will be used, including over 100 000 surgical patients and ∼10 000 intensive care unit (ICU) admissions. We will obtain the incidence of postoperative delirium in adults admitted postoperatively to the ICU who underwent structured preoperative assessment, including OSA diagnosis and screening. We will use doubly robust propensity score methods to assess whether untreated OSA independently predicts postoperative delirium. Using similar methodology, we will assess if untreated OSA independently predicts worse postoperative QoL. Ethics and dissemination This study has been approved by the Human Research Protection Office at Washington University School of Medicine. We will publish the results in a peer-reviewed venue. Because the data are secondary and high risk for reidentification, we will not publicly share the data. Data will be destroyed after 1 year of completion of active Institutional Review Board (IRB) approved projects. © Author(s) (or their employer(s)) 2019.

Author Keywords
ehr data;  obstructive sleep apnea;  postoperative delirium

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Spinal V2b neurons reveal a role for ipsilateral inhibition in speed control
(2019) eLife, 8, art. no. e47837, . 

Callahan, R.A.^a , Roberts, R.^a , Sengupta, M.^a , Kimura, Y.^b , Higashijima, S.-I.^b , Bagnall, M.W.^a

^a Washington University School of Medicine, Department of Neuroscience, St. Louis, MO, United States
^b National Institute for Basic Biology, Okazaki, Aichi, Japan

Abstract
The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These V2b subclasses synapse directly onto motor neurons with differential targeting to speed specific circuits. In vivo, optogenetic manipulation of V2b activity modulates locomotor frequency: Suppressing V2b neurons elicits faster locomotion, whereas activating V2b neurons slows locomotion. We conclude that V2b neurons serve as a brake on axial motor circuits. Together, these results indicate a role for ipsilateral inhibition in speed control. © 2019, eLife Sciences Publications Ltd. All right reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Comparison of Voxel-Wise and Histogram Analyses of Glioma ADC Maps for Prediction of Early Therapeutic Change
(2019) Tomography (Ann Arbor, Mich.), 5 (1), pp. 7-14. 

Chenevert, T.L.^a , Malyarenko, D.I.^a , Galbán, C.J.^a , Gomez-Hassan, D.M.^a , Sundgren, P.C.^b , Tsien, C.I.^c , Ross, B.D.^a

^a Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, United States
^b Department of Clinical Sciences/Radiology Lund University, Lund, Sweden; and
^c Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Noninvasive imaging methods are sought to objectively predict early response to therapy for high-grade glioma tumors. Quantitative metrics derived from diffusion-weighted imaging, such as apparent diffusion coefficient (ADC), have previously shown promise when used in combination with voxel-based analysis reflecting regional changes. The functional diffusion mapping (fDM) metric is hypothesized to be associated with volume of tumor exhibiting an increasing ADC owing to effective therapeutic action. In this work, the reference fDM-predicted survival (from previous study) for 3 weeks from treatment initiation (midtreatment) is compared to multiple histogram-based metrics using Kaplan-Meier estimator for 80 glioma patients stratified to responders and nonresponders based on the population median value for the given metric. The ADC histogram metric reflecting reduction in midtreatment volume of solid tumor (ADC < 1.25 × 10-3 mm2/s) by >8% population-median with respect to pretreatment is found to have the same predictive power as the reference fDM of increasing midtreatment ADC volume above 4%. This study establishes the level of correlation between fDM increase and low-ADC tumor volume shrinkage for prediction of early response to radiation therapy in patients with glioma malignancies.

Author Keywords
apparent diffusion coefficient;  functional diffusion map;  glioma therapy response;  quantitative response metric;  voxel-wise analysis

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology
(2019) Neuron, . 

Gutmann, D.H.^a , Kettenmann, H.^b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Cellular Neurosciences, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany

Abstract
One of the most common brain tumors in children and adults is glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the past decade, it is now appreciated that these tumors are composed of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these noncancerous cell types, monocytes (microglia and macrophages) predominate. In this Review, we discuss the complex interactions involving microglia and macrophages relevant to glioma formation, progression, and response to therapy. Like other cancers, brain tumors (gliomas) are composed of many different cell types, including non-neoplastic monocytic cells (macrophages and microglia). In this Review, Gutmann and Kettenmann discuss the importance of these cells to glioma development, maintenance, and treatment response. © 2019 Elsevier Inc.

Author Keywords
glioblastoma;  glioma;  immune;  macrophages;  microglia;  monocyte

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

An examination of the interpersonal model of binge eating over the course of treatment
(2019) European Eating Disorders Review, . 

Karam, A.M.^a , Eichen, D.M.^b , Fitzsimmons-Craft, E.E.^a , Wilfley, D.E.^a

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, University of California, San Diego, San Diego, CA, United States

Abstract
The current study examined the interpersonal model of binge eating, which posits that interpersonal problems lead to negative affect, which results in binge eating, over the course of two psychotherapy treatments (interpersonal psychotherapy and cognitive behavioural therapy) in 162 adults with binge-eating disorder. A series of longitudinal simple mediation analyses preliminarily showed that treatment addresses the mechanisms of the interpersonal model of binge eating as theoretically proposed in predicting reductions in binge eating, the primary dependent variable, and the secondary dependent variables including global eating disorder psychopathology, shape concern, and weight concern, but not reductions in restraint or eating concern. Moderated mediation analyses did not fully support treatment differences, as changes in the mechanisms of the interpersonal model occurred in both treatments and suggest both treatments addressed negative affect and interpersonal precipitants of eating disorder symptomatology. Future research should replicate this study using variables that do not overlap in time to investigate causation of the model, and more generally, further examine theoretical treatment models and treatment mediators as this research could help improve efficacy of treatment for binge-eating disorder. © 2019 John Wiley & Sons, Ltd and Eating Disorders Association.

Author Keywords
binge-eating disorder;  interpersonal model;  interpersonal problems;  negative affect;  psychological treatment

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

The Cortical Physiology of Ipsilateral Limb Movements
(2019) Trends in Neurosciences, . 

Bundy, D.T.^{a b} , Leuthardt, E.C.^{b c d}

^a Department of Rehabilitation Medicine, University of Kansas Medical Center, Kansas City, KS, United States
^b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
^c Department of Neurological Surgery, Washington University, St. Louis, MO, United States
^d Center of Innovation in Neuroscience and Technology, Washington University, St. Louis, MO, United States

Abstract
Whereas voluntary movements have long been understood to derive primarily from the cortical hemisphere contralateral to a moving limb, substantial cortical activations also occur in the same-sided, or ipsilateral, cortical hemisphere. These ipsilateral motor activations have recently been shown to be useful to decode specific movement features. Furthermore, in contrast to the classical understanding that unilateral limb movements are solely driven by the contralateral hemisphere, it appears that the ipsilateral hemisphere plays an active and specific role in the planning and execution of voluntary movements. Here we review the movement-related activations observed in the ipsilateral cortical hemisphere, interpret this evidence in light of the potential roles of the ipsilateral hemisphere in the planning and execution of movements, and describe the implications for clinical populations. © 2019 Elsevier Ltd

Author Keywords
bimanual coordination;  ipsilateral;  motor control;  voluntary movement

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

Mapping at rest: Translating resting-state functional MRI to clinical practice
(2019) Journal of Neurosurgery, 131 (3), pp. 759-761. 

Roland, J.L., Smyth, M.D.

Department of Neurological Surgery, Washington University, St. Louis Children’s Hospital, St. Louis, MI, United States

Document Type: Editorial
Publication Stage: Final
Source: Scopus
Access Type: Open Access

A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer’s disease from young adulthood and for designing prevention trials
(2019) Alzheimer’s and Dementia, . 

Xiong, C.^{a b} , Luo, J.^{a c d} , Agboola, F.^{a b} , Li, Y.^{a e} , Albert, M.^f , Johnson, S.C.^{g h} , Koscik, R.L.^g , Masters, C.L.ⁱ , Soldan, A.^f , Villemagne, V.L.^{j k} , Li, Q.-X.ⁱ , McDade, E.M.^e , Fagan, A.M.^{b e} , Massoumzadeh, P.^{b l} , Benzinger, T.^{b l} , Hassenstab, J.^{b e} , Bateman, R.J.^{b e} , Morris, J.C.^{b e m} , the Dominantly Inherited Alzheimer Networkⁿ

^a Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^b Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Siteman Cancer Center Biostatistics Core Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^g Wisconsin Alzheimer’s Institute and Alzheimer’s Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
^h Geriatric Research Education and Clinical Center, William S Middleton Veterans Memorial Hospital, Madison, WI, United States
ⁱ The Florey Institute, University of Melbourne, Melbourne, Australia
^j Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia
^k Department of Medicine, University of Melbourne, Melbourne, Australia
^l Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^m Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Large longitudinal biomarkers database focusing on middle age is needed for Alzheimer’s disease (AD) prevention. Methods: Data for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar β-amyloid with positron emission tomography, magnetic resonance imaging–based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated. Results: The harmonized database included 7779 participants with clinical/cognitive data: 3542 were 18∼65 years at the baseline, 5865 had longitudinal cognitive data for a median of 4.7 years, 2473 participated in the cerebrospinal fluid studies (906 had longitudinal data), 2496 participated in the magnetic resonance imaging studies (1283 had longitudinal data), and 1498 participated in the positron emission tomography amyloid studies (849 had longitudinal data). The database provides adequate power for detecting early biomarker changes, and demonstrates the feasibility of AD prevention trials on middle-aged individuals. Discussion: The harmonized database is an optimum resource to design AD prevention trials decades before symptomatic onset. © 2019 the Alzheimer’s Association

Author Keywords
Alzheimer disease;  Amyloid imaging with positron emission tomography (PET) using the [11C] benzothiazole tracer;  Biomarkers;  Cerebrospinal fluid (CSF);  Magnetic resonance imaging (MRI) volumetrics;  Pittsburgh Compound-B (PIB);  Preclinical stages;  Prevention trials

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

Segregated neural explants exhibit co-oriented, asymmetric, neurite outgrowth
(2019) PLoS ONE, 14 (9), art. no. e0216263, . 

Pettigrew, D.B.^a , Dobson, C.B.^b , Isaacson, L.G.^c , Leuthardt, E.C.^{d e} , Lilley, H.N.^d , Suidan, G.L.^{d f} , Crutcher, K.A.^{b d}

^a Department of Anatomy and Neuroscience, Department of Physical Therapy, University of Findlay, Findlay, OH, United States
^b Medical Device Biology Group, Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom
^c Department of Biology, Miami University, Oxford, OH, United States
^d Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^e Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^f Cerevel Therapeutics, LLC, Boston, MA, United States

Abstract
Explants of embryonic chick sympathetic and sensory ganglia were found to exhibit asymmetric radial outgrowth of neurites under standard culture conditions with or without exogenous Nerve Growth Factor [NGF]. Opposing sides of an explant exhibited: a) differences in neurite length and, b) differences in neurite morphology. Strikingly, this asymmetry exhibited co-orientation among segregated, neighboring explants. The underlying mechanism(s) of the asymmetry and its co-orientation are not known but appear to depend on cell clustering because dissociated sympathetic neurons do not exhibit co-orientation whereas re-aggregated clusters of cells do. This emergent behavior may be similar to the community effect described in other cell types. If a similar phenomenon exists in the embryo, or in maturity, it may contribute to the establishment of proper orientation of neurite outgrowth during development and/or injury-induced neuronal plasticity. © 2019 Pettigrew et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Complex task performance assessment (CTPA) and functional cognition in people with Parkinson’s disease
(2019) American Journal of Occupational Therapy, 73 (5), art. no. 7305205060, . 

^a Barnes-Jewish Hospital, St. Louis, MO, United States
^b Department of Occupational Therapy, School of Health Professions, University of Missouri, Columbia, MO, United States
^c Program in Occupational Therapy, Neurology Department, Psychiatry Department, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective. The objective of this study was to determine how Parkinson’s disease (PD) affects functional cognition as assessed by the Complex Task Performance Assessment (CTPA) and to examine the associations of CTPA performance with other indicators of executive function in people with PD. Method. Volunteers with PD without dementia (n = 20) and community control participants (n = 19) completed neuropsychological testing, patient-reported outcome measures, and the CTPA. Results. There were no group differences for CTPA performance accuracy; however, the PD group took longer to complete the CTPA than did the control group. In the PD group, inefficient CTPA performance correlated with poorer cognitive flexibility and worse reported everyday shifting and task monitoring. Conclusion. Decreased executive function, namely cognitive flexibility and attentional control, may impair functional cognition in people with PD. Future studies with larger, more diverse samples are warranted to determine the discriminant validity and sensitivity of the CTPA. Use of performance-based assessments such as the CTPA may increase the understanding of functional cognition in people with PD. © 2019 American Occupational Therapy Association, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Examination of the Lumbar Movement Pattern during a Clinical Test and a Functional Activity Test in People with and without Low Back Pain
(2019) PM and R, . 

Marich, A.V., Hwang, C.-T., Sorensen, C.J., van Dillen, L.R.

Program in Physical Therapy, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States

Abstract
Background: It is assumed that the lumbar movement pattern observed during a clinical test is representative of the movement pattern used during a functional activity. Very little is known about how the lumbar movement pattern during a clinical test is associated with the lumbar movement pattern during a functional activity and how the lumbar movement pattern is associated with functional limitation. Objective: The purpose was to examine the lumbar movement pattern during a clinical test and a functional activity test in people with and people without low back pain (LBP), and the relationship of lumbar motion to LBP-related functional limitation. Design: Observational study. Participants: 16 back-healthy adults and 32 people with chronic LBP. Methods: Participants performed a standardized clinical test of forward bending and a functional activity test of picking up an object. Main Outcome Measurements: Maximal lumbar excursion and lumbar excursion at 0% to 50% and 50% to 100% of movement time were examined. Results: Significant associations were present between the two movement tests for both back-healthy people and people with LBP (r = 0.47-0.73). In people with LBP the amount of lumbar motion in the 0% to 50% of movement time interval for both tests was significantly associated with functional limitation (r = 0.43-0.62). Conclusion: Lumbar movement patterns were similar between the two tests, and lumbar motion early in the movement of a functional test was related to self-report of functional limitation. Level of Evidence: III. © 2019 American Academy of Physical Medicine and Rehabilitation

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

Changes in whole body pain intensity and widespreadness during urologic chronic pelvic pain syndrome flares—Findings from one site of the MAPP study
(2019) Neurourology and Urodynamics, . 

Xu, T.^{a b} , Lai, H.H.^{c d} , Pakpahan, R.^b , Vetter, J.^c , Andriole, G.L.^c , Bradley, C.^e , Naliboff, B.D.^f , Colditz, G.A.^b , Sutcliffe, S.^b

^a George Warren Brown School, Washington University, St Louis, MO, United States
^b Division of Public Health Sciences, Washington University School of Medicine, St Louis, MO, United States
^c Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States
^d Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
^e Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^f Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, CA, United States

Abstract
Objective: To investigate changes in whole body pain during urologic chronic pelvic pain syndrome (UCPPS) flares. Materials and Methods: UCPPS participants at one site of the multidisciplinary approach to the study of chronic pelvic pain research network reported their daily flare status and pain levels in 7 pelvic/genital and 42 extrapelvic body areas (scale = 0-10) for 10 days at baseline and during their first flare. Linear mixed models and conditional logistic regression were used to investigate symptom changes during flares. Analyses were stratified by chronic overlapping pain condition (COPC) status. Results: Fifty-five out of 60 participants completed the study, 27 of whom provided information on both nonflare (n = 281) and flare (n = 208) days. Pelvic/genital pain intensity (mean change = 3.20 of 10) and widespreadness (mean = 1.48) increased significantly during flares for all participants (all P interaction >.1), whereas extrapelvic pain intensity increased significantly only among participants with COPCs (mean = 2.09; P interaction <.0001). Pelvic/genital and extrapelvic pain also varied on nonflare days but symptom fluctuations were generally ≤1 point (80.0%-100% of participants). Increases of ≥2 points in pelvic/genital pain intensity (odds ratio (OR) = 22.0, 95% confidence interval (CI) = 4.0-118.6) and ≥1 point in urination-related pain (OR = 9.10, 95% CI = 1.74-47.7) were independently associated with flare onset for all participants. Conclusion: Our observations of extrapelvic pain increases during flares for patients with COPCs and our independent associations between pelvic/genital/urination-related pain intensity and flare onset may provide insight into mechanisms underlying flare development (eg, common biologic pathways between UCPPS phenotypes and flares), flare management (eg, local vs systemic therapies by COPC status), and patient flare definitions. © 2019 Wiley Periodicals, Inc.

Author Keywords
chronic prostatitis;  flares;  interstitial cystitis;  longitudinal study;  symptom exacerbations

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

Two-period linear mixed effects models to analyze clinical trials with run-in data when the primary outcome is continuous: Applications to Alzheimer’s disease
(2019) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 5, pp. 450-457. 

Wang, G.^a , Aschenbrenner, A.J.^b , Li, Y.^b , McDade, E.^b , Liu, L.^a , Benzinger, T.L.S.^c , Bateman, R.J.^b , Morris, J.C.^b , Hassenstab, J.J.^{b d} , Xiong, C.^a

^a Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychological and Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Study outcomes can be measured repeatedly based on the clinical trial protocol before randomization during what is known as the “run-in” period. However, it has not been established how best to incorporate run-in data into the primary analysis of the trial. Methods: We proposed two-period (run-in period and randomization period) linear mixed effects models to simultaneously model the run-in data and the postrandomization data. Results: Compared with the traditional models, the two-period linear mixed effects models can increase the power up to 15% and yield similar power for both unequal randomization and equal randomization. Discussion: Given that analysis of run-in data using the two-period linear mixed effects models allows more participants (unequal randomization) to be on the active treatment with similar power to that of the equal-randomization trials, it may reduce the dropout by assigning more participants to the active treatment and thus improve the efficiency of AD clinical trials. © 2019 The Authors

Author Keywords
Alzheimer’s disease;  Linear mixed effects model;  Run-in clinical trials;  Two-period models;  Unequal randomization

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

The effects of aging on sleep parameters in a healthy, melatonin-competent mouse model
(2019) Nature and Science of Sleep, 11, pp. 113-121. 

Paulose, J.K.^a , Wang, C.^{a b} , O’Hara, B.F.^a , Cassone, V.M.^a

^a Department of Biology, University of Kentucky, Lexington, KY 40515, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Background: Sleep disturbances are common maladies associated with human age. Sleep duration is decreased, sleep fragmentation is increased, and the timing of sleep onset and sleep offset is earlier. These disturbances have been associated with several neurodegenerative diseases. Mouse models for human sleep disturbances can be powerful due to the accessibility to neuroscientific and genetic approaches, but these are hampered by the fact that most mouse models employed in sleep research have spontaneous mutations in the biosynthetic pathway(s) regulating the rhythmic production of the pineal hormone melatonin, which has been implicated in human sleep. Purpose and method: The present study employed a non-invasive piezoelectric measure of sleep wake cycles in young, middle-aged and old CBA mice, a strain capable of melatonin biosynthesis, to investigate naturally-occurring changes in sleep and circadian parameters as the result of aging. Results: The results indicate that young mice sleep less than do middle-aged or aged mice, especially during the night, while the timing of activity onset and acrophase is delayed in aged mice compared to younger mice. Conclusion: These data point to an effect of aging on the quality and timing of sleep in these mice but also that there are fundamental differences between control of sleep in humans and in laboratory mice. © 2019 Paulose et al.

Author Keywords
Aging;  CBA/J;  Circadian rhythms;  Piezoelectric;  Sleep

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion
(2019) Acta Neuropathologica, . 

Li, Z.^{a b c} , Farias, F.H.G.^{a b c} , Dube, U.^{a b c} , Del-Aguila, J.L.^{a b c} , Mihindukulasuriya, K.A.^{a b c} , Fernandez, M.V.^{a b c} , Ibanez, L.^{a b c} , Budde, J.P.^{a b c} , Wang, F.^{a b c} , Lake, A.M.^d , Deming, Y.^e , Perez, J.^{a b c} , Yang, C.^{a b c} , Bahena, J.A.^{a b c} , Qin, W.^{a f} , Bradley, J.L.^{a b c} , Davenport, R.^{a b c} , Bergmann, K.^{a b c} , Morris, J.C.^{a g} , Perrin, R.J.^{a g} , Benitez, B.A.^{a b c} , Dougherty, J.D.^a , Harari, O.^{a b c} , Cruchaga, C.^{a b c}

^a Department of Psychiatry, BJC Institute of Heath, Washington University School of Medicine, 425 S. Euclid Ave., Box 8134, St. Louis, MO 63110, United States
^b NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, United States
^c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^d Vanderbilt University Medical Scientist Training Program, Nashville, TN, United States
^e Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
^f Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
^g The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Apart from amyloid β deposition and tau neurofibrillary tangles, Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neuronal loss and astrocytosis in the cerebral cortex. The goal of this study is to investigate genetic factors associated with the neuronal proportion in health and disease. To identify cell-autonomous genetic variants associated with neuronal proportion in cortical tissues, we inferred cellular population structure from bulk RNA-Seq derived from 1536 individuals. We identified the variant rs1990621 located in the TMEM106B gene region as significantly associated with neuronal proportion (p value = 6.40 × 10−07) and replicated this finding in an independent dataset (p value = 7.41 × 10−04) surpassing the genome-wide threshold in the meta-analysis (p value = 9.42 × 10−09). This variant is in high LD with the TMEM106B non-synonymous variant p.T185S (rs3173615; r2 = 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD). We stratified the samples by disease status, and discovered that this variant modulates neuronal proportion not only in AD cases, but also several neurodegenerative diseases and in elderly cognitively healthy controls. Furthermore, we did not find a significant association in younger controls or schizophrenia patients, suggesting that this variant might increase neuronal survival or confer resilience to the neurodegenerative process. The single variant and gene-based analyses also identified an overall genetic association between neuronal proportion, AD and FTLD risk. These results suggest that common pathways are implicated in these neurodegenerative diseases, that implicate neuronal survival. In summary, we identified a protective variant in the TMEM106B gene that may have a neuronal protection effect against general aging, independent of disease status, which could help elucidate the relationship between aging and neuronal survival in the presence or absence of neurodegenerative disorders. Our findings suggest that TMEM106B could be a potential target for neuronal protection therapies to ameliorate cognitive and functional deficits. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Complex traits;  Cortex;  Deconvolution;  GWAS;  Neurodegeneration;  QTL

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

Web-based prescription opioid abuse prevention for adolescents: Program development and formative evaluation
(2019) Journal of Medical Internet Research, 21 (7), art. no. e12389, . 

Moore, S.K.^a , Grabinski, M.^a , Bessen, S.^b , Borodovsky, J.T.^c , Marsch, L.A.^a

^a Center for Technology and Behavioral Health, Geisel School of Medicine, Dartmouth College, 46 Centerra Parkway, Lebanon, NH 03766, United States
^b Geisel School of Medicine, Dartmouth College, Hanover, NH, United States
^c Health and Behavior Research Center, Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: The unprecedented number of youths engaged in nonmedical use of prescription opioids (POs), as well as the myriad negative consequences of such misuse, emphasizes the importance of prevention efforts targeting this public health crisis. Although there are several science-based, interactive drug abuse prevention programs focused on preventing the use of nonprescription drugs in youths, to our knowledge, there are no science-based interactive programs that focus on the prevention of PO abuse among adolescents. Objective: The aim of this study was to develop and conduct a formative evaluation of a science-based interactive Web-based program focused on the prevention of PO abuse among adolescents aged 12 to 17 years (Pop4Teens). This study was conducted to prepare for a randomized controlled trial designed to evaluate the effectiveness of Pop4Teens compared with an active control website, JustThinkTwice.com (Drug Enforcement Administration), in impacting knowledge and attitudes about POs and perceptions of risk associated with the abuse of POs, as well as intentions to use and actual use of POs. Methods: We conducted 6 focus groups with 30 youths (M=5 per group: the eligibility being aged 12-19 years) along a continuum of exposure to POs (in treatment for opioid use disorder, in general treatment for other substance use disorder, prescribed an opioid, and opioid-naïve) and writing sessions with 30 youths in treatment for opioid use disorder (12-19 years) to inform the development of the Web-based prevention tool. Feasibility and acceptability of a prototype of the Web-based intervention were then assessed through individual feedback sessions with 57 youths (drawn from the same populations as the focus groups). Results: We successfully completed the development of a Web-based PO abuse prevention program (Pop4Teens). Analyses of focus group transcripts informed the development of the program (eg, quiz content/format, script writing, and story editing). Selected writing session narratives anchored the planned scientific content by lending credibility and informing the development of compelling storylines intended to motivate the youth to engage with the program. Feedback session data indicated that the Web-based tool could be potentially useful and acceptable. In addition, feedback session participants demonstrated significant increases in their knowledge of key topics related to the prevention of PO abuse after the exposure to sections of the Web-based program. Conclusions: The opioid crisis is predicted to get worse before it gets better. An effective response will likely require a multipronged strategy inclusive of effective evidence-based prevention programs acceptable to, and accessible by, a majority of youths. © 2019 Journal of Medical Internet Research. All rights reserved.

Author Keywords
Adolescent;  Internet;  Opioids;  Prevention and control;  Randomized controlled trial

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Upper Limb Performance in Daily Life Improves Over the First 12 Weeks Poststroke
(2019) Neurorehabilitation and Neural Repair, . 

Waddell, K.J., Strube, M.J., Tabak, R.G., Haire-Joshu, D., Lang, C.E.

Washington University in St Louis, St Louis, MO, United States

Abstract
Background. Upper limb (UL) performance, or use, in daily life is complex and likely influenced by many factors. While the recovery trajectory of UL impairment poststroke is well documented, little is known about the recovery trajectory of sensor-measured UL performance in daily life early after stroke and the potential moderating role of psychosocial factors. Objective. To examine the recovery trajectory of UL performance within the first 12 weeks poststroke and characterize the potential moderating role of belief, confidence, and motivation on UL performance. Methods. This was a longitudinal, prospective cohort study quantifying UL performance and related psychosocial factors early after stroke. UL performance was quantified via bilateral, wrist-worn accelerometers over 5 assessment sessions for 24 hours. Belief, confidence, and motivation to use the paretic UL, and self-perceived barriers to UL recovery were quantified via survey. Change in 4 accelerometer variables and the moderating role of psychosocial factors was tested using hierarchical linear modeling. The relationship between self-perceived barriers and UL performance was tested via Spearman rank-order correlation analysis. Results. UL performance improved over the first 12 weeks after stroke. Belief, confidence, and motivation did not moderate UL performance over time. There was a negative relationship between UL performance and self-perceived barriers to UL recovery at week 2, which declined over time. Conclusions. Sensor-measured UL performance can improve early after stroke. Early after stroke, rehabilitation interventions may not need to directly target belief, confidence, and motivation but may instead focus on reducing self-perceived barriers to UL recovery. © The Author(s) 2019.

Author Keywords
accelerometry;  confidence;  psychosocial;  sensors;  stroke;  upper limb

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

Type-2-diabetes alters CSF but not plasma metabolomic and ad risk profiles in vervet monkeys
(2019) Frontiers in Neuroscience, 13 (JUL), art. no. 843, . 

Kavanagh, K.^{a b} , Day, S.M.^c , Pait, M.C.^c , Mortiz, W.R.^d , Newgard, C.B.^e , Ilkayeva, O.^e , Mcclain, D.A.^f , Macauley, S.L.^c

^a Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, United States
^b College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
^c Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States
^f Section of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC, United States

Abstract
Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer’s disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabaeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ40 and CSF Aβ42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ40 and CSF Aβ42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ40 and CSF Aβ42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD. Copyright © 2019 Kavanagh, Day, Pait, Mortiz, Newgard, Ilkayeva, Mcclain and Macauley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Author Keywords
Acylcarnitine;  Alzheimer’s disease;  Amino acids;  Amyloid-beta;  CSF;  Hyperglycemia;  Metabolomics;  Type 2 diabetes

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson’s disease
(2019) Clinical Autonomic Research, . 

Carricarte Naranjo, C.^a , Marras, C.^b , Visanji, N.P.^b , Cornforth, D.J.^c , Sanchez-Rodriguez, L.^d , Schüle, B.^e , Goldman, S.M.^f , Estévez, M.^g , Stein, P.K.^h , Lang, A.E.^b , Jelinek, H.F.ⁱ , Machado, A.^a

^a Facultad de Biología, Universidad de La Habana, Calle 25 No. 455, Vedado, Plaza de la Revolución, La Habana, 10400, Cuba
^b Edmond J Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, 399 Bathurst St, Toronto, ON M5T 2S8, Canada
^c School of Electrical Engineering and Computing, University of Newcastle, University Dr, Callaghan, NSW 2308, Australia
^d Department of Radiology, University of Calgary, 330 Hospital Dr NW, Calgary, AB T2N 4N1, Canada
^e Department of Pathology, Stanford School of Medicine, 300 Pasteur Dr, R271, Stanford, CA 94305, United States
^f Department of Neurology, University of California, 3333 California St, San Francisco, CA 94118, United States
^g Departamento de Neurofisiología Clínica, Instituto de Neurología y Neurocirugía, Calle 29 No. 139, Vedado, Plaza de la Revolución, La Habana, 10400, Cuba
^h School of Medicine, Washington University, 660 S Euclid Ave, St. Louis, MO 63110, United States
ⁱ School of Community Health, Charles Sturt University, Elizabeth Mitchell Dr, Albury, NSW 2640, Australia

Abstract
Purpose: Cardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson’s disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation. Methods: Short-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls. Results: Beat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls. Conclusions: Increased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Autonomic dysfunction;  Deceleration capacity of heart rate;  Heart rate variability;  LRRK2;  Parkinson’s disease;  Rényi entropy

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

Use of the CDR® plus NACC FTLD in mild FTLD: Data from the ARTFL/LEFFTDS consortium
(2019) Alzheimer’s and Dementia, . 

Miyagawa, T.^a , Brushaber, D.^a , Syrjanen, J.^a , Kremers, W.^a , Fields, J.^a , Forsberg, L.K.^a , Heuer, H.W.^b , Knopman, D.^a , Kornak, J.^b , Boxer, A.^b , Rosen, H.^b , Boeve, B.^a , Appleby, B.^c , Bordelon, Y.^d , Bove, J.^e , Brannelly, P.^f , Caso, C.^g , Coppola, G.^d , Dever, R.^b , Dheel, C.^a , Dickerson, B.^h , Dickinson, S.ⁱ , Dominguez, S.^e , Domoto-Reilly, K.^g , Faber, K.^j , Ferrell, J.^k , Fishman, A.^l , Fong, J.^b , Foroud, T.^j , Gavrilova, R.^a , Gearhart, D.^a , Ghazanfari, B.^m , Ghoshal, N.ⁿ , Goldman, J.S.^o , Graff-Radford, J.^a , Graff-Radford, N.^p , Grant, I.^q , Grossman, M.^e , Haley, D.^p , Hsiung, R.^r , Huey, E.^o , Irwin, D.^e , Jones, D.^a , Jones, L.ⁿ , Kantarci, K.^a , Karydas, A.^b , Kaufer, D.^k , Kerwin, D.^s , Kraft, R.^a , Kramer, J.^b , Kukull, W.^t , Litvan, I.^u , Lucente, D.^h , Lungu, C.^v , Mackenzie, I.^r , Maldonado, M.^d , Manoochehri, M.^o , McGinnis, S.^h , McKinley, E.^w , Mendez, M.F.^d , Miller, B.^b , Multani, N.^m , Onyike, C.^l , Padmanabhan, J.^h , Pantelyat, A.^l , Pearlman, R.^x , Petrucelli, L.^p , Potter, M.^j , Rademakers, R.^p , Ramos, E.M.^d , Rankin, K.^b , Rascovsky, K.^e , Roberson, E.D.^w , Rogalski, E.^q , Sengdy, P.^r , Shaw, L.^e , Tartaglia, M.C.^j , Tatton, N.ⁱ , Taylor, J.^b , Toga, A.^y , Trojanowski, J.Q.^e , Wang, P.^b , Weintraub, S.^q , Wong, B.^h , Wszolek, Z.^p , ARTFL/LEFFTDS Consortium^z

^a Mayo Clinic, Rochester, MN, United States
^b UCSF, San Francisco, CA, United States
^c Case Western Reserve University, Cleveland, OH, United States
^d UCLA, Los Angeles, CA, United States
^e University of Pennsylvania, Philadelphia, PA, United States
^f Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, United States
^g U Washington, Seattle, WA, United States
^h Harvard University/MGH, Boston, MA, United States
ⁱ Association for Frontotemporal Degeneration, Radnor, PA, United States
^j National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), Indiana University, Indianapolis, IN, United States
^k University of North Carolina, Chapel Hill, NC, United States
^l Johns Hopkins University, Baltimore, MD, United States
^m University of Toronto, Toronto, Ontario, Canada
ⁿ Washington University, St. Louis, MO, United States
^o Columbia University, New York, NY, United States
^p Mayo Clinic, Jacksonville, FL, United States
^q Northwestern University, Chicago, IL, United States
^r University of British Columbia, Vancouver, British Columbia, Canada
^s UTSW, Dallas, TX, United States
^t National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, United States
^u UCSD, San Diego, CA, United States
^v National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, United States
^w University of Alabama, Birmingham, AL, United States
^x Bluefield Project, San Francisco, CA, United States
^y Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, United States

Abstract
Introduction: Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD). Methods: We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium. Results: The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders. Discussion: The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD. © 2019 the Alzheimer’s Association

Author Keywords
Behavior;  CDR®;  Comportment and personality;  Frontotemporal dementia;  Frontotemporal lobar degeneration;  Language;  NACC FTLD Module;  Primary progressive aphasia

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

Microstructural fronto-striatal and temporo-insular alterations are associated with fatigue in patients with multiple sclerosis independent of white matter lesion load and depression
(2019) Multiple Sclerosis Journal, . 

Palotai, M.^a , Cavallari, M.^a , Koubiyr, I.^{a d} , Morales Pinzon, A.^a , Nazeri, A.^b , Healy, B.C.^{c e} , Glanz, B.^c , Weiner, H.L.^c , Chitnis, T.^c , Guttmann, C.R.G.^a

^a Center for Neurological Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^d INSERM U1215, Neurocentre Magendie, Bordeaux, France
^e Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

Abstract
Background: Fatigue in multiple sclerosis (MS) has been inconsistently associated with disruption of specific brain circuitries. Temporal fluctuations of fatigue have not been considered. Objective: The aim of this study was to investigate the association of fatigue with brain diffusion abnormalities, using robust criteria for patient stratification based on longitudinal patterns of fatigue. Methods: Patient stratification: (1) sustained fatigue (SF, n = 26): latest two Modified Fatigue Impact Scale (MFIS) ⩾ 38; (2) reversible fatigue (RF, n = 25): latest MFIS < 38 and minimum one previous MFIS ⩾ 38; and (3) never fatigued (NF, n = 42): MFIS always < 38 (five assessments minimum). 3T brain magnetic resonance imaging (MRI) was used to perform voxel-wise comparison of fractional anisotropy (FA) between the groups controlling for age, sex, disease duration, physical disability, white matter lesion load (T2LV), and depression. Results: SF and, to a lesser extent, RF patients showed lower FA in multiple brain regions compared to NF patients, independent of age, sex, disease duration, and physical disability. In cingulo-postcommissural-striato-thalamic regions, the differences in FA between SF and NF (but not between RF and NF or SF) patients were independent of T2LV, and in ventromedial prefronto-precommissuro-striatal and temporo-insular areas, independent of T2LV and depression. Conclusion: Damage to ventromedial prefronto-precommissuro-striatal and temporo-insular pathways appears to be a specific substrate of SF in MS. © The Author(s), 2019.

Author Keywords
diffusion tensor imaging;  fatigue;  MRI;  Multiple sclerosis;  voxel-wise analysis

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

Detecting schizophrenia early: Prediagnosis healthcare utilization characteristics of patients with schizophrenia may aid early detection
(2019) Schizophrenia Research, . 

Wallace, A.^a , Isenberg, K.^{b c} , York, W.^a , Shinde, M.^d , Barron, J.^a , Franchino-Elder, J.^e , Sand, M.^e , Sidovar, M.^e

^a HealthCore, Inc., 123 Justison Street, Suite 200, Wilmington, DE 19801, United States
^b Anthem Inc., 1831 Chestnut Street, Saint Louis, MO 63103, United States
^c Washington University School of Medicine, Department of Psychiatry, 660 S. Euclid Ave., St Louis, MO 63110, United States
^d Harvard Pilgrim HealthCare, 401 Park Drive, Suite 401A, Boston, MA 01778, United States
^e Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States

Abstract
Introduction: Many patients exhibit subsyndromal clinical findings of schizophrenia prior to diagnosis. Early treatment may mitigate schizophrenia development, yet little is known about comorbidities and healthcare resource utilization (HCRU) in these patients before diagnosis. Methods: This retrospective, longitudinal cohort study, conducted between January 1, 2007 and April 30, 2016, used claims data from the US HealthCore Integrated Research Database. Newly diagnosed patients with schizophrenia (International Classification of Diseases, Ninth Revision: 295.x or ICD 10 F20.%) were identified and matched (1:4) with non-schizophrenia comparators. Patients were 15–54 years of age with either ≥1 inpatient/emergency room claim with a primary schizophrenia diagnosis, or ≥2 claims in any setting with any schizophrenia diagnosis. Demographics, comorbidities, physician specialties, medications, and related services, and other HCRU were compared between cohorts for up to 5 years before diagnosis. Results: The schizophrenia cohort included 6732 patients (57.4% male, mean age 30.3 years for males and 36.2 years for females). All outcomes were more prevalent in the schizophrenia cohort than the comparator cohort. Substantial comorbidity, medication use, and HCRU were observed in the schizophrenia cohort even 4–5 years before diagnosis with increasing findings approaching diagnosis. From 4–5 years to 0–12 months before diagnosis, resource use increased from 20.5% to 53.3% for atypical antipsychotics, 29.3% to 48.2% for antidepressants, and 15.1% to 35.5% for psychiatric diagnostic examinations. Conclusions: Patients with schizophrenia extensively use healthcare resources up to 5 years before diagnosis. Our findings may help with developing predictive models to identify patients at high risk of schizophrenia. © 2019

Author Keywords
Antipsychotics;  Comorbidity;  Diagnosis;  Medication use;  Psychotic disorder;  Subsyndromal

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