WashU weekly Neuroscience publications

A synthesis strategy for tetracyclic terpenoids leads to agonists of ERβ
(2019) Nature Communications, 10 (1), art. no. 2448, . 

Kim, W.S.^a , Shalit, Z.A.^a , Nguyen, S.M.^b , Schoepke, E.^c , Eastman, A.^d , Burris, T.P.^c , Gaur, A.B.^b , Micalizio, G.C.^a

^a Dartmouth College, Department of Chemistry, Burke Laboratory, Hanover, NH 03755, United States
^b Dartmouth College, Geisel School of Medicine, Department of Neurology, Lebanon, NH 03756, United States
^c Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, United States
^d Dartmouth College, Geisel School of Medicine, Department of Molecular and Systems Biology, Lebanon, NH 03756, United States

Abstract
Natural product and natural product-like molecules continue to be important for the development of pharmaceutical agents, as molecules in this class play a vital role in the pipeline for new therapeutics. Among these, tetracyclic terpenoids are privileged, with >100 being FDA-approved drugs. Despite this significant pharmaceutical success, there remain considerable limitations to broad medicinal exploitation of the class due to lingering scientific challenges associated with compound availability. Here, we report a concise asymmetric route to forging natural and unnatural (enantiomeric) C19 and C20 tetracyclic terpenoid skeletons suitable to drive medicinal exploration. While efforts have been focused on establishing the chemical science, early investigations reveal that the emerging chemical technology can deliver compositions of matter that are potent and selective agonists of the estrogen receptor beta, and that are selectively cytotoxic in two different glioblastoma cell lines (U251 and U87). © 2019, The Author(s).

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

Shared genetic influences on adolescent body mass index and brain structure: A voxel-based morphometry study in twins
(2019) NeuroImage, 199, pp. 261-272. 

Kennedy, J.T., Astafiev, S.V., Golosheykin, S., Korucuoglu, O., Anokhin, A.P.

Department of Psychiatry, Washington University School of Medicine, United States

Abstract
Background: Previous research has demonstrated significant relationships between obesity and brain structure. Both phenotypes are heritable, but it is not known whether they are influenced by common genetic factors. We investigated the genetic etiology of the relationship between individual variability in brain morphology and BMIz using structural MRI in adolescent twins. Method: The sample (n = 258) consisted of 54 monozygotic and 75 dizygotic twin pairs (mean(SD) age = 13.61(0.505), BMIz = 0.608(1.013). Brain structure (volume and density of gray and white matter) was assessed using VBM. Significant voxelwise heritability of brain structure was established using the Accelerated Permutation inference for ACE models (APACE) program, with structural heritability varying from 15 to 97%, depending on region. Bivariate heritability analyses were carried out comparing additive genetic and unique environment models with and without shared genetics on BMIz and the voxels showing significant heritability in the APACE analyses. Results: BMIz was positively related to gray matter volume in the brainstem and thalamus and negatively related to gray matter volume in the bilateral uncus and medial orbitofrontal cortex, gray matter density in the cerebellum, prefrontal lobe, temporal lobe, and limbic system, and white matter density in the brainstem. Bivariate heritability analyses showed that BMIz and brain structure share ∼1/3 of their genes and that ∼95% of the phenotypic correlation between BMIz and brain structure is due to shared additive genetic influences. These regions included areas related to decision-making, motivation, liking vs. wanting, taste, interoception, reward processing/learning, caloric evaluation, and inhibition. Conclusion: These results suggested genetic factors are responsible for the relationship between BMIz and heritable BMIz related brain structure in areas related to eating behavior. © 2019 Elsevier Inc.

Author Keywords
Adolescence;  Density;  Heritability;  Obesity;  VBM;  Volume

Document Type: Article
Publication Stage: Final
Source: Scopus

Obsessions are strongly related to eating disorder symptoms in anorexia nervosa and atypical anorexia nervosa
(2019) Eating Behaviors, 34, art. no. 101298, . 

Levinson, C.A.^a , Brosof, L.C.^a , Ram, S.S.^a , Pruitt, A.^b , Russell, S.^b , Lenze, E.J.^c

^a University of Louisville, Department of Psychological & Brain Sciences, United States
^b Louisville Center for Eating Disorders/Louisville OCD Clinic, United States
^c Washington University in St. Louis, Department of Psychiatry, United States

Abstract
Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are highly comorbid. However, little research has examined which specific cognitive-behavioral aspects (e.g., checking, obsessing) of OCD are most relevant in those with AN. Furthermore, there is no research examining aspects of OCD in Atypical AN. The current two studies (N = 139 and N = 115 individuals diagnosed with AN/Atypical AN) examined a) which aspects of OCD were most related to AN symptomatology and b) if there were differences in OCD between individuals diagnosed with AN vs Atypical AN. We found that obsessing was most related to AN symptoms. We also found that there were no substantial significant differences between AN and Atypical AN. These findings add to the literature suggesting minimal differences between AN and Atypical AN, specifically regarding OCD symptomatology. These findings clarify that obsessions (rather than compulsions) may be the specific aspect of OCD most warranting treatment intervention in AN and Atypical AN. © 2019 Elsevier Ltd

Author Keywords
Anorexia nervosa;  Atypical anorexia nervosa;  Obsessions;  Obsessive-compulsive disorder

Document Type: Article
Publication Stage: Final
Source: Scopus

Response to: Goldberg et al. and Severance et al. Letters to the Editor: The clinical significance of improving remission over standard of care – The reality of treatment resistant-based therapies
(2019) Journal of Psychiatric Research, 114, pp. 211-213. 

Greden, J.F.^a , Parikh, S.V.^a , Rothschild, A.J.^b , Thase, M.E.^c , Dunlop, B.W.^d , DeBattista, C.^e , Conway, C.R.^f , Forester, B.P.^g , Mondimore, F.M.^h , Shelton, R.C.ⁱ , Macaluso, M.^j , Li, J.^k , Brown, K.^l , Gilbert, A.^k , Burns, L.^k , Jablonski, M.R.^k , Dechairo, B.^{k l}

^a University of Michigan Comprehensive Depression Center and Department of Psychiatry, and National Network of Depression Centers, 4250 Plymouth Rd, Ann Arbor, MI 48109, United States
^b University of Massachusetts Medical School and UMass Memorial Healthcare, 55 N Lake Ave, Worcester, MA 01655, United States
^c Perelman School of Medicine of the University of Pennsylvania and the Corporal Michael Crescenz VAMC, 3400 Civic Center Blvd, Philadelphia, PA 19104, United States
^d Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, 12 Executive Park Dr NE #200, Atlanta, GA 30329, United States
^e Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, 401 Quarry Rd, Stanford, CA 94305, United States
^f Washington University School of Medicine, Department of Psychiatry, and the John Cochran Veteran’s Administration Hospital, 660 S Euclid Ave, St. Louis, MO 63110, United States
^g McLean Hospital, Division of Geriatric Psychiatry, Harvard Medical School, 115 Mill St, Belmont, MA 02478, United States
^h Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, 1800 Orleans St, Baltimore, MD 21287, United States
ⁱ The University of Alabama at Birmingham, Department of Psychiatry and School of Medicine, 1720 2nd Ave S, Birmingham, AL, United States
^j University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences, 1010 N Kansas St, Wichita, KS 67214, United States
^k Assurex Health, Inc., 6960 Cintas Blvd, Mason, OH 45040, United States
^l Myriad Genetics, Inc., 320 Wakara Way, Salt Lake City, UT 84108, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

Progression of Low-Grade Glioma During Pregnancy With Subsequent Regression Postpartum Without Treatment-A Case Report
(2019) Neurosurgery, 84 (6), pp. E430-E436. 

Shah, A.S.^a , Nicoletti, L.K.^a , Kurtovic, E.^a , Tsien, C.I.^b , Benzinger, T.L.S.^c , Chicoine, M.R.^a

^a Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND AND IMPORTANCE: This report illustrates a case of a low-grade glioma that showed significant disease progression during pregnancy, and then subsequent regression spontaneously in the postpartum period without treatment. This is a rare case of spontaneous glioma regression in the postpartum period, and may suggest underlying mechanisms of hormonal influences upon glioma progression. CLINICAL PRESENTATION: The patient is a 27-yr-old female who underwent placement of a right-sided ventriculoperitoneal shunt for aqueductal stenosis at 8 wk of age. At the age of 24 yr, she was evaluated for chronic headaches and was found on magnetic resonance imaging (MRI) for the first time to have a small nonenhancing tectal glioma that remained stable on follow-up MRI. At the age of 25 yr, she returned for annual follow-up after giving birth and reported a significant increase in headache frequency and severity during the pregnancy. Repeat imaging now showed a larger, contrast-enhancing lesion. A decision was made to pursue radiosurgery, but during the pretreatment planning phase, the lesion and symptoms regressed spontaneously, and the lesion has remained stable on repeat MRI studies over a 30-mo period since delivery of her child. CONCLUSION: A young woman with a tectal glioma developed symptomatic disease progression during pregnancy, and subsequently had regression of the lesion and symptoms in the postpartum period without treatment. This case supports watchful waiting in select cases and suggests a potential role of hormones in glioma progression. Copyright © 2018 by the Congress of Neurological Surgeons.

Author Keywords
Disease Progression;  Glioma;  Headache;  Pregnancy;  Regression;  Watchful Waiting

Document Type: Article
Publication Stage: Final
Source: Scopus

Multicenter Study of Pipeline Flex for Intracranial Aneurysms
(2019) Neurosurgery, 84 (6), pp. E402-E409. Cited 1 time.

Brasiliense, L.B.C.^a , Aguilar-Salinas, P.^b , Lopes, D.K.^c , Nogueira, D.^c , DeSousa, K.^d , Nelson, P.K.^d , Moran, C.J.^e , Mazur, M.D.^f , Taussky, P.^f , Park, M.S.^f , Dabus, G.^g , Linfante, I.^g , Chaudry, I.^h , Turner, R.D.^h , Spiotta, A.M.^h , Turk, A.S.^h , Siddiqui, A.H.ⁱ , Levy, E.I.ⁱ , Hopkins, L.N.ⁱ , Arthur, A.S.^j , Nickele, C.^j , Gonsales, D.^b , Sauvageau, E.^b , Hanel, R.A.^b

^a Division of Neurosurgery, University of Arizona, Tucson, AZ, United States
^b Baptist Neurological Institute, Lyerly Neurosurgery, Baptist Health, Jacksonville, Florida
^c Department of Neurosurgery, Rush University Medical Center, Chicago, IL, United States
^d Department of Radiology and Neurosurgery, NYU Langone Medical CenterNY, United States
^e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
^g Miami Cardiac & Vascular Institute, Baptist Health South Florida, Miami, FL, United States
^h Department of Neurosurgery and Radiology, MUSC, Charleston, SC, United States
ⁱ Department of Neurosurgery and Toshiba Stroke Research Center, University at Buffalo, Buffalo, NY, United States
^j Department of Neurosurgery, University of Tennessee Health Sciences Center, Memphis, TN, United States

Abstract
BACKGROUND: The Pipeline Flex (PED Flex; Medtronic, Dublin, Ireland) was designed to facilitate deployment and navigation compared to its previous iteration to reduce the rate of technical events and complications. OBJECTIVE: To assess the neurological morbidity and mortality rates of the PED Flex at 30 d. METHODS: Information from 9 neurovascular centers was retrospectively obtained between July 2014 and March 2016. Data included patient/aneurysm characteristics, periprocedural events, clinical, and angiographic outcomes. Multivariate logistic regression was performed to determine predictors of unfavorable clinical outcome (modified Rankin Scale [mRS] > 2). RESULTS: A total of 205 patients harboring 223 aneurysms were analyzed. The 30-d neurological morbidity and mortality rates were 1.9% (4/205) and 0.5% (1/205), respectively. The rate of intraprocedural events without neurological morbidity was 6.8% (14/205), consisting of intraprocedural ischemic events in 9 patients (4.5%) and hemorrhage in 5 (2.4%). Other technical events included difficulty capturing the delivery wire in 1 case (0.5%) and device migration after deployment in another case (0.5%). Favorable clinical outcome (mRS 0-2) was achieved in 186 patients (94.4%) at discharge and in 140 patients (94.5%) at 30 d. We did not find predictors of clinical outcomes on multivariate analysis. CONCLUSION: The 30-d rates of neurological morbidity and mortality in this multicenter cohort using the PED Flex for the treatment of intracranial aneurysms were low, 1.9% (4/205) and 0.5% (1/205), respectively. In addition, technical events related to device deployment were also low, most likely due to the latest modifications in the delivery system. Copyright © 2018 by the Congress of Neurological Surgeons.

Author Keywords
Aneurysm;  Embolization;  Endovascular;  Pipeline;  Stroke

Document Type: Article
Publication Stage: Final
Source: Scopus

Analysis of motor control in patients with low back pain: A key to personalized care?
(2019) Journal of Orthopaedic and Sports Physical Therapy, 49 (6), pp. 380-388. Cited 4 times.

Van Dieën, J.H.^g , Peter Reeves, N.^{a b c} , Kawchuk, G.^d , Van Dillen, L.R.^e , Hodges, P.W.^f

^a Center for Orthopedic Research, Michigan State University, Lansing, MI, United States
^b Department of Osteopathic Surgical Specialties, Michigan State University, East Lansing, MI, United States
^c Sumaq Life LLC, East Lansing, MI, United States
^d Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada
^e Program in Physical Therapy, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
^f Clinical Centre for Research Excellence in Spinal Pain, Injury and Health, School of Health and RehabilitationSciences, University of Queensland, Brisbane, Australia
^g Department of Human Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, van der Boechorststraat 9, Amsterdam, NL-1081 BT, Netherlands

Abstract
Motor control exercise has been shown to be effective in the management of low back pain (LBP). However, the effect sizes for motor control exercise are modest, possibly because studies have used a one-size-fits-all approach, while the literature suggests that patients may differ in presence or type of motor control issues. In this commentary, we address the question of whether consideration of such variation in motor control issues might contribute to more personal¬ ized motor control exercise for patients with LBP. Such an approach is plausible, because motor control changes may play a role in persistence of pain through effects on tissue loading that may cause nociceptive afference, particularly in the case of peripheral sensitization. Subgrouping systems used in clinical practice, which comprise motor control aspects, allow reliable classification that is, in part, aligned with findings in studies on motor control in patients with LBP. Motor control issues may have heuristic value for treatment allocation, as the different presentations observed suggest different targets for motor control exercise, but this remains to be proven. Finally, clinical assessment of patients with LBP should take into account more aspects than motor control alone, including pain mechanisms, musculoskeletal health, and psychosocial factors, and may need to be embedded in a stratification approach based on prognosis to avoid undue diagnostic procedures. The authors certify that they have no affiliations with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the article. Copyright © 2019 Journal of Orthopaedic & Sports Physical Therapy®

Author Keywords
Back pain;  Diagnostics;  Exercise;  Postural control;  Subgrouping

Document Type: Review
Publication Stage: Final
Source: Scopus

Examining the Patient-Reported Outcomes Measurement Information System versus the Scoliosis Research Society–22r in adult spinal deformity
(2019) Journal of Neurosurgery: Spine, 30 (6), pp. 801-806. 

Kelly, M.P.^{a i} , Kallen, M.A.^b , Shaffrey, C.I.^c , Smith, J.S.^c , Burton, D.C.^d , Ames, C.P.^e , Lafage, V.^f , Schwab, F.J.^f , Kim, H.J.^f , Klineberg, E.O.^g , Bess, S.^h

^a Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
^c Department of Neurological Surgery, University of Virginia, Charlottesville, VA, United States
^d Department of Orthopedic Surgery, University of Kansas School of Medicine, Wichita, KS, United States
^e Department of Neurological Surgery, University of California, San Francisco, CA, United States
^f Hospital for Special Surgery, New York, NY, United States
^g Department of Orthopedic Surgery, University of California, Davis, Sacramento, CA, United States
^h Department of Spine Surgery, Denver International Spine Clinic, Presbyterian St. Luke’s/Rocky Mountain Hospital for Children, Denver, CO, United States

Abstract
OBJECTIVE After using PROsetta Stone crosswalk tables to calculate Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) and Pain Interference (PI) scores, the authors sought to examine 1) correlations with Scoliosis Research Society–22r (SRS-22r) scores, 2) responsiveness to change, and 3) the relationship between baseline scores and 2-year follow-up scores in adult spinal deformity (ASD). METHODS PROsetta Stone crosswalk tables were used to converted SF-36 scores to PROMIS scores for pain and physical function in a cohort of ASD patients with 2-year follow-up. Spearman correlations were used to evaluate the relationship of PROMIS scores with SRS-22r scores. Effect size (ES) and adjusted standardized response mean (aSRM) were used to assess responsiveness to change. Linear regression was used to evaluate the association between baseline scores and 2-year follow-up scores. RESULTS In total, 425 (425/625, 68%) patients met inclusion criteria. Strong correlations (all |r| > 0.7, p < 0.001) were found between baseline and 2-year PROMIS values and corresponding SRS-22r domain scores. PROMIS-PI showed a large ES (1.09) and aSRM (0.88), indicating good responsiveness to change. PROMIS-PF showed a moderate ES (0.52) and moderate aSRM (0.69), indicating a moderate responsiveness to change. Patients with greater baseline pain complaints were associated with greater pain improvement at 2 years for both SRS-22r Pain (B = 0.39, p < 0.001) and PROMIS-PI (B = 0.45, p < 0.001). Higher functional scores at baseline were associated with greater average improvements in both SRS-22r Activity (B = 0.62, p < 0.001) and PROMIS-PF (B = 0.40, p < 0.001). CONCLUSIONS The authors found strong correlations between the SRS-22r Pain and Activity domains with corresponding PROMIS-PI and -PF scores. Pain measurements showed similar and strong ES and aSRM while the function measurements showed similar, moderate ES and aSRM at 2-year follow-up. These data support further exploration of the use of PROMIS–computer adaptive test instruments in ASD. ©AANS 2019

Author Keywords
Adult deformity;  Outcomes;  PROMIS;  Scoliosis;  Spine

Document Type: Article
Publication Stage: Final
Source: Scopus

Motor control changes in low back pain: Divergence in presentations and mechanisms
(2019) Journal of Orthopaedic and Sports Physical Therapy, 49 (6), pp. 370-379. Cited 4 times.

Van Dieën, J.H.^a , Peter Reeves, N.^{b c d} , Kawchuk, G.^e , Van Dillen, L.R.^f , Hodges, P.W.^g

^a Department of Human Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, Netherlands
^b Center for Orthopedic Research, Michigan State University, Lansing, MI, United States
^c Department of Osteopathic Surgical Specialties, Michigan State University, East Lansing, MI, United States
^d Sumaq Life LLC, East Lansing, MI, United States
^e Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada
^f Program in Physical Therapy, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
^g Clinical Centre for Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Sciences, University of Queensland, Brisbane, Australia

Abstract
patients with low back pain demonstrate differences in all aspects of trunk motor control that are most often studied as differences in muscle activity and kinematics. However, differences in these aspects of motor control are largely inconsistent. We propose that this may reflect the existence of 2 phenotypes or possibly the ends of a spectrum, with “tight control” over trunk movement at one end and “loose control” at the other. Both may have beneficial effects, with tight control protecting against large tissue strains from uncontrolled movement and loose control protecting against high muscle forces and resulting spinal compression. Both may also have long-term negative consequences. For example, whereas tight control may cause high compressive loading on the spine and sustained muscle activity, loose control may cause excessive tensile strains of tissues. Moreover, both phenotypes could be the result of either an adaptation process aimed at protecting the low back or direct interference of low back pain and related changes with trunk motor control. The existence of such phenotypes would suggest different motor control exercise interventions. Although some promising data supporting these phenotypes have been reported, it remains to be shown whether these phenotypes are valid, how treatment can be targeted to these phenotypes, and whether this targeting yields superior clinical outcomes. Copyright ©2019 Journal of Orthopaedic & Sports Physical Therapy®

Author Keywords
Back pain;  Exercise;  Postural control;  Spine;  Subgrouping

Document Type: Review
Publication Stage: Final
Source: Scopus

Can biomechanics research lead to more effective treatment of low back pain? A point-counterpoint debate
(2019) Journal of Orthopaedic and Sports Physical Therapy, 49 (6), pp. 425-436. Cited 5 times.

Cholewicki, J.^{a i} , Breen, A.^b , Popovich, J.M., Jr.^{a i} , Peter Reeves, N.^{c i i} , Sahrmann, S.A.^d , Van Dillen, L.R.^{d e} , Vleeming, A.^{f g} , Hodges, P.W.^h

^a Department of Osteopathic Surgical Specialties, Michigan State University, East Lansing, MI, United States
^b Faculty of Science and Technology, Bournemouth University, Poole, United Kingdom
^c Sumaq Life LLC, East Lansing, MI, United States
^d Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, United States
^e Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
^f Department of Anatomy, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States
^g Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
^h Clinical Centre for Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Sciences, University of Queensland, Brisbane, Australia
ⁱ Center for Orthopedic Research, Michigan State University, McLaren Orthopedic Hospital, 2727 South Pennsylvania Avenue, Lansing, MI 48910, United States

Abstract
Although biomechanics plays a role in the development and perhaps the persistent or recurrent nature of low back pain (LBP), whether biomechanics alone can provide the basis for intervention is debated. Biomechanics, which refers to the mechanics of the body, including its neuromuscular control, has been studied extensively in LBP. But, can gains be made in understanding LBP by research focused on this component of biology in the multifactorial biopsychosocial problem of LBP? This commentary considers whether biomechanics research has the potential to advance treatment of LBP, and how likely it is that this research will lead to better treatment strategies. A point-counterpoint format is taken to present both sides of the argument. First, the challenges faced by an approach that considers biomechanics in isolation are presented. Next, we describe 3 models that place substantial emphasis on biomechanical factors. Finally, reactions to each point are presented as a foundation for further research and clinical practice to progress understanding of the place for biomechanics in guiding treatment of LBP. Copyright © 2019 Journal of Orthopaedic & Sports Physical Therapy®

Author Keywords
Biomechanics;  Low back pain;  Lumbar spine

Document Type: Review
Publication Stage: Final
Source: Scopus

Convergence and divergence of exercise-based approaches that incorporate motor control for the management of low back pain
(2019) Journal of Orthopaedic and Sports Physical Therapy, 49 (6), pp. 437-452. Cited 2 times.

Hides, J.A.^{a b h} , Donelson, R.^c , Lee, D.^d , Prather, H.^e , Sahrmann, S.A.^f , Hodges, P.W.^g

^a Mater Back Stability Research Clinic, Mater Health Services, South Brisbane, Australia
^b Menzies Health Institute Queensland, Gold Coast Campus Griffith UniversityQLD, Australia
^c SelfCare First, LLC, Hanover, NH, United States
^d Diane Lee and Associates, Surrey, Canada
^e Departments of Orthopaedic Surgery and Neurology, Washington University School of Medicine, St Louis, MO, United States
^f Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, United States
^g Clinical Centre for Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Sciences, University of Queensland, Brisbane, Australia
^h School of Allied Health Sciences, Griffith University, Nathan Campus, 170 Kessels Road, Nathan, QLD 4111, Australia

Abstract
Many approaches for low back pain (LBP) management focus on modifying motor control, which refers to motor, sensory, and central processes for control of posture and movement. A common assumption across approaches is that the way an individual loads the spine by typical postures, movements, and muscle activation strategies contributes to LBP symptom onset, persistence, and recovery. However, there are also divergent features from one approach to another. This commentary presents key principles of 4 clinical physical therapy approaches, including how each incorporates motor control in LBP management, the convergence and divergence of these approaches, and how they interface with medical LBP management. The approaches considered are movement system impairment syndromes of the lumbar spine, Mechanical Diagnosis and Therapy, motor control training, and the integrated systems model. These were selected to represent the diversity of applications, including approaches using motor control as a central or an adjunct feature, and approaches that are evidence based or evidence informed. This identification of areas of convergence and divergence of approaches is designed to clarify the key aspects of each approach and thereby serve as a guide for the clinician and to provide a platform for considering a hybrid approach tailored to the individual patient. Copyright © 2019 Journal of Orthopaedic & Sports Physical Therapy®

Author Keywords
Clinical perspectives;  Low back pain;  Motor control;  Spinal control

Document Type: Review
Publication Stage: Final
Source: Scopus

Quantitative assessment of nonpelvic pressure pain sensitivity in urologic chronic pelvic pain syndrome: a MAPP Research Network study
(2019) Pain, 160 (6), pp. 1270-1280. 

Harte, S.E.^a , Schrepf, A.^a , Gallop, R.^{b c} , Kruger, G.H.^{a d} , Lai, H.H.H.^e , Sutcliffe, S.^f , Halvorson, M.^a , Ichesco, E.^a , Naliboff, B.D.^g , Afari, N.^{h i} , Harris, R.E.^a , Farrar, J.T.^c , Tu, F.^j , Landis, J.R.^c , Clauw, D.J.^a , MAPP Research Network^k

^a Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, United States
^b Department of Mathematics, West Chester University, West Chester, PA, United States
^c Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^d Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, United States
^e Division of Urologic Surgery, Departments of Surgery and Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^f Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, MO, United States
^g Departments of Medicine and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, United States
^h Department of Psychiatry, University of California San Diego, San Diego, CA, United States
ⁱ Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
^j Department of Obstetrics and Gynecology, Northshore University Health System, Evanston, IL, United States

Abstract
Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

Document Type: Article
Publication Stage: Final
Source: Scopus

Cerebral aspergillosis within new tumour site presents as incidental new brain lesion in patient receiving temozolomide for glioblastoma multiforme
(2019) BMJ Case Reports, 12 (5), art. no. e227500, . 

Liu, S.A.^a , Sullivan, T.^b , Bryce, C.^c , Chan, A.M.^d , Cilmi, S.^b

^a Internal Medicine, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
^b Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^c Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Internal Medicine Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Abstract
Glioblastoma multiforme (GBM) is an aggressive tumour that can lead to lymphopaenia. Its standard treatment involves temozolomide (TMZ) chemotherapy with radiation, often with addition of corticosteroids for symptomatic management. Although TMZ is also immunosuppressive, patients receiving TMZ rarely develop disseminated opportunistic infections. Here, we report the case of a patient with GBM receiving TMZ, radiotherapy and corticosteroids, who develops an incidental new brain lesion that is found to be disseminated Aspergillus within a new GBM tumour site. The patient received successful early treatment of her central nervous system aspergillosis. This case illustrates the profound immunosuppressive potential of GBM in conjunction with TMZ and corticosteroids, which can lead to high-morbidity opportunistic infections concurrently with tumour progression. Future research is needed to elucidate GBM, TMZ and corticosteroids’ compound immune effects and guide management that strikes a balance between treating high-morbidity infections and continuing with immunosuppressive chemotherapy. © BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
chemotherapy;  infectious diseases;  malignant disease and immunosuppression;  neuro-oncology

Document Type: Article
Publication Stage: Final
Source: Scopus

Long-term, super-resolution imaging of amyloid structures using transient amyloid binding microscopy
(2019) Progress in Biomedical Optics and Imaging – Proceedings of SPIE, 10884, art. no. 108840J, . 

Ding, T.^a , Spehar, K.^b , Bieschke, J.^c , Lew, M.D.^a

^a Department of Electrical and Systems Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
^c MRC Prion Unit, UCL Institute of Prion Diseases, 33 Cleveland St., London, W1W 7FF, United Kingdom

Abstract
Amyloid fibrils and tangles are signatures of Alzheimer disease, but nanometer-sized aggregation intermediates are hypothesized to be the structures most toxic to neurons. The structures of these oligomers are too small to be resolved by conventional light microscopy. We have developed a simple and versatile method, called transient amyloid binding (TAB), to image amyloid structures with nanoscale resolution using amyloidophilic dyes, such as Thioflavin T, without the need for covalent labeling or immunostaining of the amyloid protein. Transient binding of ThT molecules to amyloid structures over time generates photon bursts that are used to localize single fluorophores with nanometer precision. Continuous replenishment of fluorophores from the surrounding solution minimizes photobleaching, allowing us to visualize a single amyloid structure for hours to days. We show that TAB microscopy can image both the oligomeric and fibrillar stages of amyloid-β aggregation. We also demonstrate that TAB microscopy can image the structural remodeling of amyloid fibrils by epi-gallocatechin gallate. Finally, we utilize TAB imaging to observe the non-linear growth of amyloid fibrils. © COPYRIGHT SPIE. Downloading of the abstract is permitted for personal use only.

Author Keywords
Amyloid aggregation;  Amyloid-beta peptides;  Bindingactivated fluorescence;  Single-molecule localization microscopy

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Antidepressant Treatment for Late-Life Depression: Considering Risks and Benefits
(2019) Journal of the American Geriatrics Society, . 

Lenze, E.J., Ajam Oughli, H.

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

Document Type: Editorial
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

Common Data Elements for Unruptured Intracranial Aneurysms and Aneurysmal Subarachnoid Hemorrhage: Recommendations from the Working Group on Hospital Course and Acute Therapies—Proposal of a Multidisciplinary Research Group
(2019) Neurocritical Care, . Cited 3 times.

de Oliveira Manoel, A.L.^{a b} , van der Jagt, M.^c , Amin-Hanjani, S.^d , Bambakidis, N.C.^e , Brophy, G.M.^f , Bulsara, K.^g , Claassen, J.^h , Connolly, E.S.^h , Hoffer, S.A.^e , Hoh, B.L.ⁱ , Holloway, R.G.^j , Kelly, A.G.^j , Mayer, S.A.^k , Nakaji, P.^l , Rabinstein, A.A.^m , Vajkoczy, P.ⁿ , Vergouwen, M.D.I.^o , Woo, H.^p , Zipfel, G.J.^q , Suarez, J.I.^r , Macdonald, R.L.^s , Brown, R.D.^s , de Oliveira Manoel, A.L.^s , Derdeyn, C.P.^s , Etminan, N.^s , Keller, E.^s , LeRoux, P.D.^s , Mayer, S.^s , Morita, A.^s , Rinkel, G.^s , Rufennacht, D.^s , Stienen, M.N.^s , Torner, J.^s , Wong, G.K.C.^s , Bijlenga, P.^s , Ko, N.^s , Werner, M.J.H.^s , Damani, R.^s , Broderick, J.^s , Dhar, R.^s , Jauch, E.C.^s , Kirkpatrick, P.J.^s , Martin, R.H.^s , Mocco, J.^s , Muehlschlegel, S.^s , Mutoh, T.^s , Nyquist, P.^s , Olson, D.^s , Mejia-Mantilla, J.H.^s , Bambakidis, N.^s , Brophy, G.^s , Kelly, A.^s , Rabinstein, A.^s , Chou, S.^s , Doré, S.^s , Dumont, A.S.^s , Gunel, M.^s , Kasuya, H.^s , Roederer, A.^s , Ruigrok, Y.^s , Vespa, P.M.^s , Sarrafzadeh-Khorrasani, A.S.^s , Hackenberg, K.^s , Huston, J.^s , Krings, T.^s , Lanzino, G.^s , Meyers, P.M.^s , Wintermark, M.^s , Daly, J.^s , Ogilvy, C.^s , Rhoney, D.H.^s , Roos, Y.B.^s , Siddiqui, A.^s , Algra, A.^s , Frösen, J.^s , Hasan, D.^s , Juvela, S.^s , Langer, D.J.^s , Salman, R.A.-S.^s , Hanggi, D.^s , Schweizer, T.^s , Visser-Meily, J.^s , Amos, L.^s , Ludet, C.^s , Moy, C.^s , Odenkirchen, J.^s , Ala’i, S.^s , Esterlitz, J.^s , Joseph, K.^s , Sheikh, M.^s , the Unruptured Aneurysms and SAH − CDE Project Investigators^s

^a Neuroscience Research Program in the Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, University of Toronto, Toronto, Canada
^b Adult Critical Care Unit, Department of Critical Care Medicine, Hospital Paulistano – UnitedHealth Group Brazil, Rua Martiniano de Carvalho, 741, Bela Vista, São Paulo, SP 01321-001, Brazil
^c Department of Intensive Care Adults, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
^d Department of Neurosurgery, University of Illinois at Chicago, Chicago, United States
^e Department of Neurological Surgery, UH Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, United States
^f Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Richmond, VA, United States
^g Department of Neurosurgery, University of Connecticut, Farmington, CT, United States
^h Columbia University, New York, NY, United States
ⁱ Department of Neurosurgery, University of Florida, Gainesville, FL, United States
^j Department of Neurology, University of Rochester, Rochester, NY, United States
^k Department of Neurology, Henry Ford Health System, Detroit, MI, United States
^l Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, United States
^m Department of Neurology, Mayo Clinic, Rochester, MN, United States
ⁿ Department of Neurosurgery, Charite Hospital, Universitatsmedizin, Berlin, Germany
^o Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
^p Department of Neurosurgery and Radiology, Zucker School of Medicine at Hofstra/Northwell Health, New York, NY, United States
^q Washington University in St Louis, St. Louis, MO, United States
^r Departments of Anesthesiology and Critical Care Medicine, Neurology, and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, United States

Abstract
Introduction: The Common Data Elements (CDEs) initiative is a National Institute of Health/National Institute of Neurological Disorders and Stroke (NINDS) effort to standardize naming, definitions, data coding, and data collection for observational studies and clinical trials in major neurological disorders. A working group of experts was established to provide recommendations for Unruptured Aneurysms and Aneurysmal Subarachnoid Hemorrhage (SAH) CDEs. Methods: This paper summarizes the recommendations of the Hospital Course and Acute Therapies after SAH working group. Consensus recommendations were developed by assessment of previously published CDEs for traumatic brain injury, stroke, and epilepsy. Unruptured aneurysm- and SAH-specific CDEs were also developed. CDEs were categorized into “core”, “supplemental—highly recommended”, “supplemental” and “exploratory”. Results: We identified and developed CDEs for Hospital Course and Acute Therapies after SAH, which included: surgical and procedure interventions; rescue therapy for delayed cerebral ischemia (DCI); neurological complications (i.e. DCI; hydrocephalus; rebleeding; seizures); intensive care unit therapies; prior and concomitant medications; electroencephalography; invasive brain monitoring; medical complications (cardiac dysfunction; pulmonary edema); palliative comfort care and end of life issues; discharge status. The CDEs can be found at the NINDS Web site that provides standardized naming, and definitions for each element, and also case report form templates, based on the CDEs. Conclusion: Most of the recommended Hospital Course and Acute Therapies CDEs have been newly developed. Adherence to these recommendations should facilitate data collection and data sharing in SAH research, which could improve the comparison of results across observational studies, clinical trials, and meta-analyses of individual patient data. © 2019, Neurocritical Care Society.

Author Keywords
Aneurysm;  Clinical studies;  Common Data Elements;  Data coding;  Data collection;  Standardization;  Subarachnoid hemorrhage

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

Mitochondriopathy: The unifying concept in distal neuropathies?
(2019) International Review of Neurobiology, . 

Schmidt, R.E.

Washington University School of Medicine, Saint Louis, United States

Abstract
This is a new, exciting time for the study of peripheral nerve and its diseases. For many years research in peripheral neuropathies largely involved descriptive analysis, a situation which is now rapidly giving way to hypothesis testing with the development and validation of molecular genetic tools. Although it has been known for some time that many neuropathies target the most distal portions of the longest peripheral nerves, a process variously referred to as central-peripheral distal neuropathy, “dying-back” neuropathy, or “stocking-glove” neuropathy, proposed mechanisms driving axon loss have been generally unproven/untestable. Studies have shown that mitochondrial DNA mutations accumulate in distal axons and a unifying theory of distal neuropathy has been proposed based on underlying mitochondrial aging defects in mitogenesis and, thus, distal axon susceptibility, particularly if axonal transport defects also accompanied them. Increased levels of mtDNA mutations have been described in some painful neuropathies (e.g., HIV) compared to baseline HIV patients and controls. For some time no therapies were available to preserve and prevent the development of peripheral neuropathy and, with a variety of expected pathogenetic mechanisms, complex cocktails of therapeutic agents were envisioned. Although structure and ultrastructure continue to be relevant in the studies of mitochondriopathy-driven neuropathies, more techniques have been added and more complex hypotheses now expand the concept and focus directly on mitochondrial pathology or dysfunction. It is now possible to definitively test possible pathogenetic mechanisms with a variety of new tools and to formulate new and testable hypotheses. © 2019 Elsevier Inc.

Author Keywords
Chemotherapy;  Diabetes;  HIV;  Mitochondria;  Mitochondriopathy;  Mitophagy;  mtDNA;  Mutation;  Neuropathy

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

Mere exposure effect(s) in the context of explicit memory search
(2019) Memory and Cognition, . 

Grybinas, D.^a , Kantner, J.^b , Dobbins, I.G.^a

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, Saint Louis, MO 63130, United States
^b Department of Psychology, California State University, Northridge, CA, United States

Abstract
Prior stimulus exposure often increases later ratings of positive affect (e.g., pleasantness ratings). This phenomenon – the mere exposure effect (MEE) – appears robust following subliminal and incidental exposures. However, its expression in the context of explicit memory judgment remains unclear. In four studies, memory and pleasantness ratings were combined to investigate how memory conclusions (e.g., “studied” or “unstudied”) might moderate exposure effects. Experiment 1 examined basic recognition, Experiment 2 manipulated incentives for recognition decisions, and Experiments 3 and 4 examined source memory and paired-associate recall respectively. In general, items endorsed as recognized, attributed to the queried source, or accompanied by successful recall of a paired associate (i.e., confirmations) were rated as more pleasant than baseline norms. As important, items endorsed as unstudied, rejected as originating from a queried source, or failing to yield successful recall of a paired associated were rated as less pleasant than baseline norms. This suggests that it is the outcome of memory search that alters pleasantness ratings in the context of retrieval demands, and we discuss how this confirmation of search (COS) hypothesis accounts for current and prior findings. © 2019, The Psychonomic Society, Inc.

Author Keywords
Decision making;  Judgment;  Memory;  Recognition

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

Sex differences in metabolic brain aging
(2019) Proceedings of the National Academy of Sciences of the United States of America, 166 (22), pp. 10634-10635. 

Goyal, M.S.^{a b c} , Vlassenko, A.G.^a , Raichle, M.E.^{a b c}

^a Neuroimaging Laboratories, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

Neurogenesis takes a hit in Alzheimer’s disease
(2019) Science Translational Medicine, 11 (490), art. no. eaax1726, . 

Gallardo, G.

Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
New neurons are born in healthy humans throughout aging but decline in Alzheimer’s disease, linking a loss of neurogenesis with disease progression. © 2019, American Association for the Advancement of Science.

Document Type: Review
Publication Stage: Final
Source: Scopus

Novel Nerve Transfers for Motor and Sensory Restoration in High Cervical Spinal Cord Injury
(2019) World Neurosurgery, . 

Dibble, C.F.^a , Khalifeh, J.M.^a , VanVoorhis, A.^a , Rich, J.T.^b , Ray, W.Z.^a

^a Department of Neurological Surgery, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Otolaryngology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Background: Tetraplegia caused by cervical spinal cord injury is devastating for patients and represents a significant public health problem in both developed and developing countries. Improved functional outcomes after nerve transfers are increasingly reported in the literature, but thus far, no options exist for injuries above the C5 level. Case Description: We report the cases of 2 patients with C4 spinal cord injury, American Spinal Injury Association A, who underwent successful bilateral spinal accessory nerve transfers, on 1 side to the triceps nerve with long intervening sural graft and on the other side direct transfer to the motor fascicles of the middle trunk. Patients improved from Medical Research Council 0 to 4 on the side of the nerve graft and 0 to 2 or 3 on the side of the direct transfer. Both patients also underwent transfer of the greater auricular nerve to sensory fascicles of the middle trunk, and they experienced sensory recovery in the C6 distribution. Notably, both patients were far removed from the traditional window of nerve transfer surgery at 4 years and almost 11 years out from injury. Conclusions: We describe 2 successful cases of the first and to date only option for motor and sensory reinnervation in high cervical spinal cord injuries. These procedures provide a robust nerve transfer option capable of improving quality of life in tetraplegic patients. There may be a significant undertreated population of patients with cervical spinal cord injury patients in the United States who were previously considered outside the window for benefiting from nerve transfers but who would benefit from these techniques. © 2019 Elsevier Inc.

Author Keywords
Cervical spinal cord;  Nerve transfer;  Neurotization;  Spinal cord injury;  Tetraplegia

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

Elecsys® Total-Tau and Phospho-Tau (181P) CSF assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid
(2019) Clinical Biochemistry, . 

Lifke, V.^a , Kollmorgen, G.^a , Manuilova, E.^a , Oelschlaegel, T.^a , Hillringhaus, L.^a , Widmann, M.^b , von Arnim, C.A.F.^c , Otto, M.^c , Christenson, R.H.^d , Powers, J.L.^e , Shaw, L.M.^f , Hansson, O.^{g h} , Doecke, J.D.ⁱ , Li, Q.-X.^j , Teunissen, C.^k , Tumani, H.^c , Blennow, K.^{l m}

^a Roche Diagnostics GmbH, Nonnenwald 2, Penzberg, 82377, Germany
^b Amsterdam University Medical Center, Vrije Universiteit, De Boelelaan 1117Amsterdam 1081 HV, Germany
^c Clinic for Neurology, University Clinic Ulm, Oberer Eselsberg 45, Ulm, 89081, Germany
^d Department of Pathology, University of Maryland School of Medicine, 655 W Baltimore S, Baltimore, MD 21201, United States
^e Division of Endocrinology, Metabolism and Lipid Research, School of Medicine, Washington University in St Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
^f Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, United States
^g Clinical Memory Research Unit, Lund University, VO Minnessjukdomar, Simrisbanv 14/4, Malmö, 212 24, Sweden
^h Memory Clinic, Skåne University Hospital, Inga Marie Nilssons gata 47, Malmö, 214 21, Sweden
ⁱ The Commonwealth Scientific and Industrial Research Organisation/Australian E-Health Research Centre, Butterfield St & Bowen Bridge Rd, Herston, QLD 4029, Australia
^j The Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC 3052, Australia
^k Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam University Medical Center, Vrije Universiteit, De Boelelaan 1117, Amsterdam, HV 1081, Netherlands
^l Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Göteborgsvägen 31, Mölndal, 431 80, Sweden
^m Institute of Neuroscience and Physiology, Dept. of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Wallinsgatan 6, Mölndal, 431 41, Sweden

Abstract
Background: Total tau (tTau) and phosphorylated 181P tau (pTau) are supportive diagnostic cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. Manual CSF tau assays are limited by lot-to-lot and between-laboratory variability and long incubation/turnaround times. Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF immunoassays were developed for fully automated cobas e analyzers, allowing broader access in clinical practice and trials. Methods: Analytical performance, reproducibility, method comparisons with commercially available assays, and lot-to-lot and platform comparability (cobas e 601/411) of the Elecsys® CSF assays were assessed. Tau distributions and concentration ranges were evaluated in CSF samples from two clinical cohorts. Results: Both assays showed high sensitivity (limit of quantitation [LoQ]: 63 pg/mL [tTau]; 4 pg/mL [pTau]) and linearity over the measuring range (80–1300 pg/mL; 8–120 pg/mL), which covered the entire concentration range measured in clinical samples. Lot-to-lot and platform comparability demonstrated good consistency (Pearson’s r: 0.998; 1.000). Multicenter evaluation coefficients of variation (CVs): repeatability, &lt; 1.8%; intermediate precision, &lt; 2.8%; between-laboratory variability, &lt; 2.7% (both assays); and total reproducibility, &lt; 6.7% (tTau) and &lt; 4.7% (pTau). Elecsys® CSF assays demonstrated good correlation with commercially available tau assays. Conclusions: Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF assays demonstrate good analytical performance with clinically relevant measuring ranges; data support their use in clinical trials and practice. © 2019

Author Keywords
Alzheimer’s disease;  Biomarkers;  CSF;  Fully automated immunoassay;  Phosphorylated tau;  Total tau

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