WashU weekly Neuroscience publications

Associations between depression, anxious arousal and manifestations of psychological inflexibility
(2019) Journal of Behavior Therapy and Experimental Psychiatry, 62, pp. 88-96. 

Gilbert, K.E.^a , Tonge, N.A.^b , Thompson, R.J.^b

^a Department of Psychiatry, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background and objectives: Psychological inflexibility exhibits across multiple facets of functioning, including thinking styles, personality, cognitive shifting, emotion, and physiology, with many of these manifestations showing associations with depression. As such, these facets might be part of an overarching latent construct of psychological inflexibility that explains associations with depression. We predicted that (1) five facets of inflexibility (perseverative thinking, personality rigidity, attention-shifting, negative emotional inertia, and low respiratory sinus arrhythmia reactivity) would load onto a unique latent construct of psychological inflexibility. Further, we hypothesized this latent construct of psychological inflexibility would be (2) significantly associated with higher depression; and (3) associated with depression to a greater extent than anxious arousal. Methods: Seventy-five adult community participants completed measures assessing the five indices of inflexibility and self-report measures of depression and anxious arousal. Results: Structural equation modeling identified a latent inflexibility construct reflected by perseverative thinking, personality rigidity, and emotional inertia, but did not include attention-shifting or RSA reactivity. The inflexibility construct was positively associated with depression and anxious arousal, but more strongly associated with depression than with anxious arousal. Limitations: Limitations included a small sample size, cross-sectional approach, and dimensional measures of depression and anxious arousal. Conclusions: Findings provide preliminary support that multiple facets of inflexibility may emerge from a broader overarching vulnerability for internalizing psychopathology. This overarching inflexibility construct may have stronger associations with depression than with anxious arousal. © 2018 Elsevier Ltd

Author Keywords
Anxious arousal;  Depression;  PsPychological inflexibility

Document Type: Article
Source: Scopus

Individual differences in working memory capacity and long-term memory: The influence of intensity of attention to items at encoding as measured by pupil dilation
(2019) Journal of Memory and Language, 104, pp. 25-42. 

Miller, A.L.^a , Gross, M.P.^b , Unsworth, N.^a

^a Department of Psychology, University of Oregon, United States
^b Department of Psychological & Brain Sciences, Washington University in St. Louis, United States

Abstract
The present study used pupil dilation as an index of the intensity of attention to determine if variation in attention at encoding partially accounts for the relation between working memory capacity (WMC) and long-term memory (LTM). In Experiment 1, participants completed a delayed free recall task while pupil dilation was simultaneously recorded. Results revealed high WMC individuals displayed an increase in pupil dilation across serial positions, whereas low WMC individuals exhibited a decline in pupil dilation. Experiment 2 employed a similar method but manipulated encoding conditions via value–directed remembering. Results demonstrated when later serial positions were labeled as more important, the pupillary response no longer declined for low WMC individuals. Instead, low WMC individuals increased attention across serial positions, with the caveat being that these individuals devoted less attention than high WMC individuals to all items under these conditions. Overall, results support the notion that high WMC individuals outperform low WMC individuals in delayed free recall, which is partly explained by the amount of attention devoted to items at encoding. © 2018 Elsevier Inc.

Author Keywords
Attention;  Individual differences;  Long-term memory;  Recall;  Working memory

Document Type: Article
Source: Scopus

Use of eHealth and mHealth technology by persons with multiple sclerosis
(2019) Multiple Sclerosis and Related Disorders, 27, pp. 13-19. 

Marrie, R.A.^{a b} , Leung, S.^b , Tyry, T.^c , Cutter, G.R.^d , Fox, R.^e , Salter, A.^f

^a Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
^b Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
^c Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
^d Department of Biostatistics, University of Alabama at Birmingham, BirminghamBirmingham, AL, United States
^e Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
^f Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Health communication has evolved substantially over the last few years as the field of electronic health (eHealth) technologies has emerged. It is unknown what demographic and clinical characteristics are associated with use of eHealth technologies in MS. As these technologies are more widely adopted in health settings, it is important that health care providers understand who is using them, and to recognize potential disparities if they exist. Objective: We aimed to examine the use of eHealth technologies among persons with multiple sclerosis (MS), including the adoption of mobile Health (mHealth) applications (apps) and telehealth, perceived benefits of using mHealth apps, and sociodemographic and clinical characteristics associated with use of these technologies. Methods: In the spring 2017, we surveyed participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry about their use of eHealth technologies using questions adapted from the Health Information National Trends (HINTS) 4 Cycle 4 survey. Participants reported their internet use, electronic devices used, use of health related software apps and perceived benefits from using those apps, and their interest in exchanging medical information with a health care professional electronically. We used descriptive statistics to report use of eHealth technologies and multivariable logistic regression to evaluate factors associated with use of electronic devices, use of mHealth apps, telehealth use, and perceived benefits of using mHealth apps. Results: Of 6423 participants included in the analysis most participants were female, and white, with a mean (SD) age of 59.7 (10.1) years. Overall, 5408 (84.2%) had exchanged medical information with a health professional most often using a secure online portal (1839, 28.6%), followed by email (1327, 20.7%). of the 5529 smartphone and tablet users, 2556 (46.2%) used a mHealth app. Factors associated with a higher likelihood of reporting use of smartphones or tablets, mHealth apps and with perceived benefits of using these apps included online survey response, younger age, having comorbidities, and higher income and education levels. Conclusion: Use of eHealth technologies is common in the MS population and facilitates the exchange of health care information with providers. Use of mHealth apps is perceived to have health benefits. However, use of eHealth and mHealth technologies varies substantially with sociodemographic factors, and health care providers need to be aware of these disparities as these technologies are increasingly leveraged in health care settings. © 2018 Elsevier B.V.

Author Keywords
eHealth;  mHealth;  Multiple sclerosis

Document Type: Article
Source: Scopus

Trauma exposure acutely alters neural function during Pavlovian fear conditioning
(2018) Cortex, 109, pp. 1-13. 

Harnett, N.G.^a , Ference, E.W., III^b , Wood, K.H.^{a c} , Wheelock, M.D.^{a d} , Knight, A.J.^b , Knight, D.C.^a

^a Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
^b Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, United States
^c Department of Psychology, Samford University, Homewood, AL, United States
^d Department of Psychiatry, Washington University in St. Louis, St Louis, MO, United States

Abstract
Posttraumatic stress disorder (PTSD) is associated with dysfunction of the neural circuitry that supports fear learning and memory processes. However, much of what is known about neural dysfunction in PTSD is based on research in chronic PTSD populations. Less is known about neural function that supports fear learning acutely following trauma exposure. Determining the acute effects of trauma exposure on brain function would provide new insight into the neural processes that mediate the cognitive-affective dysfunction associated with PTSD. Therefore, the present study investigated neural activity that supports fear learning and memory processes in recently Trauma-Exposed (TE) and Non-Trauma-Exposed (NTE) participants. Participants completed a Pavlovian fear conditioning procedure during functional magnetic resonance imaging (fMRI). During fMRI, participants’ threat expectancy was continuously monitored. NTE participants showed greater threat expectancy during warning than safety cues, while no difference was observed in the TE group. This finding suggests TE participants overgeneralized the fear association to the safety cue. Further, only the TE group showed a negative relationship between fMRI signal responses within dorsomedial prefrontal cortex (PFC) and threat expectancy during safety cues. These results suggest the dorsomedial PFC mediates overgeneralization of learned fear as an acute result of trauma exposure. Finally, neural activity within the PFC and inferior parietal lobule showed a negative relationship with PTSD symptom severity assessed three months posttrauma. Thus, neural activity measured acutely following trauma exposure predicted future PTSD symptom severity. The present findings elucidate the acute effects of trauma exposure on cognitive-affective function and provide new insight into the neural mechanisms of PTSD. © 2018 Elsevier Ltd

Author Keywords
Emotion;  Fear;  fMRI;  PTSD;  Trauma

Document Type: Article
Source: Scopus

Novel nanofabricated dura substitute effectively repairs dural defects independent of defect size in a canine duraplasty model
(2018) Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 14, pp. 150-155. 

MacEwan, M.R.^a , Kovacs, T.^a , Ray, W.Z.^b

^a Acera Surgical, Inc., St. Louis, MO 63132, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Dural substitutes are commonly utilized to repair dural defects incurred during routine neurosurgical procedures. The present study aims to examine whether the resorption rate of a novel non-biologic, fully-resorbable nanofabricated dura substitute is suitable for effective repair of large dural defects. Small or large dural defects were created bilaterally in a canine duraplasty model and then repaired with the nanofabricated dura substitute. Animals were monitored post-operatively for signs of cerebral spinal fluid (CSF) leak and neurological abnormalities. Repair sites were explanted 4 or 13 weeks after surgery and evaluated by histopathology to assess neoduralization, implant resorption, and local inflammation. The nanofabricated dura substitute was observed to prevent CSF leakage and infection. Histopathology confirmed that the gradual resorption of the graft was balanced by increasing neoduralization over time and revealed comparable neoduralization and vascularization between small and large defects both 4 and 13 weeks after surgery. By week 13 all defects were healed with complete neoduralization across the implant site. The nanofabricated dura substitute demonstrated an optimal time course of resorption suited for repair of both large and small dural defects. The present study demonstrates the ability of the nanofabricated dura substitute to regenerate pristine dura in variable size defects. © 2018

Author Keywords
Animal model;  Histology;  Nanofabricated dura substitute

Document Type: Article
Source: Scopus

Radiosynthesis and evaluation of a fluorine-18 labeled radioligand targeting vesicular acetylcholine transporter
(2018) Bioorganic and Medicinal Chemistry Letters, 28 (21), pp. 3425-3430. 

Yue, X.^a , Luo, Z.^a , Liu, H.^a , Kaneshige, K.^b , Parsons, S.M.^b , Perlmutter, J.S.^{a c} , Tu, Z.^a

^a Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States
^c Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing the loss of cholinergic neurons in the brain that is associated with cognitive impairment of patients. 5-Hydrotetralin compound (±)-5-OH-VAT is potent (Ki = 4.64 ± 0.32 nM) and selective for VAChT (>1800-fold and 398-fold for σ1 and σ2 receptor, respectively) with favorable hydrophilicity (LogD = 1.78), while (−)-5-OH-VAT originally serves as the radiolabeling precursor of (−)-[18F]VAT, a promising VAChT radiotracer with a logD value of 2.56. To evaluate (−)-5-OH-[18F]VAT as a radiotracer for VAChT, we performed in vitro binding assay to determine the potency of the minus enantiomer (−)-5-OH-VAT and plus enantiomer (+)-5-OH-VAT, indicating that (−)-5-OH-VAT is a more potent VAChT enantiomer. Radiosynthesis of (−)-5-OH-[18F]VAT was explored using three strategies. (−)-5-OH-[18F]VAT was achieved with a good yield (24 ± 6%) and high molar activity (∼37 GBq/µmol, at the end of synthesis) using a microwave assisted two-step one-pot procedure that started with di-MOM protected nitro-containing precursor (−)-6. MicroPET studies in the brain of nonhuman primate (NHP) suggest that (−)-5-OH-[18F]VAT readily penetrated the blood brain barrier and specifically accumulated in the VAChT-enriched striatum with improved washout kinetics from striatum compared to [18F]VAT. Nevertheless, the lower target to non-target ratio may limit its use for in vivo measurement of the VAChT level in the brain. © 2018 Elsevier Ltd

Author Keywords
Fluorine-18;  PET imaging;  Radiolabeling;  Vesicular acetylcholine transporter

Document Type: Article
Source: Scopus

Conopeptides promote itch through human itch receptor hMgprX1
(2018) Toxicon, 154, pp. 28-34. 

Espino, S.S.^a , Robinson, S.D.^{b d} , Safavi-Hemami, H.^{b c} , Gajewiak, J.^b , Yang, W.^a , Olivera, B.M.^b , Liu, Q.^a

^a Department of Anesthesiology and Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Biology, University of Utah, Salt Lake City, UT 84112, United States
^c Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, United States
^d Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD 4072, Australia

Abstract
Members of Mas related G-protein coupled receptors (Mrgpr) are known to mediate itch. To date, several compounds have been shown to activate these receptors, including chloroquine, a common antimalarial drug, and peptides of the RF-amide family. However, specific ligands for these receptors are still lacking and there is a need for novel compounds that can be used to modulate the receptors in order to understand the cellular and molecular mechanism in which they mediate itch. Some cone snail venoms were previously shown to induce itch in mice. Here, we show that the venom of Conus textile induces itch through activation of itch-sensing sensory neurons, marked by their sensitivity to chloroquine. Two RF-amide peptides, CNF-Tx1 and CNF-Tx2, were identified in a C. textile venom gland transcriptome. These belong to the conorfamide family of peptides which includes previously described peptides from the venoms of Conus victoriae (CNF-Vc1) and Conus spurius (CNF-Sr1 and CNF-Sr2). We show that CNF-Vc1 and CNF-Sr1 activate MrgprC11 whereas CNF-Vc1 and CNF-Tx2 activate the human MrgprX1 (hMrgprX1). The peptides CNF-Tx1 and CNF-Sr2 do not activate MrgprC11 or hMrgprX1. Intradermal injection of CNF-Vc1 and CNF-Tx2 into the cheek of a transgenic mouse expressing hMrgprX1 instead of endogenous mouse Mrgprs resulted in itch-related scratching thus demonstrating the in vivo activity of these peptides. Using truncated analogues of CNF-Vc1, we identified amino acids at positions 7–14 as important for activity against hMrgprX1. The conopeptides reported here are tools that can be used to advance our understanding of the cellular and molecular mechanism of itch mediated by Mrgprs. © 2018

Author Keywords
Conopeptide;  Conorfamide;  hMrgprX1;  Itch;  MrgprC11;  RF-Amide

Document Type: Article
Source: Scopus

Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease
(2018) Neurology, 91 (14), pp. e1295-e1306. 

McDade, E.^a , Wang, G.^b , Gordon, B.A.^b , Hassenstab, J.^b , Benzinger, T.L.S.^b , Buckles, V.^b , Fagan, A.M.^b , Holtzman, D.M.^b , Cairns, N.J.^b , Goate, A.M.^b , Marcus, D.S.^b , Morris, J.C.^b , Paumier, K.^b , Xiong, C.^b , Allegri, R.^b , Berman, S.B.^b , Klunk, W.^b , Noble, J.^b , Ringman, J.^b , Ghetti, B.^b , Farlow, M.^b , Sperling, R.A.^b , Chhatwal, J.^b , Salloway, S.^b , Graff-Radford, N.R.^b , Schofield, P.R.^b , Masters, C.^b , Rossor, M.N.^b , Fox, N.C.^b , Levin, J.^b , Jucker, M.^b , Bateman, R.J.^c , Dominantly Inherited Alzheimer Network^d

^a From the Department of Neurology (E.M., J.H., V.B., A.M.F., D.M.H., J.C.M., K.P., R.J.B.), Division of Biostatistics (G.W., C.X.), Department of Radiology (B.A.G., T.L.S.B., D.S.M.), and Department of Pathology (N.J.C.), Washington University School of Medicine, Saint Louis, MO; Department of Neuroscience (A.M.J.), Icahn School of Medicine at Mount Sinai, New York, NY; Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) (R.A.), Instituto de Investigaciones Neurológicas Raúl Correa, Buenos Aires, Argentina; University of Pittsburgh School of Medicine (S.B.B., W.K.), PA; College of Physicians and Surgeons (J.N.), Columbia University, New York, NY; Department of Neurology (J.R.), Keck School of Medicine of University of Southern California, Los Angeles; Department of Neurology (B.G., M.F.), Indiana University, Indianapolis; Massachusetts General Hospital (R.A.S., J.C.), Harvard Medical School, Boston; Butler Hospital and Brown University (S.S.), Providence, RI; Department of Neurology (N.R.G.-R.), Mayo Clinic Jacksonville, FL; Neuroscience Research Australia (P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales, Sydney; The Florey Institute and the University of Melbourne (C.M.), Parkville, Australia; Dementia Research Centre, Institute of Neurology (M.N.R., N.C.F.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) Munich (J.L.); Department of Neurology (J.L.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) Tübingen (M.J.); and Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen, Germany. batemanr@wustl.edu
^b From the Department of Neurology (E.M., J.H., V.B., A.M.F., D.M.H., J.C.M., K.P., R.J.B.), Division of Biostatistics (G.W., C.X.), Department of Radiology (B.A.G., T.L.S.B., D.S.M.), and Department of Pathology (N.J.C.), Washington University School of Medicine, Saint Louis, MO; Department of Neuroscience (A.M.J.), Icahn School of Medicine at Mount Sinai, New York, NY; Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) (R.A.), Instituto de Investigaciones Neurológicas Raúl Correa, Buenos Aires, Argentina; University of Pittsburgh School of Medicine (S.B.B., W.K.), PA; College of Physicians and Surgeons (J.N.), Columbia University, New York, NY; Department of Neurology (J.R.), Keck School of Medicine of University of Southern California, Los Angeles; Department of Neurology (B.G., M.F.), Indiana University, Indianapolis; Massachusetts General Hospital (R.A.S., J.C.), Harvard Medical School, Boston; Butler Hospital and Brown University (S.S.), Providence, RI; Department of Neurology (N.R.G.-R.), Mayo Clinic Jacksonville, FL; Neuroscience Research Australia (P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales, Sydney; The Florey Institute and the University of Melbourne (C.M.), Parkville, Australia; Dementia Research Centre, Institute of Neurology (M.N.R., N.C.F.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) Munich (J.L.); Department of Neurology (J.L.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) Tübingen (M.J.); and Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen, Germany
^c From the Department of Neurology (E.M., J.H., V.B., A.M.F., D.M.H., J.C.M., K.P., R.J.B.), Division of Biostatistics (G.W., C.X.), Department of Radiology (B.A.G., T.L.S.B., D.S.M.), and Department of Pathology (N.J.C.), Washington University School of Medicine, Saint Louis, MO; Department of Neuroscience (A.M.J.), Icahn School of Medicine at Mount Sinai, New York, NY; Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) (R.A.), Instituto de Investigaciones Neurológicas Raúl Correa, Buenos Aires, Argentina; University of Pittsburgh School of Medicine (S.B.B., W.K.), PA; College of Physicians and Surgeons (J.N.), Columbia University, New York, NY; Department of Neurology (J.R.), Keck School of Medicine of University of Southern California, Los Angeles; Department of Neurology (B.G., M.F.), Indiana University, Indianapolis; Massachusetts General Hospital (R.A.S., J.C.), Harvard Medical School, Boston; Butler Hospital and Brown University (S.S.), Providence, RI; Department of Neurology (N.R.G.-R.), Mayo Clinic Jacksonville, FL; Neuroscience Research Australia (P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales, Sydney; The Florey Institute and the University of Melbourne (C.M.), Parkville, Australia; Dementia Research Centre, Institute of Neurology (M.N.R., N.C.F.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) Munich (J.L.); Department of Neurology (J.L.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) Tübingen (M.J.); and Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen, Germany. ericmcdade@wustl.edu batemanr@wustl.edu

Abstract
OBJECTIVE: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.

METHODS: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals’ estimated years to symptom onset and to compare mutation carriers and noncarriers.

RESULTS: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations.

CONCLUSION: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course. © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus

Barriers to Service Utilization and Child Mental Health Treatment Attendance Among Poverty-Affected Families
(2018) Psychiatric services (Washington, D.C.), 69 (10), pp. 1101-1104. 

Bornheimer, L.A., Acri, M.C., Gopalan, G., McKay, M.M.

University of Michigan, New York University Medical Center, New York University, University of Maryland, Washington University in St. Louis, Dr. Bornheimer is with the School of Social WorkAnn Arbor. Dr. Acri is with the McSilver Institute for Poverty Policy and ResearchNew York. Dr. Gopalan is with the School of Social WorkBaltimore. Dr. McKay is with the Brown School of Social Work

Abstract
OBJECTIVE:: The majority of children who initially engage in mental health treatment in the United States drop out prematurely, a problem further exacerbated among children living in poverty. This study examined the relationships between sociodemographic characteristics, barriers to treatment use, and session attendance.

METHODS:: Data were obtained from participants (N=225) in the 4R2S field trial. Barriers were measured using the Kazdin Barriers to Treatment Participation Scale.

RESULTS:: Barriers endorsed by families attending less treatment primarily aligned with practical rather than perceptual obstacles. Critical events linked to lower attendance included moving too far away from the clinic, a job change, and a child’s moving out of the home.

CONCLUSIONS:: Child mental health programs serving low-income families may consider structural modifications to allow for greater family support as well as flexibility in treatment delivery by leveraging technology. Future research is needed to evaluate barriers to treatment and alternate modalities in relation to service utilization.

Author Keywords
Barriers to help-seeking;  Barriers to treatment;  Poverty-affected families;  Service utilization;  Structural equation modeling

Document Type: Article
Source: Scopus

The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer’s disease diagnosis: A review
(2018) Alzheimer’s and Dementia, 14 (10), pp. 1313-1333. 

Hansson, O.^{a b} , Mikulskis, A.^c , Fagan, A.M.^d , Teunissen, C.^e , Zetterberg, H.^{f g h i} , Vanderstichele, H.^j , Molinuevo, J.L.^k , Shaw, L.M.^l , Vandijck, M.^m , Verbeek, M.M.ⁿ , Savage, M.^o , Mattsson, N.^a , Lewczuk, P.^{p q} , Batrla, R.^r , Rutz, S.^s , Dean, R.A.^t , Blennow, K.^{h i}

^a Department of Neurology, Skåne University Hospital, Lund, Sweden
^b Memory Clinic, Skåne University Hospital, Malmö, Sweden
^c Biogen, Boston, MA, United States
^d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^e VU University Medical Center, Amsterdam, Netherlands
^f UK Dementia Research Institute, London, United Kingdom
^g Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
^h Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
ⁱ Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
^j ADx NeuroSciences, Gent, Belgium
^k BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
^l Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^m Fujirebio-Europe NV, Gent, Belgium
ⁿ Radboud University Medical Center, Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands
^o Merck and Company, West Point, PA, United States
^p Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Germany
^q Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Poland
^r Roche Diagnostics GmbH, Rotkreuz, Switzerland
^s Roche Diagnostics GmbH, Penzberg, Germany
^t Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
Introduction: Cerebrospinal fluid (CSF) biomarkers have the potential to improve the diagnostic accuracy of Alzheimer’s disease, yet there is a lack of harmonized preanalytical CSF handling protocols. Methods: This systematic review summarizes the current literature on the influence of preanalytical variables on CSF biomarker concentration. We evaluated the evidence for three core CSF biomarkers: β-amyloid 42, total tau, and phosphorylated tau. Results: The clinically important variables with the largest amount of conflicting data included the temperature at which samples are stored, the time nonfrozen samples can be stored, and possible effects of additives such as detergents, blood contamination, and centrifugation. Conversely, we discovered that there is consensus that tube material has a significant effect. Discussion: A unified CSF handling protocol is recommended to reduce preanalytical variability and facilitate comparison of CSF biomarkers across studies and laboratories. In future, experiments should use a gold standard with fresh CSF collected in low binding tubes. © 2018 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease diagnosis;  Biomarkers;  Cerebrospinal fluid;  Phosphorylated tau;  Preanalytical variables;  Total tau;  β-Amyloid 42

Document Type: Review
Source: Scopus

Age-specific global epidemiology of hydrocephalus: Systematic review, metanalysis and global birth surveillance
(2018) PLoS ONE, 13 (10), art. no. e0204926, . 

Isaacs, A.M.^{a b} , Riva-Cambrin, J.^{a c} , Yavin, D.^a , Hockley, A.^{a d} , Pringsheim, T.M.^{e f} , Jette, N.^{e g} , Lethebe, B.C.^h , Lowerison, M.^h , Dronyk, J.^a , Hamilton, M.G.^a

^a Division of Neurosurgery, Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
^b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada
^d Department of Orthopedic Surgery, New York University, New York, NY, United States
^e Division of Neurology, Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada
^f Department of Neurology, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada
^g Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^h Clinical Research Unit, University of Calgary, Calgary, AB, Canada

Abstract
Background Hydrocephalus is a debilitating disorder, affecting all age groups. Evaluation of its global epidemiology is required for healthcare planning and resource allocation. Objectives To define age-specific global prevalence and incidence of hydrocephalus. Methods Population-based studies reporting prevalence of hydrocephalus were identified (MEDLINE, EMBASE, Cochrane, and Google Scholar (1985-2017)). Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Two authors reviewed abstracts, full text articles and abstracted data. Metanalysis and meta-regressions were used to assess associations between key variables. Heterogeneity and publication bias were assessed. Main outcome of interest was hydrocephalus prevalence among pediatric (≤ 18 years), adults (19-64 years), and elderly (≥ 65) patients. Annual hydrocephalus incidence stratified by country income level and folate fortification requirements were obtained (2003-2014) from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Results Of 2,460 abstracts, 52 met review eligibility criteria (aggregate population 171,558,651). Mean hydrocephalus prevalence was 85/100,000 [95% CI 62, 116]. The prevalence was 88/100,000 [95% CI 72, 107] in pediatrics; 11/100,000 [95% CI 5, 25] in adults; and 175/ 100,000 [95% CI 67, 458] in the elderly. The ICBDSR-based incidence of hydrocephalus diagnosed at birth remained stable over 11 years: 81/100,000 [95% CI 69, 96]. A significantly lower incidence was identified in high-income countries. Conclusion This systematic review established age-specific global hydrocephalus prevalence. While high-income countries had a lower hydrocephalus incidence according to the ICBDSR registry, folate fortification status was not associated with incidence. Our findings may inform future healthcare resource allocation and study. © 2018 Isaacs et al.

Document Type: Review
Source: Scopus
Access Type: Open Access

Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data
(2018) The Lancet. Neurology, 17 (10), pp. 885-894. 

Al-Shahi Salman, R.^a , Frantzias, J.^b , Lee, R.J.^c , Lyden, P.D.^d , Battey, T.W.K.^e , Ayres, A.M.^e , Goldstein, J.N.^f , Mayer, S.A.^g , Steiner, T.^h , Wang, X.ⁱ , Arima, H.ⁱ , Hasegawa, H.^j , Oishi, M.^j , Godoy, D.A.^k , Masotti, L.^l , Dowlatshahi, D.^m , Rodriguez-Luna, D.ⁿ , Molina, C.A.ⁿ , Jang, D.-K.^o , Davalos, A.^p , Castillo, J.^q , Yao, X.^r , Claassen, J.^s , Volbers, B.^t , Kazui, S.^u , Okada, Y.^v , Fujimoto, S.^w , Toyoda, K.^x , Li, Q.^y , Khoury, J.^z , Delgado, P.^aa , Sabín, J.Á.^aa , Hernández-Guillamon, M.^aa , Prats-Sánchez, L.^ab , Cai, C.^ac , Kate, M.P.^ad , McCourt, R.^ad , Venkatasubramanian, C.^ae , Diringer, M.N.^af , Ikeda, Y.^ag , Worthmann, H.^ah , Ziai, W.C.^ai , d’Esterre, C.D.^aj , Aviv, R.I.^ak , Raab, P.^al , Murai, Y.^am , Zazulia, A.R.^af , Butcher, K.S.^ad , Seyedsaadat, S.M.^an , Grotta, J.C.^ao , Martí-Fàbregas, J.^ab , Montaner, J.^aa , Broderick, J.^z , Yamamoto, H.^ap , Staykov, D.^aq , Connolly, E.S.^ar , Selim, M.^as , Leira, R.^q , Moon, B.H.^o , Demchuk, A.M.^at , Di Napoli, M.^au , Fujii, Y.^j , Anderson, C.S.^av , Rosand, J.^e , VISTA-ICH Collaboration^aw , ICH Growth Individual Patient Data Meta-analysis Collaborators^ax

^a Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
^b Department of Neurosurgery, King’s College Hospital, London, United Kingdom
^c Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
^d Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^e Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^f Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
^g Department of Neurology, Henry Ford Health System, Detroit, MI, United States
^h Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt, Germany; Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
ⁱ George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
^j Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan
^k Intensive Care Unit, Hospital Interzonal de Agudos “San Juan Bautista”Catamarca, Argentina
^l Internal Medicine, Santa Maria Nuova Hospital, Florence, Italy
^m Department of Medicine (Neurology), University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada
ⁿ Stroke Unit, Department of Neurology, Vall d’Hebron Research Institute, Autonomous University of Barcelona, Vall d’Hebron University Hospital, Barcelona, Spain
^o Department of Neurosurgery, Incheon St Mary’s Hospital, College of Medicine, Catholic University of Korea, Incheon, South Korea
^p Department of Neurosciences, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, Barcelona, Spain
^q Department of Neurology, University Clinical Hospital of Santiago, Santiago de Compostela, Spain
^r Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
^s Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY, USA
^t Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany
^u Kazui Medical Office, Ikeda, Osaka, Japan
^v Department of Cerebrovascular Medicine and Neurology, National Hospital Organisation Kyushu Medical Centre, Fukuoka, Japan
^w Division of Neurology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
^x Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
^y Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
^z University of Cincinnati Medical Centre, Cincinnati, OH, United States
^aa Neurovascular Research Lab, Neurovascular Section, Institut de Recerca and Hospital Vall d’Hebron, Barcelona, Spain
^ab Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
^ac Centre for Clinical and Translational Sciences, McGovern Medical School at the University of Texas Health Science Center, Houston, TX, United States
^ad Department of Neurology, University of Alberta, Edmonton, AB, Canada
^ae Division of Stroke and Neurocritical Care, Stanford University, Palo Alto, CA, United States
^af Department of Neurology and Neurological Surgery, Washington University, St Louis, MO, United States
^ag Department of Neurosurgery, Tokyo Medical University Hachioji Medical CenterTokyo, Japan
^ah Department of Neurology, Hannover Medical School, Hannover, Germany
^ai Johns Hopkins University School of Medicine, Department of Neurology, Anaesthesia and Critical Care Medicine, Division of Neurocritical Care, Baltimore, MD, United States
^aj Department of Radiology, Foothills Medical Centre, University of Calgary, Calgary, AB, Canada
^ak Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
^al Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
^am Department of Neurological Surgery, Nippon Medical SchoolTokyo, Japan
^an Department of Radiology, Mayo Clinic, Rochester, MN, United States
^ao Memorial Hermann Hospital, Clinical Innovation and Research Institute, Houston, TX, United States
^ap Center for Advanced Clinical and Translational Sciences, National Cerebral and Cerebrovascular Center, Suita, Osaka, Japan
^aq Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany; Department of Neurology, Hospital of the Brothers of St John, Eisenstadt, Austria
^ar Department of Neurosurgery, Columbia University, College of Physicians and Surgeons, New York, NY, USA
^as Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States
^at Department of Clinical Neurosciences and Department of Radiology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
^au Neurological Service, San Camillo de’Lellis General Hospital, Rieti, Italy
^av The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; The George Institute for Global Health, China at Peking University Health Science Center, Beijing, China

Abstract
BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.

METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies’ bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.

FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07).

INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.

FUNDING: UK Medical Research Council and British Heart Foundation. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Document Type: Article
Source: Scopus
Access Type: Open Access

Does centrality in a cross-sectional network suggest intervention targets for social anxiety disorder?
(2018) Journal of Consulting and Clinical Psychology, 86 (10), pp. 831-844. 

Rodebaugh, T.L.^a , Tonge, N.A.^a , Piccirill, M.L.^a , Fried, E.^b , Horenstein, A.^c , Morrison, A.S.^d , Goldin, P.^e , Gross, J.J.^d , Lim, M.H.^a , Fernandez, K.C.^a , Blanco, C.^f , Schneier, F.R.^f , Bogdan, R.^a , Thompson, R.J.^a , Heimberg, R.G.^c

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
^b University of Amsterdam, Netherlands
^c Temple University, United States
^d Stanford University, United States
^e University of California, Davis, United States
^f Columbia University, United States

Abstract
Objective: Network analysis allows us to identify the most interconnected (i.e., central) symptoms, and multiple authors have suggested that these symptoms might be important treatment targets. This is because change in central symptoms (relative to others) should have greater impact on change in all other symptoms. It has been argued that networks derived from cross-sectional data may help identify such important symptoms. We tested this hypothesis in social anxiety disorder. Method: We first estimated a state-of-The-Art regularized partial correlation network based on participants with social anxiety disorder (n=910) to determine which symptoms were more central. Next, we tested whether change in these central symptoms were indeed more related to overall symptom change in a separate dataset of participants with social anxiety disorder who underwent a variety of treatments (n=244). We also tested. © 2018 American Psychological Association.

Document Type: Article
Source: Scopus

Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy
(2018) Journal of Neuroinflammation, 15 (1), art. no. 278, .

Bemiller, S.M.^{c e f} , Maphis, N.M.^a , Formica, S.V.^c , Wilson, G.N.^e , Miller, C.M.^c , Xu, G.^f , Kokiko-Cochran, O.N.ⁱ , Kim, K.-W.^j , Jung, S.^d , Cannon, J.L.^a , Crish, S.D.^g , Cardona, A.E.^h , Lamb, B.T.^f , Bhaskar, K.^{a b}  

^a Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87113, United States
^b Department of Neurology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM 87131, United States
^c Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
^d Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel
^e Kent State University, Kent, OH 44242, United States
^f Stark Neurosciences Research Institute, Indiana University, School of Medicine, Indianapolis, IN 46202, United States
^g Department of Pharmacology, Northeast Ohio Medical School, Rootstown, OH 44272, United States
^h Department of Biology, University of Texas San Antonio, West Campus, Tobin lab MBT 1.216, San Antonio, TX 78249, United States
ⁱ Department of Neuroscience, College of Medicine, Ohio State University, Columbus, OH 43210, United States
^j Department of Pathology and Immunology, Washington University, School of Medicine in St. Louis, Campus Box 8118, 660 S. Euclid Ave., St. Louis, MO 63110, United States

Abstract
Background: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx 3 cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. Methods: We used transgenic mice lacking endogenous Cx 3 cl1 (Cx 3 cl1 -/-) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx 3 cl1 105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. Results: First, increased basal tau levels accompanied microglial activation in Cx 3 cl1 105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx 3 cl1 -/-, and hTau/Cx 3 cl1 105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx 3 cl1 105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx 3 cr1 deletion), which likely contributes to the elevated tau pathology. Conclusions: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology. © 2018 The Author(s).

Author Keywords
Alzheimer’s disease;  CX3CL1;  CX3CR1;  Microglia;  Neuroinflammation;  Tau;  Tauopathies

Document Type: Article
Source: Scopus

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer’s disease
(2018) Alzheimer’s Research and Therapy, 10 (1), art. no. 98, . 

Gangishetti, U.^a , Christina Howell, J.^{a b} , Perrin, R.J.^{c d} , Louneva, N.^d , Watts, K.D.^a , Kollhoff, A.^a , Grossman, M.^{g h i} , Wolk, D.A.^{f i} , Shaw, L.M.^j , Morris, J.C.^{c e} , Trojanowski, J.Q.^{f g j} , Fagan, A.M.^{c e} , Arnold, S.E.^{f g k} , Hu, W.T.^{a b}

^a Department of Neurology, Emory University, 615 Michael Street, 505F, Atlanta, GA 30322, United States
^b Department of Alzheimer’s Disease Research Center, Emory University, Atlanta, GA, United States
^c Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States
^d Department of Pathology, Washington University, St. Louis, MO, United States
^e Department of Neurology, Washington University, St. Louis, MO, United States
^f Penn Memory Center, University of Pennsylvania, Philadelphia, PA, United States
^g Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, United States
^h Penn FTD Center, University of Pennsylvania, Philadelphia, PA, United States
ⁱ Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
^j Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
^k Massachusetts General Hospital, Boston, MA, United States

Abstract
Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of cognitive and functional deficits in people with altered Aβ and tau levels. While multiple previous studies identified non-Aβ, non-tau proteins as candidate neurodegenerative markers to inform the A/T/N biomarker scheme of AD, few have advanced beyond association with clinical AD diagnosis. Here we analyzed nine promising neurodegenerative markers in a three-centered cohort using independent assays to identify candidates most likely to complement Aβ and tau in the A/T/N framework. Methods: CSF samples from 125 subjects recruited at the three centers were exchanged such that each of the nine previously identified biomarkers can be measured at one of the three centers. Subjects were classified according to cognitive status and CSF AD biomarker profiles as having normal cognition and normal CSF (n = 31), normal cognition and CSF consistent with AD (n = 13), mild cognitive impairment and normal CSF (n = 13), mild cognitive impairment with CSF consistent with AD (n = 23), AD dementia (n = 32; CSF consistent with AD), and other non-AD dementia (n = 13; CSF not consistent with AD). Results: Three biomarkers were identified to differ among the AD stages, including neurofilament light chain (NfL; p < 0.001), fatty acid binding protein 3 (Fabp3; p < 0.001), and interleukin (IL)-10 (p = 0.033). Increased NfL levels were most strongly associated with the dementia stage of AD, but increased Fabp3 levels were more sensitive to milder AD stages and correlated with both CSF tau markers. IL-10 levels did not correlate with tau biomarkers, but were associated with rates of longitudinal cognitive decline in mild cognitive impairment due to AD (p = 0.006). Prefreezing centrifugation did not influence measured CSF biomarker levels. Conclusion: CSF proteins associated with AD clinical stages and progression can complement Aβ and tau markers to inform neurodegeneration. A validated panel inclusive of multiple biomarker features (etiology, stage, progression) can improve AD phenotyping along the A/T/N framework. © 2018 The Author(s).

Author Keywords
Biomarkers;  Fatty acid binding protein;  Interleukin-10;  Mild cognitive impairment;  Neurofilament light chain

Document Type: Article
Source: Scopus

Adverse childhood experiences and symptoms of urologic chronic pelvic pain syndrome: A multidisciplinary approach to the study of chronic pelvic pain research network study
(2018) Annals of Behavioral Medicine, 52 (10), pp. 865-877. 

Schrepf, A.^a , Naliboff, B.^{b c} , Williams, D.A.^a , Stephens-Shields, A.J.^d , Landis, J.R.^d , Gupta, A.^e , Mayer, E.^e , Rodriguez, L.V.^f , Lai, H.^{g h} , Luo, Y.ⁱ , Bradley, C.^{i j} , Kreder, K.ⁱ , Lutgendorf, S.K.^k

^a Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States
^b Department of Medicine, University of California, Los Angeles, CA, United States
^c Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, United States
^d Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^e Oppenheimer Center for Neurobiology of Streß, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States
^f Department of Urology, University of Southern California, Los Angeles, CA, United States
^g Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Urology, University of Iowa, Iowa City, IA, United States
^j Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States
^k Department of Psychological and Brain Sciences and Urology, University of Iowa, Iowa City, IA, United States

Abstract
Background Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illneß, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS). Purpose We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the aßociation of ACE severity with psychological factors known to impact pain and to determine whether ACEs are aßociated with patterns of improvement or worsening of symptom over a year of naturalistic observation. Methods For longitudinal analyses we used functional clusters identifying broad claßes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being. Results ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly aßociated with factors aßociated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and leß likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year. Conclusions These results confirm the aßociation between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS. Clinical Trial registration NCT01098279. © Society of Behavioral Medicine 2018. All rights reserved.

Author Keywords
Chronic Prostatitis with Chronic Pelvic Pain Syndrome;  Interstitial Cystitis/Painful Bladder Syndrome;  Psychological Trauma;  Sexual Abuse

Document Type: Article
Source: Scopus

Multifocal stroke with proliferation of small cerebral arteries in hepatopulmonary syndrome
(2018) Neurology: Clinical Practice, 8 (3), pp. e15-e17. 

Younce, J.R.^a , Cross, D.T.^b , Goyal, M.S.^b , Lee, J.-M.^{a b c}

^a Department of Neurology, Mallinckrodt Institute of Radiology, United States
^b Biomedical Engineering, United States
^c Washington University School of Medicine, St. Louis, MO, United States

Abstract
Cirrhosis of the liver has been linked to several changes in risk of cerebrovascular disease and may increase the risk of hemorrhage while reducing the risk of ischemic stroke. 1,2 The pathophysiology underlying these changes remains unclear, though intracranial hemorrhage and vascular malformations related to liver disease have been described. 1,3 Cirrhosis may be complicated by hepatopulmonary syndrome (HPS), in which distal pulmonary arteries dilate, become tortuous, produce shunt physiology, and often produce arteriovenous (AV) malformations. 4. © © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus

Progressive multifocal leukoencephalopathy with extended natalizumab dosing
(2018) Neurology: Clinical Practice, 8 (3), pp. e12-e14. 

Baldassari, L.E.^a , Jones, S.E.^{b c} , Clifford, D.B.^c , Fox, R.J.^a

^a Mellen Center for Multiple Sclerosis, United States
^b Imaging Institute, Cleveland ClinicOH, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
A 53-year-old man with an 18-year history of multiple sclerosis (MS) was treated with natalizumab for 7 years. Two years prior to presentation, natalizumab treatment interval was increased to every 6 weeks in attempt to reduce the risk of PML. Medical history was notable for cutaneous T-cell lymphoma status-post CHOP chemotherapy. JCV serology was positive (index 2.8). He presented to our tertiary referral center for consultation due to 8 months of progressive left-sided paresthesias, 4 months of right arm clumsiness, and several weeks of expressive aphasia. Neurologic examination was consistent with these symptoms. Serial brain MRIs demonstrated progressive development of a subcortical, multifocal T2/fluid-attenuated inversion recovery hyperintensity in the left frontoparietal white matter (figure 1). Subtle but definite MRI abnormalities were present in the same area 12 months prior. His clinical course and MRI findings prompted urgent evaluation for PML. © © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus

A multinational study on motor function in early-onset FSHD
(2018) Neurology, 90 (15), pp. e1333-e1338. 

Mah, J.K.^a , Feng, J.^b , Jacobs, M.B.^b , Duong, T.^c , Carroll, K.^d , De Valle, K.^d , Carty, C.L.^b , Morgenroth, L.P.^{a n} , Guglieri, M.^e , Ryan, M.M.^d , Clemens, P.R.^f , Thangarajh, M.^l , Webster, R.^g , Smith, E.^h , Connolly, A.M.ⁱ , McDonald, C.M.^j , Karachunski, P.^k , Tulinius, M.^a , Harper, A.^m , Cnaan, A.^a , Chen, Y.-W.^a

^a University of Calgary, Alberta Children’s Hospital, Canada
^b Children’s National Medical Centerc, Washington, DC, United States
^c Stanford UniversityCA, United States
^d Royal Children’s Hospital, Melbourne, Australia
^e Newcastle Upon Tyne Hospitals, United Kingdom
^f University of Pittsburgh, Department of Veteran Affairs Medical CenterPA, United States
^g Children’s Hospital at Westmead, Sydney, Australia
^h Duke Medical Center, Durham, NC, United States
ⁱ Washington University, St. Louis, MO, United States
^j University of California at Davis Medical Center, Sacramento, United States
^k University of Minnesota, Minneapolis, United States
^l Gothenburg University, Queen Silvia Children’s Hospital, Sweden
^m Carolinas Medical Center, Charlotte, NC, United States
ⁿ Therapeutic Research in Neuromuscular Disorders Solutions, LLC, Kensington, MD, United States

Abstract
Objectives To investigate motor function associations with age, sex, and D4Z4 repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age. Methods We collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and D4Z4 repeats. Results Among 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs (p = 0.003). When adjusted for enrollment age, sex, and D4Z4 repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores (p < 0.05). Conclusion Significant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population. © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus

Preschool Executive Function Predicts Childhood Resting-State Functional Connectivity and Attention-Deficit/Hyperactivity Disorder and Depression
(2018) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, . Article in Press. 

Hawkey, E.J.^a , Tillman, R.^b , Luby, J.L.^b , Barch, D.M.^{a b c d}

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^d The Program in Neuroscience, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Measures of executive function (EF), such as the Behavior Rating Inventory of Executive Function, distinguish children with attention-deficit/hyperactivity disorder (ADHD) from control subjects, but less work has examined relationships to depression or brain network organization. This study examined whether early childhood EF predicted new onset or worsening of ADHD and/or depression and examined how early childhood EF related to functional connectivity of brain networks at school age. Methods: Participants included 247 children who were enrolled at 3 to 6 years of age from a prospective study of emotion development. The Behavior Rating Inventory of Executive Function Global Executive Composite score was used as the measure of EF in early childhood to predict ADHD and depression diagnoses and symptoms across school age. Resting-state functional magnetic resonance imaging network analyses examined global efficiency in the frontoparietal, cingulo-opercular, salience, and default mode networks and six “hub” seed regions selected to examine between-network connectivity. Results: Early childhood EF predicted new onset and worsening of ADHD and depression symptoms across school age. Greater EF deficits in preschool predicted increased global efficiency in the salience network and altered connectivity with four regions for the dorsal anterior cingulate cortex hub and one region with the insula hub at school age. This altered connectivity was related to increasing ADHD and depression symptoms. Conclusions: Early executive deficits may be an early common liability for risk of developing ADHD and/or depression and were associated with altered functional connectivity in networks and hub regions relevant to executive processes. Future work could help clarify whether specific EF deficits are implicated in the development of both disorders. © 2018 Society of Biological Psychiatry

Author Keywords
Attention-deficit/hyperactivity disorder;  Behavior Rating Inventory of Executive Function;  Depression;  Executive function;  fMRI;  Resting-state functional connectivity

Document Type: Article in Press
Source: Scopus

Resting state functional connectivity in patients with remitted psychotic depression: A multi-centre STOP-PD study
(2018) EBioMedicine, . Article in Press. 

Neufeld, N.H.^{a b c d} , Mulsant, B.H.^{b c d} , Dickie, E.W.^{a b c} , Meyers, B.S.^e , Alexopoulos, G.S.^e , Rothschild, A.J.^f , Whyte, E.M.^g , Hoptman, M.J.^{h i j} , Nazeri, A.^{a b c k} , Downar, J.^{d l} , Flint, A.J.^{d l} , Voineskos, A.N.^{a b c d}

^a Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, 250 College Street, Toronto, ON M5T 1R8, Canada
^b Campbell Family Mental Health Research Institute, 250 College Street, Toronto, ON M5T 1R8, Canada
^c Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada
^d Department of Psychiatry, University of Toronto, 250 College Street, Toronto, ON M5T 1R8, Canada
^e Weill Cornell Medical College, 21 Bloomingdale Road, White Plains, NY 10605, United States
^f University of Massachusetts Medical School and UMass Memorial Medical Centre, 55 Lake Avenue North, Worcester, MA 01655, United States
^g University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213, United States
^h Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States
ⁱ Department of Psychiatry, NYU School of Medicine, 550 First Avenue, New York, NY 10016, United States
^j Department of Psychology, CUNY Graduate Centre, 365 Fifth Avenue, New York, NY 10016, United States
^k Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Saint Louis, MO 63110, United States
^l University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada

Abstract
Background: There is paucity of neurobiological knowledge about major depressive disorder with psychotic features (“psychotic depression”). This study addresses this knowledge gap by using resting state functional magnetic resonance imaging (R-fMRI) to compare functional connectivity in patients with psychotic depression and healthy controls. Methods: We scanned patients who participated in a randomized controlled trial as well as healthy controls. All patients achieved remission from depressive and psychotic symptoms with sertraline and olanzapine. We employed Independent Component Analysis in independent samples to isolate the default mode network (DMN) and compared patients and controls. Findings: The Toronto sample included 28 patients (mean [SD], age 56·2 [13·7]) and 39 controls (age 55·1 [13·5]). The Replication sample included 29 patients (age 56·1 [17·7]) and 36 controls (age 48·3 [17·9]). Patients in the Toronto sample demonstrated decreased between-network functional connectivity between the DMN and bilateral insular, somatosensory/motor, and auditory cortices with peak activity in the right planum polare (t = 4·831; p = 0·001, Family Wise Error (FWE) corrected). A similar pattern of between-network functional connectivity was present in our Replication sample with peak activity in the right precentral gyrus (t = 4·144; p = 0·003, FWE corrected). Interpretation: Remission from psychotic depression is consistently associated with an absence of increased DMN-related functional connectivity and presence of decreased between-network functional connectivity. Future research will evaluate this abnormal DMN-related functional connectivity as a potential biomarker for treatment trajectories. Funding: National Institute of Mental Health. © 2018 The Authors

Author Keywords
Biomarkers;  Default mode network;  Functional connectivity;  Major depressive disorder;  Psychosis;  Remission

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

Absence of the Pronator Quadratus Muscle Precluding Distal Nerve Transfer
(2018) Journal of Hand Surgery, . Article in Press. 

Dy, C.J.^{a b} , Brogan, D.M.^a , Colorado, B.S.^a

^a Department of Orthopaedic Surgery, Division of Hand and Upper Extremity Surgery, St. Louis, MO, United States
^b Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The branch of the anterior interosseous nerve to the pronator quadratus (PQ) is increasingly used as a donor nerve for end-to-end and reverse end-to-side nerve transfers. The anatomy of the PQ (and its nerve branch) is generally considered reliable in the absence of prior trauma. In this report, we describe a patient with an absent PQ despite intact clinical examination of other muscles supplied by the anterior interosseous nerve. The absence of the PQ precluded the use of its nerve as a donor nerve for transfer. © 2018 American Society for Surgery of the Hand

Author Keywords
nerve transfer;  peripheral nerve;  Pronator quadratus;  reverse end-to-side;  supercharge

Document Type: Article in Press
Source: Scopus

Extending the Human Connectome Project across ages: Imaging protocols for the Lifespan Development and Aging projects
(2018) NeuroImage, . Article in Press. 

Harms, M.P.^a , Somerville, L.H.^{f g} , Ances, B.M.^b , Andersson, J.^h , Barch, D.M.^{a c e} , Bastiani, M.^h , Bookheimer, S.Y.^k , Brown, T.B.^c , Buckner, R.L.^{f g m n} , Burgess, G.C.^a , Coalson, T.S.^d , Chappell, M.A.^{h i} , Dapretto, M.^k , Douaud, G.^h , Fischl, B.^{m o} , Glasser, M.F.^{c d p} , Greve, D.N.^m , Hodge, C.^a , Jamison, K.W.^q , Jbabdi, S.^h , Kandala, S.^a , Li, X.^r , Mair, R.W.^{g m} , Mangia, S.^r , Marcus, D.^c , Mascali, D.^t , Moeller, S.^r , Nichols, T.E.^{h j u} , Robinson, E.C.^v , Salat, D.H.^m , Smith, S.M.^h , Sotiropoulos, S.N.^{h w} , Terpstra, M.^r , Thomas, K.M.^s , Tisdall, M.D.^x , Ugurbil, K.^r , van der Kouwe, A.^{m n} , Woods, R.P.^{k l} , Zöllei, L.^m , Van Essen, D.C.^d , Yacoub, E.^r

^a Department of Psychiatry, 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 Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Psychology, Harvard University, Cambridge, MA, United States
^g Center for Brain Science, Harvard University, Cambridge, MA, United States
^h Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
ⁱ Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom
^j Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
^k Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States
^l Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States
^m Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
ⁿ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^o Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, United States
^p St. Luke’s Hospital, St. Louis, MO, United States
^q Department of Radiology, Weill Cornell Medical College, New York, NY, United States
^r Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States
^s Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
^t Centro Fermi – Museo Storico della Fisica e Centro Studi e Ricerche “Enrico Fermi”, Rome, Italy
^u Department of Statistics, University of Warwick, Coventry, United Kingdom
^v Department of Biomedical Engineering, King’s College London, London, United Kingdom
^w Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom
^x Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Abstract
The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100+ years of age. HCP-D is enrolling 1300+ healthy children, adolescents, and young adults (ages 5–21), and HCP-A is enrolling 1200+ healthy adults (ages 36–100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200+ participants, aged 22–35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain. © 2018 Elsevier Inc.

Author Keywords
Aging;  Connectomics;  Development;  Diffusion;  Functional connectivity;  Lifespan;  Perfusion;  Resting-state;  Task

Document Type: Article in Press
Source: Scopus

Diagnosis of niemann-pick C1 by measurement of bile acid biomarkers in archived newborn dried blood spots
(2018) Molecular Genetics and Metabolism, . Article in Press. 

Jiang, X.^a , Sidhu, R.^a , Orsini, J.J.^b , Farhat, N.Y.^c , Porter, F.D.^c , Berry-Kravis, E.^d , Schaffer, J.E.^a , Ory, D.S.^a

^a Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^b New York State Dept. of Health, Wadsworth Center, Albany, NY 12201, United States
^c Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD 20892, United States
^d Rush University Medical Center, Chicago, IL 60612, United States

Abstract
Background: Niemann-Pick disease type C1 (NPC1) is a rare, neurodegenerative cholesterol storage disorder. Diagnostic delay of >5 years is common due to the rarity of the disease and non-specific early symptoms. To improve diagnosis and facilitate early intervention, we previously developed a newborn screening assay based on newly identified plasma bile acid biomarkers. Because the newborn screen had been validated using dried blood spots (DBS) from already diagnosed NPC1 patients, an unanswered question was whether the screen would be able to detect individuals with NPC1 at birth. Methods: To address this critical question, we obtained the newborn DBS for already diagnosed NPC1 subjects (n = 15) and carriers (n = 3) residing in California, New York, and Michigan states that archive residual DBS in biorepositories. For each of the DBS, we obtained two neighbor controls – DBS from patients born on the same day and in the same hospital as the NPC1 patients and carriers. 3β,5α,6β-trihydroxycholanic acid (bile acid A) and trihydroxycholanic acid glycine conjugate (bile acid B) were measured in the DBS using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Results: Bile acid B, the more specific biomarker for which the fully validated DBS assay was developed, was detected in 8/15 NPC1 patients, and elevated above the cut-off in 2/15 patients (the two samples with the shortest storage time). Bile acid B was detected in 2/2, 6/10, and 0/7 NPC1 samples that have been stored for <10.5 years, 13–20 years, and > 20 years, respectively, indicating that the glycine conjugate is detectable in DBS but may have reduced long-term stability compared with bile acid A, the precursor trihydroxycholanic acid, which was elevated in 15/15 NPC1 subjects, but not in carriers and controls. Conclusions: These results demonstrate that newborn screening for NPC1 disease is feasible using bile acid biomarkers. © 2018

Author Keywords
Bile acid;  Biomarker;  Newborn screening;  Niemann-pick C disease

Document Type: Article in Press
Source: Scopus

Fetal brain growth portrayed by a spatiotemporal diffusion tensor MRI atlas computed from in utero images
(2018) NeuroImage, . Article in Press. 

Khan, S.^a , Vasung, L.^b , Marami, B.^{a c} , Rollins, C.K.^d , Afacan, O.^a , Ortinau, C.M.^e , Yang, E.^a , Warfield, S.K.^a , Gholipour, A.^a

^a Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^b Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^c Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^e Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Altered structural fetal brain development has been linked to neuro-developmental disorders. These structural alterations can be potentially detected in utero using diffusion tensor imaging (DTI). However, acquisition and reconstruction of in utero fetal brain DTI remains challenging. Until now, motion-robust DTI methods have been employed for reconstruction of in utero fetal DTIs. However, due to the unconstrained fetal motion and permissible in utero acquisition times, these methods yielded limited success and have typically resulted in noisy DTIs. Consequently, atlases and methods that could enable groupwise studies, multi-modality imaging, and computer-aided diagnosis from in utero DTIs have not yet been developed. This paper presents the first DTI atlas of the fetal brain computed from in utero diffusion-weighted images. For this purpose an algorithm for computing an unbiased spatiotemporal DTI atlas, which integrates kernel-regression in age with a diffeomorphic tensor-to-tensor registration of motion-corrected and reconstructed individual fetal brain DTIs, was developed. Our new algorithm was applied to a set of 67 fetal DTI scans acquired from healthy fetuses each scanned at a gestational age between 21 and 39 weeks. The neurodevelopmental trends in the fetal brain, characterized by the atlas, were qualitatively and quantitatively compared with the observations reported in prior ex vivo and in utero studies, and with results from imaging gestational-age equivalent preterm infants. Our major findings revealed early presence of limbic fiber bundles, followed by the appearance and maturation of projection pathways (characterized by an age related increase in FA) during late 2nd and early 3rd trimesters. During the 3rd trimester association fiber bundles become evident. In parallel with the appearance and maturation of fiber bundles, from 21 to 39 gestational weeks gradual disappearance of the radial coherence of the telencephalic wall was qualitatively identified. These results and analyses show that our DTI atlas of the fetal brain is useful for reliable detection of major neuronal fiber bundle pathways and for characterization of the fetal brain reorganization that occurs in utero. The atlas can also serve as a useful resource for detection of normal and abnormal fetal brain development in utero. © 2018 Elsevier Inc.

Document Type: Article in Press
Source: Scopus

Relationship between Amyloid-β Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults
(2018) Journal of Alzheimer’s Disease, 65 (4), pp. 1313-1325. 

Dang, C.^{a b} , Harrington, K.D.^{b c} , Lim, Y.Y.^b , Ames, D.^{d e} , Hassenstab, J.^{f g h} , Laws, S.M.^{c i j} , Yassi, N.^{b k} , Hickey, M.^a , Rainey-Smith, S.^{l m} , Robertson, J.^b , Sohrabi, H.R.^{l p} , Salvado, O.^q , Weinborn, M.^{l m r} , Villemagne, V.L.^{b n o} , Rowe, C.C.^{n o} , Masters, C.L.^b , Maruff, P.^{b s}

^a Department of Obstetrics and Gynaecology, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia
^b Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC 3052, Australia
^c Cooperative Research Centre for Mental Health, Parkville, VIC, Australia
^d Department of Psychiatry, Academic Unit for Psychiatry of Old Age, University of Melbourne, Parkville, VIC, Australia
^e National Ageing Research Institute, Parkville, VIC, Australia
^f Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
ⁱ Collaborative Genomics Group, Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
^j School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin UniversityWA, Australia
^k Department of Medicine and Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia
^l Centre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, WA, Australia
^m Australian Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, WA, Australia
ⁿ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia
^o Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia
^p School of Psychiatry and Clinical Neurosciences, University of WA, Nedlands, WA, Australia
^q CSIRO Health and Biosecurity, Australian EHealth Research Centre, Brisbane, QLD, Australia
^r School of Psychological Science, University of Western Australia, Crawley, WA, Australia
^s CogState Ltd., Melbourne, VIC, Australia

Abstract
Background: Preclinical Alzheimer’s disease (AD) is defined by cerebral amyloid-β positivity (A+β) in cognitively normal (CN) older adults. Objective: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to A+, APOE ϵ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. Results: 17.7% A+ and 8.1% A-progressed over 8 years (OR: 2.43). Risk of progression for A+ was 65-104% greater than A-. A+ APOE ϵ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in A+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ϵ4 carriage (HR: 2.63); only age was a significant risk factor in A-(HR: 1.09). A-progressors were not near the threshold for A+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Conclusion: A+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOE ϵ4 carriage provides further predictive value in the presence of A+. These data suggest that A-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated A deposition may be the result of neuropathological processes other than AD that accumulate with age. © 2018-IOS Press and the authors. All rights reserved.

Author Keywords
Alzheimer’s disease;  APOE ϵ4;  biomarkers;  dementia;  mild cognitive impairment

Document Type: Article
Source: Scopus

Mechanics of cortical folding: Stress, growth and stability
(2018) Philosophical Transactions of the Royal Society B: Biological Sciences, 373 (1759), art. no. 20170321, . Cited 1 time.

Garcia, K.E.^{a b} , Kroenke, C.D.^c , Bayly, P.V.^a

^a Mechanical Engineering and Materials Science, Washington University in Saint Louis, Saint Louis, MO, United States
^b Engineering, University of Southern Indiana, Evansville, IN, United States
^c Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR, United States

Abstract
Cortical folding, or gyrification, coincides with several important developmental processes. The folded shape of the human brain allows the cerebral cortex, the thin outer layer of neurons and their associated projections, to attain a large surface area relative to brain volume. Abnormal cortical folding has been associated with severe neurological, cognitive and behavioural disorders, such as epilepsy, autism and schizophrenia. However, despite decades of study, the mechanical forces that lead to cortical folding remain incompletely understood. Leading hypotheses have focused on the roles of (i) tangential growth of the outer cortex, (ii) spatio-temporal patterns in the birth and migration of neurons, and (iii) internal tension in axons. Recent experimental studies have illuminated not only the fundamental cellular and molecular processes underlying cortical development, but also the stress state, mechanical properties and spatio-temporal patterns of growth in the developing brain. The combination of mathematical modelling and physical measurements has allowed researchers to evaluate hypothesized mechanisms of folding, to determine whether each is consistent with physical laws. This review summarizes what physical scientists have learned from models and recent experimental observations, in the context of recent neurobiological discoveries regarding cortical development. Here, we highlight evidence of a combined mechanism, in which spatio-temporal patterns bias the locations of primary folds (i), but tangential growth of the cortical plate induces mechanical instability (ii) to propagate primary and higher-order folds. This article is part of the Theo Murphy meeting issue ‘Mechanics of development’. © 2018 The Author(s).

Author Keywords
Cortical folding;  Growth;  Gyrification;  Instability;  Modelling;  Stress

Document Type: Review
Source: Scopus