Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“The immediate benefits and long-term consequences of briefly presented masked primes on episodic recollection” (2019) Journal of Memory and Language

The immediate benefits and long-term consequences of briefly presented masked primes on episodic recollection
(2019) Journal of Memory and Language, 106, pp. 77-94. 

Maddox, G.B.a , Balota, D.A.b , Kumar, A.A.b , Millar, P.R.b , Churchill, L.b

a Department of Psychology, Rhodes College, Memphis, TN 38112, United States
b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO 63130, United States

Abstract
Within-trial priming paradigms have been widely used to measure lexical retrieval and familiarity-based processes in speeded pronunciation, perceptual identification, lexical decision, lexical retrieval, and episodic recognition tasks. Here, we introduce a novel within-trial priming paradigm to examine cued recall, which is considered a more recollection-based task. In each experiment, participants initially studied a list of paired-associates (e.g., BADGE-gold). During each recall test trial, 500 ms after the onset of the stimulus cue (BADGE-??????), a pattern-masked prime was briefly presented for either 48 ms or 125 ms, with the task to recall the word (e.g., gold) paired with the cue (BADGE). Across seven experiments, the primes were identical (gold), semantically related (silver), orthographically related (good), or unrelated (chair) to the to-be-recalled response item (gold). The results consistently indicated that the masked identity primes benefited immediate recall at both the 48 ms and 125 ms durations. There was no benefit from the orthographically related prime condition, suggesting that participants were not using partial letter information as an additional cue for memory retrieval. Semantically related primes only produced a benefit in immediate recall at the 125 ms prime duration. Delayed cued recall performance indicated that the facilitatory priming effects observed in immediate recall were eliminated. In addition, results from conditional analyses suggest that the benefits of retrieval in an immediate recall condition are reversed in the delayed recall condition. We consider multiple interpretations of these delayed recall results and argue that the results are in part due to priming influencing an activation-based mechanism in the immediate recall task, which decreases the retrieval demands for the response item to the paired associate cue, and hence, decreases the long-term benefits of retrieval practice. © 2019 Elsevier Inc.

Author Keywords
Automaticity;  Desirable difficulty;  Memory;  Priming;  Recollection

Document Type: Article
Publication Stage: Final
Source: Scopus

“Triage of mild head-injured intoxicated patients could be aided by use of an electroencephalogram-based biomarker” (2019) Journal of Neuroscience Nursing

Triage of mild head-injured intoxicated patients could be aided by use of an electroencephalogram-based biomarker
(2019) Journal of Neuroscience Nursing, 51 (2), pp. 62-66. Cited 1 time.

Michelson, E.d , Huff, J.S.a , Garrett, J.b , Naunheim, R.c

a University of Virginia, School of Medicine, Charlottesville, VA, United States
b Baylor University Medical Center, Dallas, TX, United States
c Washington University, Barnes Jewish Medical Center, St Louis, MO, United States
d Department of Emergency Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States

Abstract
Objective: Drug and alcohol (DA)-related emergency department (ED) visits represent an increasing fraction the head-injured population seen in the ED. Such patients present a challenge to the evaluation of head injury and determination of need for computed tomographic (CT) scan and further clinical path. This effort examined whether an electroencephalogram (EEG)-based biomarker could aid in reducing unnecessary CT scans in the intoxicated ED population. Method: This is a retrospective secondary study of an independent prospective US Food and Drug Administration validation trial that demonstrated the efficacy of (1) an automatic Structural Injury Classifier for the likelihood of injury visible on a CT (CT+) and (2) an EEG-based Brain Function Index to assess functional impairment in minimally impaired, head-injured adults presenting within 3 days of injury. Impact on the biomarker performance in patients who presented with or without DA was studied. Results: Structural Injury Classifier sensitivity was not significantly impacted by the presence of DA. Although specificity decreased, it remained several times higher than obtained using standard CT decision rules. Furthermore, the potential to reduce the number of unnecessary scans by approximately 30% was demonstrated when the Structural Injury Classifier was integrated into CT clinical triage. The Brain Function Index was demonstrated to be independent of the presence of DA. Conclusion: This EEG-based assessment technology used to identify the likelihood of structural or functional brain injury in mildly head-injured patients represents an objective way to aid in triage patients with DA on presentation, with the potential to decrease overscanning while not sacrificing sensitivity to injuries visible on CT. © 2019 American Association of Neuroscience Nurses.

Author Keywords
brain electrical activity;  brain function index;  drug and alcohol intoxication;  EEG;  quantitative electrophysiological measures;  structural brain injury;  structural injury classifier;  TBI;  traumatic brain injury

Document Type: Article
Publication Stage: Final
Source: Scopus

“Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial” (2019) The Lancet

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial
(2019) The Lancet, 393 (10175), pp. 1021-1032. Cited 1 time.

Hanley, D.F.a , Thompson, R.E.c , Rosenblum, M.c , Yenokyan, G.c , Lane, K.a , McBee, N.a , Mayo, S.W.d , Bistran-Hall, A.J.a , Gandhi, D.e , Mould, W.A.a , Ullman, N.f , Ali, H.a , Carhuapoma, J.R.b , Kase, C.S.g , Lees, K.R.h , Dawson, J.i , Wilson, A.h , Betz, J.F.c , Sugar, E.A.c , Hao, Y.a , Avadhani, R.a , Caron, J.-L.j , Harrigan, M.R.k , Carlson, A.P.l , Bulters, D.m , LeDoux, D.n , Huang, J.b , Cobb, C.o , Gupta, G.p , Kitagawa, R.q , Chicoine, M.R.r , Patel, H.s , Dodd, R.t , Camarata, P.J.u , Wolfe, S.v , Stadnik, A.w , Money, P.L.w , Mitchell, P.x , Sarabia, R.y , Harnof, S.z , Barzo, P.aa , Unterberg, A.ab , Teitelbaum, J.S.ac , Wang, W.ad , Anderson, C.S.ae af , Mendelow, A.D.ag , Gregson, B.ag , Janis, S.ah , Vespa, P.ai , Ziai, W.a , Zuccarello, M.aj , Awad, I.A.w , Abdul-Rahim, A.ak , Abou-Hamden, A.ak , Abraham, M.ak , Ahmed, A.ak , Alba, C.A.ak , Aldrich, E.F.ak , Altschul, D.ak , Amin-Hanjani, S.ak , Anderson, D.ak , Ansari, S.ak , Antezana, D.ak , Ardelt, A.ak , Arikan, F.ak , Baguena, M.ak , Baker, A.ak , Barrer, S.J.ak , Becker, K.J.ak , Bergman, T.ak , Boström, A.ak , Braun, J.ak , Brindley, P.ak , Broaddus, W.C.ak , Brown, R.ak , Buki, A.ak , Cao, B.ak , Cao, Y.ak , Carrion-Penagos, J.ak , Chalela, J.ak , Chang, T.ak , Chorro, I.M.ak , Chowdhry, S.ak , Corral, L.ak , Csiba, L.ak , Davies, J.ak , Díaz, A.T.ak , Dierdeyn, C.P.ak , Diringer, M.ak , Dlugash, R.ak , Ecker, R.ak , Economas, T.ak , Enriquez, P.ak , Ezer, E.ak , Fan, Y.ak , Feng, H.ak , Franz, D.ak , Freeman, W.D.ak , Fusco, M.ak , Galicich, W.ak , Gelea, M.L.ak , Goldstein, J.ak , Gonzalez, A.C.ak , Grabarits, C.ak , Greenberg, S.ak , Gress, D.ak , Gu, E.ak , Hall, C.ak , Hernandez, F.M.ak , Hoesch, R.ak , Hoh, B.L.ak , Houser, J.ak , Hu, R.ak , Huang, Y.ak , Hussain, M.A.ak , Insinga, S.ak , Jadhav, A.ak , Jaffe, J.ak , Jahromi, B.S.ak , Jallo, J.ak , James, M.ak , James, R.F.ak , Jankowitz, B.ak , Jeon, E.ak , Jichici, D.ak , Jonczak, K.ak , Jonker, B.ak , Karlen, N.ak , Keric, N.ak , Kerz, T.ak , Knopman, J.ak , Koenig, C.ak , Krishnamurthy, S.ak , Kumar, A.ak , Kureshi, I.ak , Laidlaw, J.ak , Lakhanpal, A.ak , Latorre, J.G.ak , Leifer, D.ak , Leiphart, J.ak , Lenington, S.ak , Li, Y.ak , Lopez, G.ak , Lovick, D.ak , Lumenta, C.ak , Luo, J.ak , Maas, M.B.ak , MacDonald, J.ak , MacKenzie, L.ak , Madan, V.ak , Majkowski, R.ak , Major, O.ak , Malhorta, R.ak , Malkoff, M.ak , Mangat, H.ak , Maswadeh, A.ak , Matouk, C.ak , McArthur, K.ak , McCaul, S.ak , Medow, J.ak , Mezey, G.ak , Mighty, J.ak , Miller, D.ak , Mohan, K.K.ak , Muir, K.ak , Muñoz, L.ak , Nakaji, P.ak , Nee, A.ak , Nekoovaght-Tak, S.ak , Nyquist, P.ak , O’Kane, R.ak , Okasha, M.ak , O’Kelly, C.ak , Ostapkovich, N.ak , Pandey, A.ak , Parry-Jones, A.ak , Perla, K.R.ak , Pollack, A.ak , Polster, S.ak , Pouratian, N.ak , Quinn, T.ak , Rajajee, V.ak , Reddy, K.ak , Rehman, M.ak , Reimer, R.ak , Rincon, F.ak , Rybinnik, I.ak , Sanchez, B.ak , Sansing, L.ak , Schneck, M.ak , Schuerer, L.ak , Schul, D.ak , Schweitzer, J.ak , Seder, D.B.ak , Seyfried, D.ak , Sheth, K.ak , Spiotta, A.ak , Stechison, M.ak , Szabo, K.ak , Tamayo, G.ak , Tanczos, K.ak , Taussky, P.ak , Terry, J.ak , Testai, F.ak , Thomas, K.ak , Thompson, C.B.ak , Thompson, G.ak , Torner, J.C.ak , Tran, H.ak , Tucker, K.ak , Ungar, L.ak , Varelas, P.ak , Vargas, N.M.ak , Vatter, H.ak , Venkatasubramanian, C.ak , Vermillion, K.ak , Vollmer, D.ak , Wang, Y.ak , Wang, Y.ak , Wen, J.ak , Whitworth, L.T.ak , Willis, B.ak , Wrencher, M.ak , Wright, S.E.ak , Xu, Y.ak , Yanase, L.ak , Yi, X.ak , Yu, Z.ak , Zomorodi, A.ak , MISTIE III Investigatorsal

a Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, MD, United States
b School of Medicine, Johns Hopkins University, Baltimore, MD, United States
c Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, United States
d Emissary International, Austin, TX, United States
e University of Maryland, Baltimore, MD, United States
f The Children’s Hospital, Philadelphia, PA, United States
g Emory University, Atlanta, GA, United States
h School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United Kingdom
i Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
j University of Texas Health, San Antonio, TX, United States
k University of Alabama, Birmingham, AL, United States
l University of New Mexico, Albuquerque, NM, United States
m University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
n Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
o Mercy Neurological Institute Stroke Center, Sacramento, California, United States
p Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States
q University of Texas, McGovern Medical Center, Houston, TX, United States
r Washington University School of Medicine, St Louis, MO, United States
s Salford Royal Hospital, Salford, United Kingdom
t Stanford University School of Medicine, Stanford, California, United States
u University of Kansas, Kansas City, KS, United States
v Wake Forest School of Medicine, Winston-Salem, NC, United States
w University of Chicago, Chicago, IL, United States
x Newcastle Royal Infirmary, Newcastle, United Kingdom
y Hospital Universitario Rio Hortega, Valladolid, Spain
z Rabin Medical Center, Petah Tikva, Israel
aa University of Szeged, Szeged, Hungary
ab University of Heidelberg, Heidelberg, Germany
ac Montreal Neurological Institute and Hospital at McGill University, Montreal, QC, Canada
ad Guangzhou Neuroscience Institute, Guangzhou Liuhua Qiao Hospital, Guangzhou, China
ae The George Institute for Global Health China at Peking University Health Science Center, Beijing, China
af The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
ag Newcastle University, Newcastle, United Kingdom
ah National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
ai University of California, Los Angeles, CA, United States
aj University of Cincinnati, Cincinnati, OH, United States

Abstract
Background: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. Methods: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. Findings: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0–3 at 365 days (adjusted risk difference 4% [95% CI −4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). Interpretation: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. Funding: National Institute of Neurological Disorders and Stroke and Genentech. © 2019 Elsevier Ltd

Document Type: Article
Publication Stage: Final
Source: Scopus

“De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome” (2019) American Journal of Human Genetics

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome
(2019) American Journal of Human Genetics, 104 (3), pp. 542-552. 

Palmer, E.E.a b c d , Hong, S.e , Al Zahrani, F.f , Hashem, M.O.f , Aleisa, F.A.e , Ahmed, H.M.J.e , Kandula, T.a b , Macintosh, R.a , Minoche, A.E.c , Puttick, C.c , Gayevskiy, V.c , Drew, A.P.c , Cowley, M.J.c g , Dinger, M.c g , Rosenfeld, J.A.h , Xiao, R.h i , Cho, M.T.j , Yakubu, S.F.e , Henderson, L.B.j , Guillen Sacoto, M.J.j , Begtrup, A.j , Hamad, M.k , Shinawi, M.l , Andrews, M.V.l , Jones, M.C.m , Lindstrom, K.n , Bristol, R.E.o , Kayani, S.p , Snyder, M.q , Villanueva, M.M.r , Schteinschnaider, A.r , Faivre, L.s t , Thauvin, C.s , Vitobello, A.s , Roscioli, T.a u v , Kirk, E.P.a b u , Bye, A.a b , Merzaban, J.w , Jaremkoe , Jaremko, M.w , Sachdev, R.K.a b , Alkuraya, F.S.f x , Arold, S.T.e

a Sydney Children’s Hospital, Randwick, NSW 2031, Australia
b School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW 2031, Australia
c The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
d Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia
e King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal, 23955-6900, Saudi Arabia
f Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia
g St. Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia
h Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
i Baylor Genetics, Houston, TX 77021, United States
j GeneDx, Gaithersburg, Maryland, 20877, United States
k King Khalid University Hospital, King Saud University, Riyadh, 11472, Saudi Arabia
l Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
m Division of Genetics, Department of Pediatrics, University of California, San Diego and Rady Children’s Hospital, San Diego, CA 92123, United States
n Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, AZ 85016, United States
o Division of Pediatric Neurosurgery, Phoenix Children’s Hospital, Phoenix, AZ 85016, United States
p University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
q Department of Neurology, Children’s Health, Dallas, TX 75235, United States
r Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Montañeses, Buenos Aires, 2325, Argentina
s Inserm U1231, Lipides, Nutrition, Burgundy University, Cancer UMR 1231 Génétique des Anomalies du Développement, Dijon, 21079, France
t Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, 21079, France
u New South Wales Health Pathology Genomic Laboratory, Prince of Wales Hospital, Randwick, 2031, Australia
v Neuroscience Research Australia, University of New South Wales 2031, Australia
w King Abdullah University of Science and Technology, Division of Biological and Environmental Sciences and EngineeringThuwal 23955-6900, Saudi Arabia
x Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, 11442, Saudi Arabia

Abstract
Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid “HX repeat” motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions. © 2019 American Society of Human Genetics

Author Keywords
allelic disorders;  developmental delay;  dysmorphic;  HX repeat;  intellectual disability

Document Type: Article
Publication Stage: Final
Source: Scopus

“Spontaneous low-frequency fluctuations in the neural system for emotional perception in major psychiatric disorders: amplitude similarities and differences across frequency bands” (2019) Journal of psychiatry & neuroscience : JPN

Spontaneous low-frequency fluctuations in the neural system for emotional perception in major psychiatric disorders: amplitude similarities and differences across frequency bands
(2019) Journal of psychiatry & neuroscience : JPN, 44 (2), pp. 132-141. 

Chang, M., Edmiston, E.K., Womer, F.Y., Zhou, Q., Wei, S., Jiang, X., Zhou, Y., Ye, Y., Huang, H., Zuo, X.-N., Xu, K., Tang, Y., Wang, F.

From the Department of Radiology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China (Chang, Jiang, Wang, Wei, Xu); the Department of Psychiatry, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China (Tang, Q. Zhou, Y. Zhou); the Brain Function Research Section, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China (Chang, Edmiston, Jiang, Tang, Wang, Wei, Xu, Q. Zhou, Y. Zhou); the Department of Psychiatry, Washington University School of Medicine, St. Louis, MO (Womer); the Division of Biostatistics, University of California, Berkeley, Berkeley, CA (Huang, Ye); the CAS Key Laboratory of Behavioral Science, Institute of Psychology, Beijing, PR China (Zuo); and the Department of Psychology, University of Chinese Academy of Sciences, Beijing, PR China (Zuo)

Abstract
Background: Growing evidence indicates both shared and distinct features of emotional perception in schizophrenia, bipolar disorder and major depressive disorder. In these disorders, alterations in spontaneous low-frequency fluctuations have been reported in the neural system for emotional perception, but the similarities and differences in the amplitude of low-frequency fluctuation (ALFF) across the 3 disorders are unknown. Methods: We compared ALFF and its signal balance in the neural system for emotional perception at 2 frequency bands (slow-5 and slow-4) in 119 participants with schizophrenia, 100 with bipolar disorder, 123 with major depressive disorder and 183 healthy controls. We performed exploratory Pearson partial correlation analyses to determine the relationship between ALFF signal balance and clinical variables. Results: We observed commonalities in ALFF change patterns across the 3 disorders for emotional perception neural substrates, such as increased ALFF in the anterior cerebrum (including subcortical, limbic, paralimbic and heteromodal cortical regions) and decreased ALFF in the posterior visual cortices. Schizophrenia, bipolar disorder and major depressive disorder showed significantly decreased ALFF signal balance in the neural system for emotional perception at both slow-5 and slow-4 frequency bands, with the greatest alterations for schizophrenia, followed by bipolar disorder and major depressive disorder. We found a negative correlation between ALFF signal balance and negative/disorganized symptoms in slow-4 across the 3 disorders. Limitations: The relatively broad age range in our sample and the cross-sectional study design may not account for our findings. Conclusion: The extent of the commonalities we observed further support the concept of core neurobiological disruptions shared among the 3 disorders; ALFF signal balance could be an important neuroimaging marker for the diagnosis and treatment of schizophrenia, bipolar disorder and major depressive disorder. © 2019 Joule Inc. or its licensors

Document Type: Article
Publication Stage: Final
Source: Scopus

“Changing Conceptions of Death as a Function of Depression Status, Suicidal Ideation, and Media Exposure in Early Childhood” (2019) Journal of the American Academy of Child and Adolescent Psychiatry

Changing Conceptions of Death as a Function of Depression Status, Suicidal Ideation, and Media Exposure in Early Childhood
(2019) Journal of the American Academy of Child and Adolescent Psychiatry, 58 (3), pp. 339-349. Cited 1 time.

Hennefield, L., Whalen, D.J., Wood, G., Chavarria, M.C., Luby, J.L.

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

Abstract
Objective: This study characterized 3- to 6-year-old children’s understanding of death as a function of depression status, suicidal ideation (SI), and media consumption. Method: Participants were 79 children with depression (3.0–6.11 years old) who completed a comprehensive psychiatric assessment and experimenter-led death interview and a comparison group of 60 healthy children (4.0–7.12 years old). The interview assessed children’s understanding of 5 concepts of death: universality, applicability, irreversibility, cessation, and causality. Children’s mastery of each concept and overall understanding of death was examined as a function of depression and SI status: depressed with SI (n = 22), depressed without SI (n = 57), and healthy (n = 60). Children’s observed emotional reactions to hearing about natural death, accidental death, and suicide were assessed by death-themed stories. Parent reports of children’s television and videogames/internet consumption assessed links between media exposure and understanding of death. Results: Children with depression and SI scored higher on overall understanding of death than those with depression without SI and healthy children. They also exhibited more sad and anxious affect listening to death-themed stories and were more likely to describe death as caused by violence. Across this sample, older children also were more likely to depict death as violent. More television use was associated with less understanding of death, including the concept of irreversibility. Conclusion: Children with depression and SI have a more advanced understanding of death than their peers, dispelling the myth that these ideations arise in the context of a poor understanding of death. The increase in violence attributions across early childhood could indicate increasing normalization of violence in children’s perceptions of death. Clinical trial registration information: A Randomized Controlled Trial of PCIT-ED for Preschool Depression; http://clinicaltrials.gov; NCT00595283. © 2019 American Academy of Child and Adolescent Psychiatry

Author Keywords
death understanding;  depression;  early childhood;  media;  suicidality

Document Type: Article
Publication Stage: Final
Source: Scopus

“Editorial: Could a Treatment for Youth Anxiety Specifically Prevent the Emergence of Depression 2 Years Later?” (2019) Journal of the American Academy of Child and Adolescent Psychiatry

Editorial: Could a Treatment for Youth Anxiety Specifically Prevent the Emergence of Depression 2 Years Later?
(2019) Journal of the American Academy of Child and Adolescent Psychiatry, 58 (3), pp. 317-318. 

Glowinski, A.L.

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

Abstract
The comorbidity of depression and anxiety is a major global health problem. A 2015 report examining response patterns of 74,000 adults across 27 World Mental Health surveys in 24 countries showed a very high comorbidity between a diagnosis of lifetime DSM-IV 1 major depressive disorder and a diagnosis of any anxiety disorder in the past 12 months or lifetime anxiety disorder at similar rates in high-income and mid- to low-income countries. In addition, the report highlighted that almost 70% of people with lifetime depression and anxiety first developed anxiety and that the course and burden of lifetime depression comorbid with anxiety was usually more impairing than depression without anxiety. 2 © 2019 American Academy of Child and Adolescent Psychiatry

Document Type: Editorial
Publication Stage: Final
Source: Scopus

“Practice variation in anti-epileptic drug use for neonatal hypoxic-ischemic encephalopathy among regional NICUs” (2019) BMC Pediatrics

Practice variation in anti-epileptic drug use for neonatal hypoxic-ischemic encephalopathy among regional NICUs
(2019) BMC Pediatrics, 19 (1), art. no. 67, . 

Dizon, M.L.V.a , Rao, R.b , Hamrick, S.E.c , Zaniletti, I.d , Digeronimo, R.e , Natarajan, G.f , Kaiser, J.R.g , Flibotte, J.h , Lee, K.-S.i , Smith, D.j , Yanowitz, T.k , Mathur, A.M.b , Massaro, A.N.l

a Ann and Robert H. Lurie Children’s Hospital of Chicago and Feinberg School of Medicine, Northwestern University, 225 East Chicago Ave, Box 45, Chicago, IL 60611, United States
b Washington University, St. Louis, MO, United States
c Children’s Healthcare of Atlanta, Atlanta, GA, United States
d Children’s Hospital Association, Overland Park, KS, United States
e Seattle Children’s Hospital/University of Washington, Seattle, WA, United States
f Children’s Hospital of Michigan, Detroit, MI, United States
g Penn State Health Children’s Hospital, Hershey, PA, United States
h Children’s Hospital of Philadelphia, Philadelphia, PA, United States
i Hospital for Sick Children, Toronto, ON, Canada
j Children’s Hospital Colorado, Denver, CO, United States
k University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
l Children’s National Health Systems, Washington, DC, United States

Abstract
Background: While intercenter variation (ICV) in anti-epileptic drug (AED) use in neonates with seizures has been previously reported, variation in AED practices across regional NICUs has not been specifically and systematically evaluated. This is important as these centers typically have multidisciplinary neonatal neurocritical care teams and protocolized approaches to treating conditions such as hypoxic ischemic encephalopathy (HIE), a population at high risk for neonatal seizures. To identify opportunities for quality improvement (QI), we evaluated ICV in AED utilization for neonates with HIE treated with therapeutic hypothermia (TH) across regional NICUs in the US. Methods: Children’s Hospital Neonatal Database and Pediatric Health Information Systems data were linked for 1658 neonates ≥36 weeks’ gestation, > 1800 g birthweight, with HIE treated with TH, from 20 NICUs, between 2010 and 2016. ICV in AED use was evaluated using a mixed-effect regression model. Rates of AED exposure, duration, prescription at discharge and standardized AED costs per patient were calculated as different measures of utilization. Results: Ninety-five percent (range: 83-100%) of patients with electrographic seizures, and 26% (0-81%) without electrographic seizures, received AEDs. Phenobarbital was most frequently used (97.6%), followed by levetiracetam (16.9%), phenytoin/fosphenytoin (15.6%) and others (2.4%; oxcarbazepine, topiramate and valproate). There was significant ICV in all measures of AED utilization. Median cost of AEDs per patient was 89.90 (IQR 24.52,258.58). Conclusions: Amongst Children’s Hospitals, there is marked ICV in AED utilization for neonatal HIE. Variation was particularly notable for HIE patients without electrographic seizures, indicating that this population may be an appropriate target for QI processes to harmonize neuromonitoring and AED practices across centers. © 2019 The Author(s).

Author Keywords
Anti-epileptic drugs;  Hypoxic-ischemic encephalopathy;  Neonatal seizures

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

“Dural lymphatics regulate clearance of extracellular tau from the CNS” (2019) Molecular Neurodegeneration

Dural lymphatics regulate clearance of extracellular tau from the CNS
(2019) Molecular Neurodegeneration, 14 (1), art. no. 11, . 

Patel, T.K.a , Habimana-Griffin, L.b , Gao, X.b , Xu, B.b , Achilefu, S.b c , Alitalo, K.d , McKee, C.A.a , Sheehan, P.W.a , Musiek, E.S.a , Xiong, C.e , Coble, D.e , Holtzman, D.M.a

a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Radiology, Washington University, St. Louis, MO 63110, United States
c Department of Biochemistry and Molecular Biophysics, Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, United States
d Wihuri Research Institute, Translational Cancer Biology Program, Biomedicum Helsinki University of Helsinki, Helsinki, Finland
e Division of Biostatistics, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63110, United States

Abstract
Background: Alzheimer’s disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating Aβ pathology prompted us to investigate its role in regulating extracellular tau clearance. Methods: To study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice. Results: Our results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72 h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice. Conclusions: The dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function. © 2019 The Author(s).

Author Keywords
Alzheimer’s disease;  Dural lymphatic system;  Glymphatic system;  Neurodegeneration;  Tau;  Tau clearance;  Tau imaging;  Tauopathy

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

“The Extended Treatment Window’s Impact on Emergency Systems of Care for Acute Stroke” (2019) Academic Emergency Medicine

The Extended Treatment Window’s Impact on Emergency Systems of Care for Acute Stroke
(2019) Academic Emergency Medicine, . Cited 1 time.

Miller, J.B.a b , Heitsch, L.c , Madsen, T.E.d , Oostema, J.e , Reeves, M.f , Zammit, C.G.g , Sabagha, N.a , Sozener, C.h , Lewandowski, C.a b , Schrock, J.W.i

a Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI, United States
b Wayne State University, Detroit, MI, United States
c Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Emergency Medicine, Brown University School of Medicine, Providence, RI, United States
e Department of Emergency Medicine, Michigan State University College of Human Medicine, East Lansing, MI, United States
f Department of Epidemiology and Biostatistics, Michigan State University College of Human Medicine, East Lansing, MI, United States
g Departments of Emergency Medicine, Neurology, and Neurosurgery, University of Rochester Medical Center, Rochester, NY, United States
h Department of Emergency Medicine, University of Michigan, Ann Arbor, MI, United States
i Department of Emergency Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, United States

Abstract
The window for acute ischemic stroke treatment was previously limited to 4.5 hours for intravenous tissue plasminogen activator and to 6 hours for thrombectomy. Recent studies using advanced imaging selection expand this window for select patients up to 24 hours from last known well. These studies directly affect emergency stroke management, including prehospital triage and emergency department (ED) management of suspected stroke patients. This narrative review summarizes the data expanding the treatment window for ischemic stroke to 24 hours and discusses these implications on stroke systems of care. It analyzes the implications on prehospital protocols to identify and transfer large-vessel occlusion stroke patients, on issues of distributive justice, and on ED management to provide advanced imaging and access to thrombectomy centers. The creation of high-performing systems of care to manage acute ischemic stroke patients requires academic emergency physician leadership attentive to the rapidly changing science of stroke care. © 2019 by the Society for Academic Emergency Medicine

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

“Cerebellar hemorrhage: a 10-year evaluation of risk factors” (2019) Journal of Maternal-Fetal and Neonatal Medicine

Cerebellar hemorrhage: a 10-year evaluation of risk factors
(2019) Journal of Maternal-Fetal and Neonatal Medicine, . 

Vesoulis, Z.A., Herco, M., El Ters, N.M., Whitehead, H.V., Mathur, A.

Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: While cerebellar hemorrhage (CH) has been linked with adverse neurodevelopmental outcome in preterm infants, it remains under-recognized and the underlying mechanisms are not fully understood. Objective: To determine risk factors for CH in premature infants. Methods: A retrospective cohort study included all inborn infants ≤ 30 weeks EGA admitted to the NICU from 2007 to 2016. Comprehensive perinatal and clinical factors were collected. CH size, sidedness, and symmetry were noted. Factors associated with CH were evaluated using univariate and multivariate logistic regression. Results: Of the 352 identified infants, 69 (20%) had CH. Those with CH were born at earlier EGA, received less antenatal steroids, more frequently had an admission temperature <36 °C, had more severe lung disease, received more inotropes, and had higher rates of intraventricular hemorrhage (IVH). In the regression model, low admission temperature (OR = 3.5), inotrope exposure (OR = 2.6), chorioamnionitis (OR = 2.3), and increased ventilator days (OR = 1.02) were associated with increased risk, while antenatal steroids (OR = 0.3) and male sex (OR = 0.5) were associated with decreased risk. Imaging modality at first diagnosis was split between ultrasound and MRI (52 versus 48%). Median age at diagnosis was 4 d; 52% of cases were unilateral, and size was punctate, small, and large in 23, 45, and 32% of cases, respectively. Conclusions: CH is common in premature infants and can be diagnosed using ultrasound or MRI. Clinically modifiable risk factors have been identified and should serve as the basis for improved clinical strategies in temperature, ventilator, and blood pressure management. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Brain injury;  cerebellar hemorrhage;  premature infants;  risk factors

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

“The effect of urbanicity on internalizing disorders” (2019) Journal of Clinical Psychology

The effect of urbanicity on internalizing disorders
(2019) Journal of Clinical Psychology, . 

Piccirillo, M.L., Levinson, C.A., Rodebaugh, T.L.

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

Abstract
Objectives: Urbanicity is a known risk factor for psychopathology, yet the term urbanicity has been used to describe multiple constructs, resulting in mixed findings across the social sciences literature. Methods: We used the National Survey of American Life (N = 6,082) to construct a structural equation model of urbanicity and internalizing disorders. Urbanicity was measured using both neighborhood characteristics, as well as population-based measures. We hypothesized that urbanicity would predict higher rates of internalizing disorders. Results: Neighborhood quality (b* = 0.18, p < 0.001) was the strongest predictor of psychopathology in the final model. Population-based indicators were not significant predictors of internalizing disorders. Conclusions: Results suggest that neighborhood characteristics, rather than population-based indicators, may be better predictors of psychopathology. Future research should continue to develop and examine structural interventions. Integration of allied mental health professionals may help to alleviate negative health outcomes associated with poor neighborhood quality. © 2019 Wiley Periodicals, Inc.

Author Keywords
internalizing disorders;  mental health disparity;  psychopathology;  urbanicity;  urbanization

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

“Resting-State Functional Connectivity and Psychotic-like Experiences in Childhood: Results From the Adolescent Brain Cognitive Development Study” (2019) Biological Psychiatry

Resting-State Functional Connectivity and Psychotic-like Experiences in Childhood: Results From the Adolescent Brain Cognitive Development Study
(2019) Biological Psychiatry, . 

Karcher, N.R.a , O’Brien, K.J.a , Kandala, S.a , Barch, D.M.a b c

a Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine in St Louis, St. Louis, MO, United States
c Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Psychotic-like experiences (PLEs) during childhood are associated with greater risk of developing a psychotic disorder (and other mental disorders), highlighting the importance of identifying neural correlates of childhood PLEs. Three major cortical networks—the cingulo-opercular network (CON), default mode network (DMN), and frontoparietal network—are consistently implicated in psychosis and PLEs in adults. However, it is unclear whether variation in functional connectivity is associated with PLEs in school-aged children. Methods: Using hierarchical linear models, we examined the relationships between childhood PLEs and resting-state functional connectivity of the CON, DMN, and frontoparietal network, as well as the other networks, using an a priori network parcellation, using data from 9- to 11-year-olds (n = 3434) in the ABCD (Adolescent Brain Cognitive Development) study. We examined within-network, between-network, and subcortical connectivity. Results: Decreased CON and DMN connectivity, as well as cinguloparietal (CPAR) network connectivity, were associated with greater PLEs, even after accounting for family history of psychotic disorders, internalizing symptoms, and cognitive performance. Decreased DMN connectivity was more strongly associated with increased delusional ideation, whereas decreased CON connectivity was more strongly associated with increased perceptual distortions. Increased CON-cerebellar and decreased CPAR-cerebellar connectivity were also associated with increased PLEs, and CPAR-cerebellar connectivity was more strongly associated with increased perceptual distortions. Conclusions: Consistent with hypotheses about the dimensionality of psychosis, our results provide novel evidence that neural correlates of PLEs, such as reduced functional connectivity of higher-order cognitive networks, are present even in school-aged children. The results provide further validation for continuity of PLEs across the life span. © 2019 Society of Biological Psychiatry

Author Keywords
Delusional ideation;  Perceptual distortions;  Psychotic-like experiences;  Resting-state functional connectivity;  Subcortical connectivity;  Within-network connectivity

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

“Achilles-Mediated and Sex-Specific Regulation of Circadian mRNA Rhythms in Drosophila” (2019) Journal of Biological Rhythms

Achilles-Mediated and Sex-Specific Regulation of Circadian mRNA Rhythms in Drosophila
(2019) Journal of Biological Rhythms, . 

Li, J.a , Yu, R.Y.b , Emran, F.b , Chen, B.E.b c , Hughes, M.E.a

a Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, Montreal General Hospital, Montréal, QC, Canada
c Departments of Medicine and Neurology and Neurosurgery, McGill University, Montréal, QC, Canada

Abstract
The circadian clock is an evolutionarily conserved mechanism that generates the rhythmic expression of downstream genes. The core circadian clock drives the expression of clock-controlled genes, which in turn play critical roles in carrying out many rhythmic physiological processes. Nevertheless, the molecular mechanisms by which clock output genes orchestrate rhythmic signals from the brain to peripheral tissues are largely unknown. Here we explored the role of one rhythmic gene, Achilles, in regulating the rhythmic transcriptome in the fly head. Achilles is a clock-controlled gene in Drosophila that encodes a putative RNA-binding protein. Achilles expression is found in neurons throughout the fly brain using fluorescence in situ hybridization (FISH), and legacy data suggest it is not expressed in core clock neurons. Together, these observations argue against a role for Achilles in regulating the core clock. To assess its impact on circadian mRNA rhythms, we performed RNA sequencing (RNAseq) to compare the rhythmic transcriptomes of control flies and those with diminished Achilles expression in all neurons. Consistent with previous studies, we observe dramatic upregulation of immune response genes upon knock-down of Achilles. Furthermore, many circadian mRNAs lose their rhythmicity in Achilles knock-down flies, suggesting that a subset of the rhythmic transcriptome is regulated either directly or indirectly by Achilles. These Achilles-mediated rhythms are observed in genes involved in immune function and in neuronal signaling, including Prosap, Nemy and Jhl-21. A comparison of RNAseq data from control flies reveals that only 42.7% of clock-controlled genes in the fly brain are rhythmic in both males and females. As mRNA rhythms of core clock genes are largely invariant between the sexes, this observation suggests that sex-specific mechanisms are an important, and heretofore under-appreciated, regulator of the rhythmic transcriptome. © 2019 The Author(s).

Author Keywords
Achilles (Achl);  circadian rhythms;  clock-controlled genes (CCGs);  RNA sequencing (RNAseq);  sex specificity

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

“Microwave-induced thermoacoustic tomography through an adult human skull” (2019) Medical Physics

Microwave-induced thermoacoustic tomography through an adult human skull
(2019) Medical Physics, . 

Yan, A.a b , Lin, L.b c , Liu, C.a , Shi, J.b , Na, S.b , Wang, L.V.b

a School of Electronics and Information Engineering, Sichuan University, Chengdu, 610064, China
b Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng, Department of Medical Engineering, Department of Electrical Engineering, California Institute of Technology, Pasadena, CA 91125, United States
c Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MI 63130, United States

Abstract
Purpose: To demonstrate the feasibility of microwave-induced thermoacoustic tomography (TAT) of adult human brain. Methods: We analyzed the electric field distribution radiated from an antenna to acquire homogeneous illumination. We first imaged the anatomical structures in a rat’s trunk to validate the thermoacoustic contrast in vivo. We then imaged an agar cylinder through an adult human skull ex vivo to demonstrate transcranial penetration of both microwave and ultrasound. We also analyzed the specific absorption rate to show the conformance to the safety standard for human electromagnetic exposure. Results: We successfully acquired cross-sectional images of the rat’s trunk in vivo. Major blood vessels and organs are clearly visible. The transcranial image shows that TAT can image through the adult human skull and reveal an agar enclosed by the skull. Conclusions: Microwave-induced TAT of a rat’s trunk in vivo and an agar phantom through an adult human skull ex vivo has been demonstrated experimentally. This study demonstrates both the TAT contrasts in vivo and the capability of transcranial imaging, showing potential of TAT for adult human brain imaging with high contrast and penetration. © 2019 American Association of Physicists in Medicine

Author Keywords
adult human brain;  microwave-induced thermoacoustic tomography;  specific absorption rate (SAR);  transcranial imaging

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

“Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer’s disease” (2019) Alzheimer’s and Dementia

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer’s disease
(2019) Alzheimer’s and Dementia, . 

Schindler, S.E.a b , Li, Y.c , Todd, K.W.c , Herries, E.M.d , Henson, R.L.a b e , Gray, J.D.a b e , Wang, G.c , Graham, D.L.f , Shaw, L.M.g , Trojanowski, J.Q.g h , Hassenstab, J.J.a b , Benzinger, T.L.S.a b i , Cruchaga, C.b e j , Jucker, M.k l , Levin, J.k m , Chhatwal, J.P.n , Noble, J.M.o , Ringman, J.M.p , Graff-Radford, N.R.q , Holtzman, D.M.a b e , Ladenson, J.H.d , Morris, J.C.a b , Bateman, R.J.a b e , Xiong, C.a b c , Fagan, A.M.a b e , Dominantly Inherited Alzheimer Networkr

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
f Biomarkers, Research and Early Development, Biogen, Cambridge, MA, United States
g Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
h Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
i Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
j Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
k German Center for Neurodegenerative Diseases (DZNE), Germany
l Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
m Department of Neurology, Ludwig Maximilians University, Munich, Germany
n Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
o Department of Neurology, Columbia University Medical Center, New York City, NY, United States
p Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, United States
q Department of Neurology, Mayo Clinic, Jacksonville, FL, United States

Abstract
Introduction: Four less well-studied but promising “emerging” cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Methods: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. Results: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15–19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. Discussion: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation. © 2019 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  Autosomal-dominant Alzheimer’s disease;  Biomarkers;  Cerebrospinal fluid;  Dementia;  Neuroinflammation

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