Hope Center member publications

Cerebrospinal fluid neurofilament light chain is a marker of aging and white matter damage
(2022) Neurobiology of Disease, 166, art. no. 105662, . 

Meeker, K.L.^a , Butt, O.H.^a , Gordon, B.A.^b , Fagan, A.M.^a , Schindler, S.E.^a , Morris, J.C.^a , Benzinger, T.L.S.^b , Ances, B.M.^a

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

Abstract
Background: Cerebrospinal fluid (CSF) neurofilament light chain (NfL) reflects neuro-axonal damage and is increasingly used to evaluate disease progression across neurological conditions including Alzheimer disease (AD). However, it is unknown how NfL relates to specific types of brain tissue. We sought to determine whether CSF NfL is more strongly associated with total gray matter, white matter, or white matter hyperintensity (WMH) volume, and to quantify the relative importance of brain tissue volume, age, and AD marker status (i.e., APOE genotype, brain amyloidosis, tauopathy, and cognitive status) in predicting CSF NfL. Methods: 419 participants (Clinical Dementia Rating [CDR] Scale > 0, N = 71) had CSF, magnetic resonance imaging (MRI), and neuropsychological data. A subset had amyloid positron emission tomography (PET) and tau PET. Pearson correlation analysis was used to determine the association between CSF NfL and age. Multiple regression was used to determine which brain volume (i.e., gray, white, or WMH volume) most strongly associated with CSF NfL. Stepwise regression and dominance analyses were used to determine the individual contributions and relative importance of brain volume, age, and AD marker status in predicting CSF NfL. Results: CSF NfL increased with age (r = 0.59, p < 0.001). Elevated CSF NfL was associated with greater total WMH volume (p < 0.001), but not gray or white matter volume (p’s > 0.05) when considered simultaneously. Age and WMH volume were consistently more important (i.e., have greater R2 values) than AD markers when predicting CSF NfL. Conclusions: CSF NfL is a non-specific marker of aging and white matter integrity with limited sensitivity to specific markers of AD. CSF NfL likely reflects processes associated with cerebrovascular disease. © 2022

Author Keywords
Aging;  Alzheimer disease;  Cerebrospinal fluid;  Cerebrovascular disease;  Neurofilament light;  White matter

Funding details
UL1 TR000448
National Institutes of HealthNIHK01AG053474, K23AG053426, P01AG00391, P01AG005681, P01AG026276, R01AG052550, R01AG057680, R01NR012657, R01NR012907, R01NR014449, R03AG050921, U19AG032438
Alzheimer’s AssociationAABAND-19-613876
Hope Center for Neurological Disorders18F-AV-1451, 18F-AV-45, Flortaucipir F18

Document Type: Article
Publication Stage: Final
Source: Scopus

Astrocytic α2-Na+/K+ ATPase inhibition suppresses astrocyte reactivity and reduces neurodegeneration in a tauopathy mouse model
(2022) Science Translational Medicine, 14 (632), p. eabm4107. 

Mann, C.N.^a b , Devi, S.S.^a b , Kersting, C.T.^a b , Bleem, A.V.^a b , Karch, C.M.^b c d , Holtzman, D.M.^a b d , Gallardo, G.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
^b Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA
^c Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
^d Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63110, USA

Abstract
Alzheimer’s disease (AD) is the most dominant form of dementia characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tau tangles (NFTs). In addition to these pathologies, an emerging pathophysiological mechanism that influences AD is neuroinflammation. Astrocytes are a vital type of glial cell that contribute to neuroinflammation, and reactive astrocytes, or astrogliosis, are a well-known pathological feature of AD. However, the mechanisms by which astrocytes contribute to the neurodegenerative process in AD have not been fully elucidated. Here, we showed that astrocytic α2-Na+/K+ adenosine triphosphatase (α2-NKA) is elevated in postmortem human brain tissue from AD and progressive nuclear palsy, a primary tauopathy. The increased astrocytic α2-NKA was also recapitulated in a mouse model of tauopathy. Pharmacological inhibition of α2-NKA robustly suppressed neuroinflammation and reduced brain atrophy. In addition, α2-NKA knockdown in tauopathy mice halted the accumulation of tau pathology. We also demonstrated that α2-NKA promoted tauopathy, in part, by regulating the proinflammatory protein lipocalin-2 (Lcn2). Overexpression of Lcn2 in tauopathy mice increased tau pathology, and prolonged Lcn2 exposure to primary neurons promoted tau uptake in vitro. These studies collectively highlight the contribution of reactive astrocytes to tau pathogenesis in mice and define α2-NKA as a major regulator of astrocytic-dependent neuroinflammation.

Document Type: Article
Publication Stage: Final
Source: Scopus

Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors
(2022) Science Translational Medicine, 14 (632), p. eabj8186. 

Tavares-Ferreira, D.^a , Shiers, S.^a , Ray, P.R.^a , Wangzhou, A.^a , Jeevakumar, V.^a , Sankaranarayanan, I.^a , Cervantes, A.M.^b , Reese, J.C.^b , Chamessian, A.^c , Copits, B.A.^c , Dougherty, P.M.^d , Gereau, R.W., 4th^c , Burton, M.D.^a , Dussor, G.^a , Price, T.J.^a

^a Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, United States
^b Southwest Transplant Alliance, Dallas, United States
^c Department of Anesthesiology , Washington University Pain Center, St. Louis, MO 63110, USA
^d Department of Pain Medicine, Division of Anesthesiology and Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States

Abstract
Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha (CALCA) expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.

Document Type: Article
Publication Stage: Final
Source: Scopus

Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques
(2022) Neurology, 98 (7), pp. e688-e699. 

Li, Y., Schindler, S.E., Bollinger, J.G., Ovod, V., Mawuenyega, K.G., Weiner, M.W., Shaw, L.M., Masters, C.L., Fowler, C.J., Trojanowski, J.Q., Korecka, M., Martins, R.N., Janelidze, S., Hansson, O., Bateman, R.J.

From the Department of Neurology (Y.L., S.E.S., J.G.B., V.O., K.G.M., R.J.B.), Division of Biostatistics (Y.L.), Knight Alzheimer’s Disease Research Center (S.E.S., R.J.B.), and Hope Center for Neurological Disorders (R.J.B.), Washington University School of Medicine, St. Louis, MO; Departments of Psychiatry, Radiology and Biomedical Imaging, Medicine, and Neurology (M.W.W.), Center for Imaging and Neurodegenerative Diseases, Northern California Institute for Research and Education, Department of Veterans Affairs Medical Center, University of California San Francisco; Department of Pathology and Laboratory Medicine (S.M.L., J.Q.T., M.K.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; The Florey Institute of Neuroscience and Mental Health (C.L.M., C.J.F.), University of Melbourne, Victoria; Edith Cowan University (R.N.M.), Joondalup, Australia; Department of Clinical Sciences, Clinical Memory Research Unit (S.J., O.H.), Lund University; and Memory Clinic (O.H.), Skåne University Hospital, Malmö, Sweden

Abstract
BACKGROUND AND OBJECTIVES: To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols. METHODS: Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40. RESULTS: In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals. DISCUSSION: Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants. © 2021 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Depressive Symptomatology and Functional Status Among Stroke Survivors: A Network Analysis
(2022) Archives of Physical Medicine and Rehabilitation, .

Lau, S.C.L.^a , Connor, L.T.^a b , Lee, J.-M.^b , Baum, C.M.^a b c

^a Program in Occupational Therapy, Washington University School of Medicine, MO, St. Louis
^b Department of Neurology, Washington University School of Medicine, MO, St. Louis
^c Brown School of Social Work, Washington University in St Louis, St Louis, MO, United States

Abstract
Objective: To (1) characterize poststroke depressive symptom network and identify the symptoms most central to depression and (2) examine the symptoms that bridge depression and functional status. Design: Secondary data analysis of the Stroke Recovery in Underserved Population database. Networks were estimated using regularized partial correlation models. Topology, network stability and accuracy, node centrality and predictability, and bridge statistics were investigated. Setting: Eleven inpatient rehabilitation facilities across 9 states of the United States. Participants: Patients with stroke (N=1215) who received inpatient rehabilitation. Interventions: Not applicable. Main Outcome Measures: The Center for Epidemiologic Studies Depression Scale and FIM were administered at discharge from inpatient rehabilitation. Results: Depressive symptoms were positively intercorrelated within the network, with stronger connections between symptoms within the same domain. “Sadness” (expected influence=1.94), “blues” (expected influence=1.14), and “depressed” (expected influence=0.97) were the most central depressive symptoms, whereas “talked less than normal” (bridge expected influence=−1.66) emerged as the bridge symptom between depression and functional status. Appetite (R2=0.23) and sleep disturbance (R2=0.28) were among the least predictable symptoms, whose variance was less likely explained by other symptoms in the network. Conclusions: Findings illustrate the potential of network analysis for discerning the complexity of poststroke depressive symptomology and its interplay with functional status, uncovering priority treatment targets and promoting more precise clinical practice. This study contributes to the need for expansion in the understanding of poststroke psychopathology and challenges clinicians to use targeted intervention strategies to address depression in stroke rehabilitation. © 2022 The American Congress of Rehabilitation Medicine

Author Keywords
Depression;  Functional Status;  Rehabilitation;  Stroke

Funding details
Washington University in St. LouisWUSTL

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

An affordable and easy-to-use focused ultrasound device for noninvasive and high precision drug delivery to the mouse brain
(2022) IEEE Transactions on Biomedical Engineering, . 

Hu, Z., Chen, S., Yang, Y., Gong, Y., Chen, H.

Department of Biomedical Engineering, Washington University in St Louis, 7548 St Louis, Missouri, United States

Abstract
Objective: Focused ultrasound (FUS) combined with microbubble-mediated blood-brain barrier (BBB) opening (FUS-BBBO) is not only a promising technique for clinical applications but also a powerful tool for preclinical research. However, existing FUS devices for preclinical research are expensive, bulky, and lack the precision needed for small animal research, which limits the broad adoption of this promising technique by the research community. Our objective was to design and fabricate an affordable, easy-to-use, high-precision FUS device for small animal research. Methods: We designed and fabricated in-house mini-FUS transducers (~$80 each in material cost) with three frequencies (1.5, 3.0, and 6.0 MHz) and integrated them with a stereotactic frame for precise mouse brain targeting using established stereotactic procedures. The BBB opening volume by FUS-BBBO at different acoustic pressures (0.20-0.57 MPa) was quantified using T1-weighted contrast-enhanced magnetic resonance imaging of gadolinium leakage and fluorescence imaging of Evans blue extravasation. Results: The targeting accuracy of the device as measured by the offset between the desired target location and the centroid of BBBO was 0.63 ± 0.19 mm. The spatial precision of the device in targeting individual brain structures was improved by the use of higher frequency FUS transducers. The BBB opening volume had high linear correlations with the cavitation index (defined by the ratio between acoustic pressure and frequency) and mechanical index (defined by the ratio between acoustic pressure and the square root of frequency). The correlation coefficient of cavitation index was higher than that of the mechanical index. Conclusion: This study demonstrated that spatially accurate and precise BBB opening was achievable using an affordable and easy-to-use FUS device. The BBB opening volume was tunable by modulating the cavitation index. This device is expected to decrease the barriers for the adoption of FUS-BBBO technique by the broad research community. IEEE

Author Keywords
Acoustics;  Blood-brain barrier;  Brain drug delivery;  Cavitation index;  Drug delivery;  Focused ultrasound;  Indexes;  Mechanical inde;  Mice;  Three-dimensional displays;  Transducers;  Ultrasonic imaging

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

Differential Placebo Responses for Pharmacotherapy and Neurostimulation in Late-Life Depression
(2022) Neuromodulation, . 

Wathra, R.A.^a b , Mulsant, B.H.^a b , Reynolds, C.F., III^c , Lenze, E.J.^d , Karp, J.F.^e , Daskalakis, Z.J.^f , Blumberger, D.M.^a b

^a Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, ON, Canada
^b Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
^c Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, University of Arizona College of Medicine – Tucson, Tucson, AZ, United States
^f Department of Psychiatry, University of California San Diego, San Diego, CA, United States

Abstract
Background: The magnitude of the placebo response depends on both the modality used as the “placebo” and the intervention with which it is compared, both of which can complicate the interpretation of randomized controlled trials (RCTs) for depression in late life. Given that neurostimulation and pharmacotherapy are among the most common interventions studied for late-life depression, comparing the relative placebo responses in studies of these interventions can aid interpretation of relative effect sizes. Materials and Methods: We analyzed data from two RCTs of adults aged ≥60 years in an episode of treatment-resistant major depression, one comparing aripiprazole and matching placebo pills and the other comparing deep repetitive transcranial magnetic stimulation (rTMS) and sham rTMS. In both RCTs, depression was assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17). The primary comparison occurred after four weeks using analysis of covariance (ANCOVA) of HDRS-17 scores in participants who received placebo pills or sham rTMS. Relevant covariates included years of education, duration of depressive episode, and baseline HDRS-17 score. Results: Accounting for covariates, there was a larger reduction of HDRS-17 after four weeks in the sham rTMS group (estimated marginal mean ± SE: −5.90 ± 1.45; 95% CI: [−8.82, 2.98]) than in the placebo pills group (−1.07 ± 1.45; [−3.98, 1.85]). There were no significant differences between these groups in the binary outcome analysis of response and remission rates at four weeks or any outcome at trial end point comparison. Conclusions: Sham rTMS may have a larger placebo response than placebo pills early in the treatment of older adults with treatment-resistant depression. Differential placebo responses should be considered in both the interpretation and design of RCTs. © 2021 International Neuromodulation Society

Author Keywords
Aripiprazole;  depression;  geriatric;  placebo;  rTMS

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

SIRT1 mediates hypoxic postconditioning- and resveratrol-induced protection against functional connectivity deficits after subarachnoid hemorrhage
(2022) Journal of Cerebral Blood Flow and Metabolism, . 

Clarke, J.V.^a , Brier, L.M.^b , Rahn, R.M.^b , Diwan, D.^a , Yuan, J.Y.^a , Bice, A.R.^b , Imai, S.-I.^c , Vellimana, A.K.^a , Culver, J.P.^b , Zipfel, G.J.^a

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States

Abstract
Functional connectivity (FC) is a sensitive metric that provides a readout of whole cortex coordinate neural activity in a mouse model. We examine the impact of experimental SAH modeled through endovascular perforation, and the effectiveness of subsequent treatment on FC, through three key questions: 1) Does the endovascular perforation model of SAH induce deficits in FC; 2) Does exposure to hypoxic conditioning provide protection against these FC deficits and, if so, is this neurovascular protection SIRT1-mediated; and 3) does treatment with the SIRT1 activator resveratrol alone provide protection against these FC deficits? Cranial windows were adhered on skull-intact mice that were then subjected to either sham or SAH surgery and either left untreated or treated with hypoxic post-conditioning (with or without EX527) or resveratrol for 3 days. Mice were imaged 3 days post-SAH/sham surgery, temporally aligned with the onset of major SAH sequela in mice. Here we show that the endovascular perforation model of SAH induces global and network-specific deficits in FC by day 3, corresponding with the time frame of DCI in mice. Hypoxic conditioning provides SIRT1-mediated protection against these network-specific FC deficits post-SAH, as does treatment with resveratrol. Conditioning-based strategies provide multifaceted neurovascular protection in experimental SAH. © The Author(s) 2022.

Author Keywords
delayed cerebral ischemia;  experimental subarachnoid hemorrhage;  Functional connectivity;  optical intrinsic signal;  sirtuins

Funding details
National Institute on AgingNIAF30AG061932
National Institute of Neurological Disorders and StrokeNINDSP01NS080675, R01NS091603, R01NS099429
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU54HD087011

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