An investigation of the potential clinical utility of critical slowing down as an early warning sign for recurrence of depression
(2024) Journal of Behavior Therapy and Experimental Psychiatry, 82, art. no. 101922, .
Tonge, N.A.a , Miller, J.P.b , Kharasch, E.D.c , Lenze, E.J.d , Rodebaugh, T.L.a
a Department of Psychology & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
c Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States
d Department of Psychiatry, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
Abstract
Background and objectives: Much of the burden of depressive illness is due to relapses that occur after treatment into remission. Prediction of an individual’s imminent depressive relapse could lead to just-in-time interventions to prevent relapse, reducing depression’s substantial burden of disability, costs, and suicide risk. Increasingly strong relationships in the form of autocorrelations between depressive symptoms, a signal of a phenomenon described as critical slowing down (CSD), have been proposed as a means of predicting relapse. Methods: In the current study, four participants in remission from depression, one of whom relapsed, responded to daily smartphone surveys with depression symptoms. We used p-technique factor analysis to identify depression factors from over 100 survey responses. We then tested for the presence of CSD using time-varying vector autoregression and detrended fluctuation analysis. Results: We found evidence that CSD provided an early warning sign for depression in the participant who relapsed, but we also detected false positive indications of CSD in participants who did not relapse. Results from time-varying vector autoregression and detrended fluctuation analysis were not in agreement. Limitations: Limitations include use of secondary data and a small number of participants with daily responding to a subset of depression symptoms. Conclusions: CSD provides a compelling framework for predicting depressive relapse and future research should focus on improving detection of early warning signs reliably. Improving early detection methods for depression is clinically significant, as it would allow for the development of just-in-time interventions. © 2023 Elsevier Ltd
Author Keywords
Complex dynamic systems; Critical slowing down; Depression; Early warning signs; Ecological momentary assessment; Relapse
Funding details
National Institutes of HealthNIHU01FD004899
International Colour AssociationAIC
Document Type: Article
Publication Stage: Final
Source: Scopus
Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits
(2023) Cell Reports, 42 (11), art. no. 113411, .
Beard, D.C.a , Zhang, X.a , Wu, D.Y.a , Martin, J.R.a , Erickson, A.a , Boua, J.V.a , Hamagami, N.a , Swift, R.G.b c , McCullough, K.B.b c , Ge, X.d h , Bell-Hensley, A.e f , Zheng, H.f , Palmer, C.W.b h , Fuhler, N.A.b h , Lawrence, A.B.g , Hill, C.A.g , Papouin, T.a , Noguchi, K.K.b h , McAlinden, A.f , Garbow, J.R.d h h , Dougherty, J.D.b c h , Maloney, S.E.b h , Gabel, H.W.a h
a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, United States
f Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Pathology and Anatomical Science, University of Missouri School of Medicine, Columbia, MO 65212, United States
h Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3aP900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease. © 2023 The Authors
Author Keywords
ASD; CP: Neuroscience; DNA methylation; DNMT3A; enhancer; heterogeneity; mCA; MeCP2; NDD; neurodevelopment; non-CpG
Funding details
F31HD100098, P50HD103525
R01MH117405
National Institute of Neurological Disorders and StrokeNINDSR01NS04102
Simons Foundation Autism Research InitiativeSFARI
Musculoskeletal Research Center, Washington University in St. LouisMRC
Document Type: Article
Publication Stage: Final
Source: Scopus
Relationship between baseline plasma p-tau181 and longitudinal changes in cognition and structural brain measures in a cohort of cognitively unimpaired older adults
(2023) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 15 (4), art. no. e12487, .
Pais, M.V.a b , Kuo, C.-L.c , Ances, B.M.d , Wetherell, J.L.e , Lenze, E.J.f , Diniz, B.S.a
a UConn Center on Aging, University of Connecticut Health Center, Farmington, CT, United States
b Laboratory of Neuroscience (LIM-27), Departamento e Instituto de Psiquiatria, Faculdade de Medicina, Universidade de Sao Paulo (FMUSP), Sao Paulo, Brazil
c Department of Public Health Sciences, University of Connecticut Health Center, Farmington, CT, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e VA San Diego Healthcare System and University of California San Diego, San Diego, CA, United States
f Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
INTRODUCTION: Preclinical Alzheimer’s disease (AD) affects a significant proportion of cognitively unimpaired (CU) older adults. Currently, blood-based biomarkers detect very early changes in the AD continuum with great accuracy. METHODS: We measured baseline plasma phosphorylated tau (p-tau)181 using electrochemiluminescence (ECL)-based assay (MesoScale Discovery) in 533 CU older adults. Follow-up lasted up to 18 months. Cognitive performance assessment included memory and cognitive control. Structural brain measures included cortical thickness, which includes the AD magnetic resonance imaging (AD MRI) signature, and hippocampal volume. RESULTS: In this cohort of CU older adults, baseline plasma p-tau181 levels were not associated with short-term changes in cognition and structural brain measures. Also, baseline plasma p-tau levels did not influence the effects of behavioral interventions (exercise or mindfulness) on cognitive and structural brain changes. DISCUSSION: The short follow-up and healthy status of this CU cohort might have limited the sensitivity of plasma p-tau181 in detecting changes associated with AD pathology. © 2023 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; Alzheimer’s disease magnetic resonance imaging signature; cortical thickness; hippocampal volume; plasma phosphorylated tau 181
Funding details
National Institutes of HealthNIHR01AG049689, R01AG072694, R01MH115953
Document Type: Article
Publication Stage: Final
Source: Scopus
Chronic GCPII (glutamate-carboxypeptidase-II) inhibition reduces pT217Tau levels in the entorhinal and dorsolateral prefrontal cortices of aged macaques
(2023) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 9 (4), art. no. e12431, .
Bathla, S.a , Datta, D.a b , Liang, F.c , Barthelemy, N.d , Wiseman, R.e , Slusher, B.S.e , Asher, J.f , Zeiss, C.f , Ekanayake-Alper, D.f , Holden, D.g , Terwilliger, G.f , Duque, A.b , Arellano, J.b , van Dyck, C.a , Bateman, R.J.g , Xie, Z.f , Nairn, A.C.a , Arnsten, A.F.T.b
a Departments of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b Departments of Neuroscience, Yale University School of Medicine, New Haven, CT, United States
c Department of Anesthesiology, Harvard University School of Medicine, Boston, MA, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Johns Hopkins University Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, United States
f Departments of Comparative Medicine, Yale University School of Medicine, New Haven, CT, United States
g Departments of Radiology, Yale University School of Medicine, New Haven, CT, United States
Abstract
Introduction: Current approaches for treating sporadic Alzheimer’s disease (sAD) focus on removal of amyloid beta 1-42 (Aβ1-42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post-synaptic, on spines, where they regulate cAMP-calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally-occurring tau pathology. Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),. Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),. Results: Aged macaques that received 2-MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2-MPPA- and vehicle-treated monkeys showed cognitive improvement; 2-MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2-MPPA administration, confirmed in dlPFC samples. Discussion: These data provide proof-of-concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights: Inflammation is a key driver of sporadic Alzheimer’s disease. GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium. Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys. GCPII inhibition is a novel strategy to help prevent tau pathology at early stages. © 2023 The Authors. Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
calcium; CSF; dorsolateral prefrontal cortex; entorhinal cortex; macaque; mGluR3; plasma; pT217Tau
Funding details
MH113257
National Institutes of HealthNIHAG047270, AG062306, AG066508, DA018343
Connecticut State Department of Mental Health and Addiction ServicesDMHAS
Document Type: Article
Publication Stage: Final
Source: Scopus