Inflammation is associated with pain and fatigue in older adults
(2024) Brain, Behavior, and Immunity – Health, 42, art. no. 100874, .
Norton, S.A.a , Blaydon, L.M.a , Niehaus, M.a b , Miller, A.P.c , Hill, P.L.a , Oltmanns, T.F.a , Bogdan, R.a
a Department of Psychological & Brain Sciences, Washington University in Saint Louis, United States
b University of Missouri Saint Louis, United States
c Department of Psychiatry, Washington University in Saint Louis, United States
Abstract
Introduction: Increasing evidence suggests that inflammation may play a pivotal role in the development of chronic pain and fatigue in aging individuals. This study investigated the relationship between three inflammatory markers (IL-6, CRP, and TNFα) and pain and fatigue, both cross-sectionally and longitudinally, in a sample of older adults from the Saint Louis Personality and Aging (SPAN) study. Methods: SPAN study participants provided blood samples at two in-person sessions approximately 2 years apart for the analysis of the inflammatory biomarkers IL-6, CRP, and TNFα. Pain and fatigue were assessed using the RAND-36 Health Status Inventory. Correlations (with false discovery rate correction for multiple testing) and follow-up linear regressions including potentially confounding demographic (e.g., annual household income) and health (e.g., BMI, medication use) covariates were used to estimate cross sectional and longitudinal associations. Analytic ns ranged from 533 to 815. Results: Cross-sectional analyses revealed that higher IL-6 and CRP were associated with greater reported pain and fatigue, even after accounting for covariates (βs > .098, ps < .05). TNFα was associated with greater fatigue only (β = .100, p = .012). Longitudinally, CRP and IL-6 predicted future pain and fatigue, although only the relationship between CRP and future fatigue survived the inclusion of covariates (β = .104, p = .022). Both pain and fatigue predicted higher levels of IL-6 and CRP approximately 2 years later, although only the associations with IL-6 survived the inclusion of covariates (βs > .12, ps < .01). Discussion: Our study adds to a growing body of literature showing that inflammation is associated with greater pain and fatigue in older adults. Our longitudinal data showing temporal bidirectional associations is consistent with evidence from non-human animal models that heightened inflammation causally contributes to fatigue and also suggests that the experience of pain and fatigue may contribute to inflammation. It will be important for future work to identify how lifestyle factors associated with pain and fatigue (e.g., physical activity) may contribute to these associations. © 2024
Author Keywords
Aging; C-Reactive protein; CRP; Fatigue; IL-6; Inflammation; Pain; TNFα
Document Type: Article
Publication Stage: Final
Source: Scopus
Cardiorespiratory Fitness and Sleep, but not Physical Activity, are Associated with Functional Connectivity in Older Adults
(2024) Sports Medicine – Open, 10 (1), art. no. 113, .
Wing, D.a b , Roelands, B.f j , Wetherell, J.L.d e , Nichols, J.F.a b , Meeusen, R.f j k , Godino, J.G.a b , Shimony, J.S.i , Snyder, A.Z.i , Nishino, T.c , Nicol, G.E.c , Nagels, G.h , Eyler, L.T.e g , Lenze, E.J.c
a Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, United States
b Exercise and Physical Activity Resource Center (EPARC), University of California, San Diego, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Mental Health Service, VA San Diego Healthcare System, San Diego, United States
e Department of Psychiatry, University of California, San Diego, United States
f Human Physiology & amp; Sports Physiotherapy Research Group, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
g Education, and Clinical Center, Desert-Pacific Mental Illness Research, San Diego Veterans Administration Healthcare System, San Diego, United States
h Department of Neurology, Brussels, Belgium/Center for Neurosciences (C4N), UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium
i Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
j Vrije Universiteit Brussel, Brussels, Belgium
k Department of Sports, Recreation, Exercise and Sciences, Community and Health Sciences, University of the Western Cape, Cape Town, South Africa
Abstract
Background: Aging results in changes in resting state functional connectivity within key networks associated with cognition. Cardiovascular function, physical activity, sleep, and body composition may influence these age-related changes in the brain. Better understanding these associations may help clarify mechanisms related to brain aging and guide interventional strategies to reduce these changes. Methods: In a large (n = 398) sample of healthy community dwelling older adults that were part of a larger interventional trial, we conducted cross sectional analyses of baseline data to examine the relationships between several modifiable behaviors and resting state functional connectivity within networks associated with cognition and emotional regulation. Additionally, maximal aerobic capacity, physical activity, quality of sleep, and body composition were assessed. Associations were explored both through correlation and best vs. worst group comparisons. Results: Greater cardiovascular fitness, but not larger quantity of daily physical activity, was associated with greater functional connectivity within the Default Mode (p = 0.008 r = 0.142) and Salience Networks (p = 0.005, r = 0.152). Better sleep (greater efficiency and fewer nighttime awakenings) was also associated with greater functional connectivity within multiple networks including the Default Mode, Executive Control, and Salience Networks. When the population was split into quartiles, the highest body fat group displayed higher functional connectivity in the Dorsal Attentional Network compared to the lowest body fat percentage (p = 0.011; 95% CI − 0.0172 to − 0.0023). Conclusion: These findings confirm and expand on previous work indicating that, in older adults, higher levels of cardiovascular fitness and better sleep quality, but not greater quantity of physical activity, total sleep time, or lower body fat percentage are associated with increased functional connectivity within key resting state networks. © The Author(s) 2024.
Author Keywords
Body composition; Brain health; Functional connectivity; Maximal cardiovascular fitness; Physical activity; Sleep quality; Sleep quantity; Successful aging
Document Type: Article
Publication Stage: Final
Source: Scopus
Two F-18 radiochemistry methods to synthesize a promising transient receptor potential canonical 5 (TRPC5) radioligand
(2024) Journal of Fluorine Chemistry, 280, art. no. 110367, .
Yu, Y.a , Jadhav, S.B.a , Xing, Z.a , Jiang, H.a , Qiu, L.a , Huang, T.a , Perlmutter, J.S.a b , Li, Z.c , Tu, Z.a
a Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
b Department of Neurology and Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
c Department of Radiology, University of North Carolina at Chapel Hill, ChapelHill, NC 27599, United States
Abstract
TRPC5 is a member of the mammalian transient receptor potential (TRP) channel superfamily and it has been implicated in various physiological and pathological mechanisms of neurological and psychiatric diseases. Fluorine-18 is one of the most widely used radionuclides for PET imaging due to its favorable chemical characteristics and nuclear-physical properties. Herein, we describe two complementary radiosynthetic approaches and preliminary in vivo evaluation for [18F]TZ78141 as a novel and promising fluorine-18 labeled radiotracer for imaging TRPC5. The latter strategy employed a ruthenium-mediated radiofluorination method, facilitating the rapid synthesis of the desired radiotracer with substantial advantages in simplicity and efficiency. © 2024 Elsevier B.V.
Author Keywords
Fluorine -18; PET tracer; Radiolabeling; TRPC5
Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDS
National Institute on AgingNIANS075527, NS103988, NS103957, NS134586
National Institute on AgingNIA
Document Type: Article
Publication Stage: Final
Source: Scopus
CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease
(2024) Cell, 187 (22), pp. 6309-6326.e15.
Shen, Y.a b , Timsina, J.a b , Heo, G.a b , Beric, A.a b , Ali, M.a b , Wang, C.a b , Yang, C.a b , Wang, Y.a b , Western, D.a b , Liu, M.a b , Gorijala, P.a b , Budde, J.a b , Do, A.a b , Liu, H.c , Gordon, B.c , Llibre-Guerra, J.J.c , Joseph-Mathurin, N.d , Perrin, R.J.e z , Maschi, D.f , Wyss-Coray, T.g h , Pastor, P.i , Renton, A.E.j k l , Surace, E.I.m , Johnson, E.C.B.n o z , Levey, A.I.o z , Alvarez, I.p , Levin, J.q r z , Ringman, J.M.s , Allegri, R.F.t , Seyfried, N.u , Day, G.S.v , Wu, Q.w , Fernández, M.V.x , Tarawneh, R.y , McDade, E.c z , Morris, J.C.c , Bateman, R.J.c z , Goate, A.j k z , Noble, J.M.z , Day, G.S.z , Graff-Radford, N.R.z , Voglein, J.z , Allegri, R.z , Mendez, P.C.z , Surace, E.z , Berman, S.B.z , Ikonomovic, S.z , Nadkarni, N.z , Lopera, F.z , Ramirez, L.z , Aguillon, D.z , Leon, Y.z , Ramos, C.z , Alzate, D.z , Baena, A.z , Londono, N.z , Mathias Jucker, S.M.z , Laske, C.z , Kuder-Buletta, E.z , Graber-Sultan, S.z , Preische, O.z , Hofmann, A.z , Ikeuchi, T.z , Kasuga, K.z , Niimi, Y.z , Ishii, K.z , Senda, M.z , Sanchez-Valle, R.z , Rosa-Neto, P.z , Fox, N.z , Cash, D.z , Lee, J.-H.z , Roh, J.H.z , Riddle, M.z , Menard, W.z , Bodge, C.z , Surti, M.z , Takada, L.T.z , Farlow, M.z , Chhatwal, J.P.z , Sanchez-Gonzalez, V.J.z , Orozco-Barajas, M.z , Renton, A.z , Esposito, B.z , Karch, C.M.z , Marsh, J.z , Cruchaga, C.a b c z , Fernandez, V.z , Gordon, B.A.z , Fagan, A.M.z , Jerome, G.z , Herries, E.z , Llibre-Guerra, J.z , Seyfried, N.T.z , Schofield, P.R.z , Brooks, W.z , Bechara, J.z , Hassenstab, J.z , Franklin, E.z , Benzinger, T.L.S.z , Chen, A.z , Chen, C.z , Flores, S.z , Friedrichsen, N.z , Hantler, N.z , Hornbeck, R.z , Jarman, S.z , Keefe, S.z , Koudelis, D.z , Massoumzadeh, P.z , McCullough, A.z , McKay, N.z , Nicklaus, J.z , Pulizos, C.z , Wang, Q.z , Mishall, S.z , Sabaredzovic, E.z , Deng, E.z , Candela, M.z , Smith, H.z , Hobbs, D.z , Scott, J.z , Xiong, C.z , Wang, P.z , Xu, X.z , Li, Y.z , Gremminger, E.z , Ma, Y.z , Bui, R.z , Lu, R.z , Martins, R.z , Sosa Ortiz, A.L.z , Daniels, A.z , Courtney, L.z , Mori, H.z , Supnet-Bell, C.z , Xu, J.z , Ringman, J.z , Ibanez, L.a b c , Sung, Y.J.a b c , Dominantly Inherited Alzheimer Networkaa
a Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
b NeuroGenomics and Informatics, Washington University, St. Louis, MO 63110, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Mallinckrodt Institute of Radiology, Washington University St Louis, St Louis, MO 63110, United States
e Department of Pathology and Immunology, Washington University St. Louis, St. Louis, MO 63110, United States
f Department of Cell Biology and Physiology, Washington University St. Louis, St. Louis, MO 63110, United States
g Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, United States
h Department of Neurology & Neurological Sciences, Stanford University, Stanford, CA 94305, United States
i Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, 08916, Spain
j Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
k Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
l Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
m Laboratory of Neurodegenerative Diseases, Institute of Neurosciences (INEU-Fleni-CONICET), Buenos Aires, Argentina
n Goizueta Alzheimer’s Disease Research Center, Emory University School of Medicine, Atlanta, GA 30307, United States
o Department of Neurology, Emory University School of Medicine, Atlanta, GA 30307, United States
p Department of Neurology, University Hospital Mútua de Terrassa and Fundació Docència i Recerca Mútua de Terrassa, Barcelona, Terrassa, 08221, Spain
q Department of Neurology, LMU University Hospital, LMU Munich, Munich, 80336, Germany
r German Center for Neurodegenerative Diseases, site Munich, Munich, 80336, Germany
s Alzheimer’s Disease Research Center, Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA 90033, United States
t Department of Cognitive Neurology, Neuropsychology and Neuropsychiatry, FLENI, Buenos Aires, Argentina
u Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30307, United States
v Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL 32224, United States
w Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
x Fundacio ACE Institut de Neurosciencies Aplicades, Barcelona, 08029, Spain
y The University of New Mexico, Albuquerque, NM 87131, United States
Abstract
In this high-throughput proteomic study of autosomal dominant Alzheimer’s disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers. © 2024 The Author(s)
Author Keywords
autosomal dominant Alzheimer’s disease; microglia; mitochondrial damage; neurodegeneration; neuronal death; proteomics; pseudotrajectory analysis; Somascan
Document Type: Article
Publication Stage: Final
Source: Scopus
The representation of decision variables in orbitofrontal cortex is longitudinally stable
(2024) Cell Reports, 43 (10), art. no. 114772, .
Zhang, M.a b , Livi, A.a , Carter, M.a , Schoknecht, H.a , Burkhalter, A.a , Holy, T.E.a b , Padoa-Schioppa, C.a b c
a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Economics, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
The computation and comparison of subjective values underlying economic choices rely on the orbitofrontal cortex (OFC). In this area, distinct groups of neurons encode the value of individual options, the binary choice outcome, and the chosen value. These variables capture both the choice input and the choice output, suggesting that the cell groups found in the OFC constitute the building blocks of a decision circuit. Here, we show that this neural circuit is longitudinally stable. Using two-photon calcium imaging, we record from the OFC of mice engaged in a juice-choice task. Imaging of individual cells continues for up to 40 weeks. For each cell and each session pair, we compare activity profiles using cosine similarity, and we assess whether the neuron encodes the same variable in both sessions. We find a high degree of stability and a modest representational drift. Quantitative estimates indicate that this drift would not randomize the circuit within the animal’s lifetime. © 2024 The Author(s)
Author Keywords
calcium imaging; decision circuit; decision making; economic choice; longitudinal stability; Neuroscience; orbitofrontal cortex; representational drift; subjective value; two-photon microscopy
Funding details
National Institutes of HealthNIHR01-DA055709, R01-DA032758, R21-DA042882, R01-DC020034
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock
(2024) Cell Reports, 43 (10), art. no. 114865, .
Sun, J.a , Zhang, Y.a , Adams, J.A.a , Higgins, C.B.a , Kelly, S.C.a , Zhang, H.b c d , Cho, K.Y.b c d , Johnson, U.G.e f , Swarts, B.M.e f , Wada, S.-I.g , Patti, G.J.b c d , Shriver, L.P.b c d , Finck, B.N.d , Herzog, E.D.h , DeBosch, B.J.a i
a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, United States
c Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, United States
f Biochemistry, Cellular, and Molecular Biology Program, Central Michigan University, Mount Pleasant, MI, United States
g Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Tokyo, Shinagawa-ku, 141-0021, Japan
h Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
i Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Organisms integrate circadian and metabolic signals to optimize substrate selection to survive starvation, yet precisely how this occurs is unclear. Here, we show that hepatocyte Period 1 (Per1) is selectively induced during fasting, and mice lacking hepatocyte Per1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. Transcriptomic analyses show failed induction of the fasting hepatokine Fgf21 in Per1-deficient mice, and single-nucleus multiome sequencing defines a putative responding hepatocyte subpopulation that fails to induce the chromatin accessibility near the Fgf21 locus. In vivo isotopic tracing and indirect calorimetry demonstrate that hepatocyte Per1-deficient mice fail to transit from oxidation of glucose to fat, which is completely reversible by exogenous FGF21 or by inhibiting pyruvate dehydrogenase. Strikingly, disturbing other core circadian genes does not perturb Per1 induction during fasting. We thus describe Per1 as an important mechanism by which hepatocytes integrate internal circadian rhythm and external nutrition signals to facilitate proper fuel utilization. © 2024 The Author(s)
Author Keywords
circadian clock; CP: Metabolism; fasting; glucose oxidation; liver metabolism; metabolite tracing; single-nucleus multiome sequencing
Document Type: Article
Publication Stage: Final
Source: Scopus
The fully activated open state of KCNQ1 controls the cardiac “fight-or-flight” response
(2024) PNAS Nexus, 3 (10), art. no. pgae452, .
Hou, P.a c , Zhao, L.a , Zhong, L.a , Shi, J.a , Wang, H.Z.b , Gao, J.b , Liu, H.b , Zuckerman, J.b , Cohen, I.S.b , Cui, J.a
a Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Washington University, St. Louis, MO 63130, United States
b Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Washington University, St. Louis, MO 63130, United States
c Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau
Abstract
The cardiac KCNQ1 + KCNE1 (IKs) channel regulates heart rhythm under both normal and stress conditions. Under stress, the β-Adrenergic stimulation elevates the intracellular cyclic adenosine monophosphate (cAMP) level, leading to KCNQ1 phosphorylation by protein kinase A and increased IKs, which shortens action potentials to adapt to accelerated heart rate. An impaired response to the β-Adrenergic stimulation due to KCNQ1 mutations is associated with the occurrence of a lethal congenital long QT syndrome (type 1, also known as LQT1). However, the underlying mechanism of β-Adrenergic stimulation of IKs remains unclear, impeding the development of new therapeutics. Here, we find that the unique properties of KCNQ1 channel gating with two distinct open states are key to this mechanism. KCNQ1’s fully activated open (AO) state is more sensitive to cAMP than its intermediate open state. By enhancing the AO state occupancy, the small molecules ML277 and C28 are found to effectively enhance the cAMP sensitivity of the KCNQ1 channel, independent of KCNE1 association. This finding of enhancing AO state occupancy leads to a potential novel strategy to rescue the response of IKs to β-Adrenergic stimulation in LQT1 mutants. The success of this approach is demonstrated in cardiac myocytes and also in a high-risk LQT1 mutation. In conclusion, the present study not only uncovers the key role of the AO state in IKs channel phosphorylation, but also provides a target for antiarrhythmic strategy. © 2024 The Author(s).
Author Keywords
“fight-or-fight” response; antiarrhythmia; IKschannel; long QT syndrome; phosphorylation
Funding details
Fundo para o Desenvolvimento das Ciências e da TecnologiaFDCT0074/2022/A2, 0098/2023/RIA2
Fundo para o Desenvolvimento das Ciências e da TecnologiaFDCT
United States-Israel Binational Science FoundationBSFRO1 HL166628, HL166628, 2019159
United States-Israel Binational Science FoundationBSF
American Heart AssociationAHA18POST34030203
American Heart AssociationAHA
National Natural Science Foundation of ChinaNSFC32171221, 0098/2023/RIA2
National Natural Science Foundation of ChinaNSFC
National Institutes of HealthNIHRO1 HL126774, HL155398
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Development and Validation of a Prechiasmatic Mouse Model of Subarachnoid Hemorrhage to Measure Long-Term Cognitive Deficits
(2024) Advanced Science, .
Diwan, D.a , Mehla, J.a , Nelson, J.W.a , Quirk, J.D.b , Song, S.-K.b , Cao, S.a , Meron, B.a , Mostofa, A.a , Zipfel, G.J.a
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long-term neurocognitive deficits that affect the survivor’s quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH – especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced significant and trackable long-term cognitive deficits. SAH is induced by performing double blood injections into the prechiasmatic cistern – a simple modification to the well-characterized single prechiasmatic injection mouse model of SAH. Following SAH, mice recapitulated key characteristics of SAH patients, including cerebral edema measured by MRI – an indicator of early brain injury (EBI), neuroinflammation, apoptosis, and long-term cognitive impairment. This newly developed SAH mouse model is considered an ideal paradigm for investigating the complex SAH pathophysiology and identifying novel druggable therapeutic targets for treating SAH severity and SAH-associated long-term neurocognitive deficits in patients. © 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH.
Author Keywords
long-term cognitive impairment; prechiasmatic cistern; subarachnoid hemorrhage
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Cognitive Profile of Older Adults With Treatment-Resistant Depression: An Analysis of the OPTIMUM Randomized Controlled Trial
(2024) American Journal of Geriatric Psychiatry, .
Ainsworth, N.J.a b , Oughli, H.c , Lavretsky, H.c , Blumberger, D.M.a b , Brown, P.J.d , Butters, M.A.e , Karp, J.F.f , Lenard, E.g , Lenze, E.J.g , McAndrews, M.P.h , Miller, J.P.i , Pollock, B.G.a b , Reynolds, C.F.e , Mulsant, B.H.a b , OPTIMUM Research Groupj
a Centre for Addiction and Mental Health (NJA. DMB, BGP, BHM), Toronto, ON, Canada
b Department of Psychiatry (NJA, DMB, BGP, BHM), University of Toronto, Toronto, ON, Canada
c Department of Psychiatry and Biobehavioral Sciences (HO, HL), University of California, Los Angeles, CA, United States
d Department of Psychiatry, Columbia University College of Physicians and Surgeons (PJB), New York, NY, United States
e Department of Psychiatry (MAB, CFR), University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
f Department of Psychiatry (JFK), College of Medicine, University of Arizona, Tucson, AZ, United States
g Department of Psychiatry (EL, EJL), Washington University School of Medicine, St. Louis, MO, United States
h Department of Psychology (MPM), University of Toronto, Toronto, ON, Canada
i Institute for Informatics, Data Science and Biostatistics (JPM), Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: Major depressive disorder in older adults (late-life depression; LLD) is frequently associated with cognitive impairment, and some deficits (e.g., executive function) have been associated with a higher level of treatment resistance. However, the cognitive profile of treatment-resistant LLD (TR-LLD) has not been characterized. We hypothesized that patients with TR-LLD would show deficits in cognitive function, especially executive function, and that executive function deficits would predict poorer response to pharmacotherapy. Design: Secondary analysis of baseline cognitive data from OPTIMUM, a multicenter RCT evaluating pharmacotherapy strategies for TR-LLD. Setting: Five outpatient academic medical centers (4 US, 1 Canada). Participants: About 369 participants aged 60 and older from the OPTIMUM study. Measurements: Baseline scores on individual tasks and composite scores from the NIH Toolbox-Cognition Battery were transformed into demographically-adjusted T-scores and compared to published norms. Impairments in the set shifting and inhibitory control tasks were investigated as predictors of depressive symptom change following treatment using ANCOVA models. Results: Participants had low performance on tasks evaluating inhibitory control, processing speed, verbal/nonverbal memory, and the fluid composite, but normative performance on working memory and set shifting. Participants had high estimated premorbid IQ (superior Performance on oral reading recognition). Age and physical comorbidity negatively associated with processing speed. Impairments in set shifting predicted less improvement in depressive symptoms; impairments in inhibitory control did not. Conclusions: Participants with TR-LLD presented with broad cognitive deficits relative to healthy norms. Given poorer outcomes following standard pharmacotherapy associated with impaired set shifting, future research needs to identify alternative treatment strategies. © 2024 The Authors
Author Keywords
Aging; clinical trials; cognition; depression; executive function
Document Type: Article
Publication Stage: Article in Press
Source: Scopus