Publications

Hope Center Member Publications

Scopus list of publications for December 19, 2022

White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology” (2022) Frontiers in Molecular Neuroscience

White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology
(2022) Frontiers in Molecular Neuroscience, 15, art. no. 1037481, . 

Jindachomthong, K.a h i , Yang, C.b , Huang, Y.c , Coman, D.c , Rapanelli, M.a , Hyder, F.c d , Dougherty, J.b , Frick, L.a h i , Pittenger, C.a e f g

a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States
d Department of Biomedical Engineering, Yale University School of Medicine, New Haven, CT, United States
e Yale Child Study Center, Yale University School of Medicine, New Haven, CT, United States
f Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, United States
g Center for Brain and Mind Health, Yale University School of Medicine, New Haven, CT, United States
h Department of Ophthalmology, Ohio State University, Columbus, OH, United States
i Department of Neurology, Clinical and Translational Research Center, University at Buffalo, Buffalo, NY, United States

Abstract
Introduction: An inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS. Materials and methods: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI. Results: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum. Discussion: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality. Copyright © 2022 Jindachomthong, Yang, Huang, Coman, Rapanelli, Hyder, Dougherty, Frick and Pittenger.

Author Keywords
animal model;  histamine;  myelin;  striatum;  tourette syndrome

Funding details
National Institute of Mental HealthNIMHR01 MH091861, R01MH067528
National Institute of Neurological Disorders and StrokeNINDSP30NS052519
Brain and Behavior Research FoundationBBRF
National Alliance for Research on Schizophrenia and DepressionNARSAD
Allison Family Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study
(2022) Geriatrics and Gerontology International, . 

Akasaka, H.a , Nakagami, H.b , Sugimoto, K.c , Yasunobe, Y.a , Minami, T.a , Fujimoto, T.a , Yamamoto, K.a , Hara, C.d , Shiraki, A.d , Nishida, K.d , Asano, K.e , Kanou, M.f g , Yamana, K.g h , Imai, S.-I.i , Rakugi, H.a

a Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
b Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Suita, Japan
c Department of General and Geriatric Medicine, Kawasaki Medical University, Okayama, Japan
d Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan
e Academic Clinical Research Center, Department of Medical Innovation, Osaka University Hospital, Suita, Japan
f Nutraceutical Group, Division of New Business in Healthcare Business, Teijin Ltd, Chiyoda, Japan
g NOMON Co., Ltd., Tokyo, Japan
h Management Coordinator for the President Healthcare Business of Teijin Group, Chiyoda, Japan
i Department of Developmental Biology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Nicotinamide adenine dinucleotide regulates various biological processes. Nicotinamide mononucleotide (NMN) increases its intracellular levels and counteracts age-associated changes in animal models. We investigated the safety and efficacy of oral nicotinamide mononucleotide supplementation in older patients with diabetes and impaired physical performance. Method: We carried out a 24-week placebo-controlled, double-blinded study of male patients with diabetes aged ≥65 years with reduced grip strength (<26 kg) or walking speed (<1.0 m/s). The primary end-points were to determine the safety of NMN oral administration (250 mg/day), and changes in grip strength and walking speed. The secondary end-points were to determine the changes in various exploratory indicators. Results: We studied 14 participants aged 81.1 ± 6.4 years. NMN was tolerable without any severe adverse events. The changes in grip strength and walking speed showed no difference between the two groups: 1.25 kg (95% confidence interval −2.31 to 4.81) and 0.033 m/s (−0.021 to 0.087) in the NMN group, and −0.44 kg (−4.15 to 3.26) and 0.014 m/s (−0.16 to −0.13) in the placebo group, respectively. There were no significant differences in any exploratory indicators between the two groups. However, improved prevalence of frailty in the NMN group (P = 0.066) and different changes in central retinal thickness between the two groups (P = 0.051) was observed. Conclusion: In older male patients with diabetes and impaired physical performance, NMN supplementation for 24 weeks was safe, but did not improve grip strength and walking speed. Geriatr Gerontol Int 2022; ••: ••–••. © 2022 Japan Geriatrics Society.

Author Keywords
clinical medicine;  diabetes mellitus;  geriatric medicine;  musculoskeletal

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

Adverse driving behaviors increase over time as a function of preclinical Alzheimer’s disease biomarkers” (2022) Alzheimer’s and Dementia

Adverse driving behaviors increase over time as a function of preclinical Alzheimer’s disease biomarkers
(2022) Alzheimer’s and Dementia, . 

Doherty, J.M.a , Murphy, S.A.a , Bayat, S.b c d , Wisch, J.K.a , Johnson, A.M.e , Walker, A.a , Schindler, S.E.a g h , Ances, B.M.a f g h , Morris, J.C.a f g h , Babulal, G.M.a h i j k

a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada
c Department of Geomatics Engineering, University of Calgary, Calgary, AB, Canada
d Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
e Center for Clinical Studies, Washington University in St. Louis, St. Louis, MO, United States
f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
g Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
h Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
i Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
j Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
k Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Abstract
Introduction: We investigated the relationship between preclinical Alzheimer’s disease (AD) biomarkers and adverse driving behaviors in a longitudinal analysis of naturalistic driving data. Methods: Naturalistic driving data collected using in-vehicle dataloggers from 137 community-dwelling older adults (65+) were used to model driving behavior over time. Cerebrospinal fluid (CSF) biomarkers were used to identify individuals with preclinical AD. Additionally, hippocampal volume and cognitive biomarkers for AD were investigated in exploratory analyses. Results: CSF biomarkers predicted the longitudinal trajectory of the incidence of adverse driving behavior. Abnormal amyloid beta (Aβ42/Aβ40) ratio was associated with an increase in adverse driving behaviors over time compared to ratios in the normal/lower range. Discussion: Preclinical AD is associated with increased adverse driving behavior over time that cannot be explained by cognitive changes. Driving behavior as a functional, neurobehavioral marker may serve as an early detection for decline in preclinical AD. Screening may also help prolong safe driving as older drivers age. © 2022 the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  cerebrospinal fluid biomarkers;  driving;  older adults

Funding details
P01AG026276, P30 AG066444, R01AG057680, U19 AG024904, U19 AG032438
National Institutes of HealthNIH
National Institute on AgingNIAR01AG056466, R01AG067428, R01AG068183

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

Electrical stimulation or tacrolimus (FK506) alone enhances nerve regeneration and recovery after nerve surgery, while dual use reduces variance and combines strengths of each in promoting enhanced outcomes” (2022) Muscle and Nerve

Electrical stimulation or tacrolimus (FK506) alone enhances nerve regeneration and recovery after nerve surgery, while dual use reduces variance and combines strengths of each in promoting enhanced outcomes
(2022) Muscle and Nerve, . 

Marsh, E.B., Schellhardt, L., Hunter, D.A., Mackinnon, S.E., Snyder-Warwick, A.K., Wood, M.D.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction/Aims: Repaired nerve injuries can fail to achieve functional recovery. Therapeutic options beyond surgery, such as systemic tacrolimus (FK506) and electrical stimulation (E-stim), can improve recovery. We tested whether dual administration of FK506 and E-stim enhances regeneration and recovery more than either therapeutic alone. Methods: Rats were randomized to four groups: E-stim, FK506, FK506 + E-stim, and repair alone. All groups underwent tibial nerve transection and repair. Two sets of animals were created to measure outcomes of early nerve regeneration using nerve histology (n = 36) and functional recovery (n = 42) (21- and 42-day endpoints, respectively). Functional recovery was measured by behavioral analyses (walking track and grid walk) and, at the endpoint, muscle mass and force. Results: Dual E-stim and FK506 administration produced histomorphometric measurements of nerve regeneration no different than either therapeutic alone. All treatments were superior to repair alone (FK506, P <.0001; E-stim, P <.05; FK506 + E-stim, P <.05). The E-stim and FK506 + E-stim groups had improved behavioral recovery compared with repair alone (at 6 weeks: E-stim, P <.05; FK506 + E-stim, P <.01). The FK506 group had improved recovery based on walking-track analysis (at 6 weeks: P <.001) and muscle force and mass (P <.05). The concurrent use of both therapies ensured earlier functional recovery and decreased variability in functional outcomes compared with either therapy alone, suggesting a moderate benefit. Discussion: Dual administration of FK506 and E-stim showed minimal additive effects to further improve regeneration or recovery compared with either therapy alone. The data suggest the combination of FK506 and E-stim appears to combine the relative strengths of each therapeutic. © 2022 Wiley Periodicals LLC.

Author Keywords
electrical stimulation;  FK506;  functional recovery;  peripheral nerve;  regeneration;  tacrolimus;  tibial nerve

Funding details
Washington University School of Medicine in St. Louis WUSM

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