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Li S, Ma H, Ding XQ. Resveratrol Protects Photoreceptors in Mouse Models of Retinal Degeneration. Antioxidants (Basel) 2025; 14:154. [PMID: 40002341 PMCID: PMC11851417 DOI: 10.3390/antiox14020154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/22/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
Photoreceptor/retinal degeneration is the major cause of blindness. Induced and inherited mouse models of retinal degeneration are valuable tools for investigating disease mechanisms and developing therapeutic interventions. This study investigated the potential of the antioxidant resveratrol to relieve photoreceptor degeneration using mouse models. Clinical studies have shown a potential association between thyroid hormone (TH) signaling and age-related retinal degeneration. Excessive TH signaling induces oxidative stress/damage and photoreceptor death in mice. C57BL/6 (rod-dominant) and Nrl-/- (cone-dominant) mice at postnatal day 30 (P30) received triiodothyronine (T3) via drinking water (20 µg/mL) with or without concomitant treatment with resveratrol via drinking water (120 µg/mL) for 30 days, followed by evaluation of photoreceptor degeneration, oxidative damage, and retinal stress responses. In experiments using Leber congenital amaurosis model mice, mother Rpe65-/- and Rpe65-/-/Nrl-/- mice received resveratrol via drinking water (120 µg/mL) for 20 days and 10-13 days, respectively, beginning on the day when the pups were at P5, and pups were then evaluated for cone degeneration. Treatment with resveratrol significantly diminished the photoreceptor degeneration induced by T3 and preserved photoreceptors in Rpe65-deficient mice, manifested as preserved retinal morphology/outer nuclear layer thickness, increased cone density, reduced photoreceptor oxidative stress/damage and apoptosis, reduced upregulation of genes involved in cell death/inflammatory responses, and reduced macroglial cell activation. These findings demonstrate the role of oxidative stress in photoreceptor degeneration, associated with TH signaling and Rpe65 deficiency, and support the therapeutic potential of resveratrol/antioxidants in the management of retinal degeneration.
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Affiliation(s)
| | | | - Xi-Qin Ding
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (S.L.); (H.M.)
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Li P, Liu X, Wu L, Dong L, Zhou J, Song Z. Thyroid Function and Brain Structure: Insight from a Mendelian Randomization Study. Neuroendocrinology 2024; 115:60-71. [PMID: 39653027 DOI: 10.1159/000542955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 12/02/2024] [Indexed: 01/18/2025]
Abstract
INTRODUCTION Thyroid hormones play a critical role in brain development. However, the precise causal associations between thyroid function and structural changes in specific brain regions remain uncertain. METHODS We applied the univariate Mendelian randomization (UVMR) method to assess the causal effects of thyroid function on brain structure. Genome-wide association study (GWAS) data on thyroid-related traits from the ThyroidOmics Consortium including free thyroxine (FT4), free tri-iodothyronine (FT3), thyroid-stimulating hormone (TSH), FT3/FT4 ratio, as well as dichotomized high and low TSH levels were used as exposures. GWAS data on cortical thickness, surface area, and volume of subcortical structures served as outcomes. Inverse variance weighted was the main estimate method. Subsequently, multivariable MR (MVMR) was conducted to validate significant causal associations identified in UVMR. RESULTS UVMR analysis demonstrated a statistically significant inverse association between genetically predicted FT4 and putamen volume (β = -71.91 mm3, 95% confidence interval: -112.11 mm3 to -31.71 mm3, p = 4.54 × 10-4). The findings were robust in sensitivity analysis. MVMR analysis further confirmed a persistent causal relationship between FT4 and putamen volume after adjusting for FT3, TSH, and neuropsychiatric disorders. Functional enrichment analyses indicated the pathways by which FT4 influences putamen volume may be related to the thyroid hormone signaling pathway, sodium-independent organic anion transport, and Rap1 signaling pathway. CONCLUSION MR analysis provides evidence for causal relationships between thyroid function and brain structural alterations, particularly highlighting the impact of FT4 on putamen volume. Further research is warranted to elucidate the underlying mechanisms by which thyroid hormones modulate brain structure.
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Affiliation(s)
- Ping Li
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China,
| | - Xiao Liu
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Liming Wu
- Department of Urology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, China
| | - Liming Dong
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jianbo Zhou
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Zhihui Song
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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Uneri A, McArdle CJ, Deng Z, Barth SH, Keene D, Craft S, Raab-Graham KF. DJ-1-mediated repression of the RNA-binding protein FMRP is predicted to impact known Alzheimer's disease-related protein networks. J Alzheimers Dis 2024; 102:763-777. [PMID: 39610285 DOI: 10.1177/13872877241291175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
BACKGROUND RNA-binding proteins (RBPs) modulate the synaptic proteome and are instrumental in maintaining synaptic homeostasis. Moreover, aberrant expression of an RBP in a disease state would have deleterious downstream effects on synaptic function. While many underlying mechanisms of synaptic dysfunction in Alzheimer's disease (AD) have been proposed, the contribution of RBPs has been relatively unexplored. OBJECTIVE To investigate alterations in RBP-messenger RNA (mRNA) interactions in AD, and its overall impact on the disease-related proteome. METHODS We first utilized RNA-immunoprecipitation to investigate interactions between RBP, DJ-1 (Parkinson's Disease protein 7) and target mRNAs in controls and AD. Surface Sensing of Translation - Proximity Ligation Assay (SUnSET-PLA) and western blotting additionally quantified alterations in mRNA translation and protein expression of DJ-1 targets. Finally, we utilized an unbiased bioinformatic approach that connects AD-related pathways to two RBPs, DJ-1 and FMRP (Fragile X messenger ribonucleoprotein 1). RESULTS We find that oligomeric DJ-1 in AD donor synapses were less dynamic in their ability to bind and unbind mRNA compared to synapses from cognitively unimpaired, neuropathologically-verified controls. Furthermore, we find that DJ-1 associates with the mRNA coding for FMRP, Fmr1, leading to its reduced synaptic expression in AD. Through the construction of protein-protein interaction networks, aberrant expression of DJ-1 and FMRP are predicted to lead to the upregulation of key AD-related pathways, such as thyroid hormone stimulating pathway, autophagy, and ubiquitin mediated proteolysis. CONCLUSIONS DJ-1 and FMRP are novel targets that may restore established neurobiological mechanisms underlying AD.
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Affiliation(s)
- Ayse Uneri
- Department of Translational Neuroscience, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Colin J McArdle
- Department of Translational Neuroscience, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Zhiyong Deng
- Department of Translational Neuroscience, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Samuel H Barth
- Department of Translational Neuroscience, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Dirk Keene
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
- Department of Gerontology and Geriatric Medicine, Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA
| | - Suzanne Craft
- Department of Gerontology and Geriatric Medicine, Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA
| | - Kimberly F Raab-Graham
- Department of Translational Neuroscience, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
- Department of Gerontology and Geriatric Medicine, Wake Forest Alzheimer's Disease Research Center, Winston-Salem, NC, USA
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Huang YC, Liu TC, Lu CJ. Establishing a machine learning dementia progression prediction model with multiple integrated data. BMC Med Res Methodol 2024; 24:288. [PMID: 39578765 PMCID: PMC11583646 DOI: 10.1186/s12874-024-02411-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
OBJECTIVE Dementia is a significant medical and social issue in most developed countries. Practical tools for predicting the progression of degenerative dementia are highly valuable. Machine learning (ML) methods facilitate the construction of effective models using real-world data, which may include missing values and various integrated datasets. METHOD This retrospective study analyzed data from 679 patients diagnosed with degenerative dementia at Fu Jen Catholic University Hospital, who were evaluated by neurologists, psychologists and followed for over two years. Predictive variables were categorized into demographic (D), clinical dementia rating (CDR), mini-mental state examination (MMSE), and laboratory data value (LV) groups. These categories were further integrated into three subgroups (D-CDR, D-CDR-MMSE, and D-CDR-MMSE-LV). We utilized the extreme gradient boosting (XGB) model to rank the importance of variables and identify the most effective feature combination via a step-wise approach. RESULT The D-CDR-MMSE-LV model combination showed robust performance with an excellent area under the receiver operating characteristic curve (AUC) and the highest sensitivity value (84.66). Employing both demographic and neuropsychiatric variables, our prediction model achieved an AUC of 83.74. By incorporating additional clinical information from laboratory data and applying our proposed feature selection strategy, we constructed a model based on eight variables that achieved an AUC of 85.12 using the XGB technique. CONCLUSION We established a machine-learning model to monitor the progression of dementia using a limited, real-world clinical dataset. The XGB technique identified eight critical variables across our integrated datasets, potentially providing clinicians with valuable guidance.
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Affiliation(s)
- Yung-Chuan Huang
- Department of Neurology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Tzu-Chi Liu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Chi-Jie Lu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, New Taipei City, Taiwan.
- Artificial Intelligence Development Center, Fu Jen Catholic University, New Taipei City, Taiwan.
- Department of Information Management, Fu Jen Catholic University, New Taipei City, Taiwan.
- Graduate Institute of Business Administration, Fu Jen Catholic University, No.510, Zhongzheng Rd., Xinzhuang Dist, New Taipei City, 242062, Taiwan.
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Sepúlveda P, Ferreira AFF, Sandoval C, Bergoc G, Moreno ACR, Nunes MT, Torrão ADS. Thyroid Hormone Supplementation Restores Cognitive Deficit, Insulin Signaling, and Neuroinflammation in the Hippocampus of a Sporadic Alzheimer's-like Disease Rat Model. Cells 2024; 13:1793. [PMID: 39513900 PMCID: PMC11545223 DOI: 10.3390/cells13211793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/03/2024] [Accepted: 07/16/2024] [Indexed: 11/16/2024] Open
Abstract
Thyroid hormones play a crucial role in the development of the central nervous system and are considered pivotal to cognitive functions in the adult brain. Recently, thyroid dysfunction has been associated with Alzheimer's disease. The aim of this study was to assess the neuroprotective effects of triiodothyronine (T3) on insulin signaling, neuroinflammation, apoptosis, and cognitive function in a streptozotocin (STZ)-induced sporadic Alzheimer's disease-like model. Male Wistar rats underwent stereotaxic surgery for intracerebroventricular injections of streptozotocin (STZ; 2 mg/kg) or vehicle in the lateral ventricles to induce an AD-like model. The animals received a daily dose of 1.5 μg of T3/100 g body weight or the same volume of vehicle for 30 days and were subdivided into four experimental groups: (1) animals receiving citrate treated with saline (Control = CTL); (2) animals receiving citrate treated with T3 (T3); (3) animals receiving STZ treated with saline (STZ); and (4) animals receiving STZ treated with T3 (STZ + T3). The novel object recognition test was used to measure cognitive function. Serum analysis, real-time RT-PCR, immunohistochemistry, and immunoblotting analyses were also carried out. Our results demonstrated that T3 treatment reversed cognitive impairment and increased Akt and GSK3 phosphorylation in the treated group, while also reducing microglial activation (Iba-1) and GFAP expression (reactive astrocytes), along with TNF-α, IL-6, and IL-1β levels in the hippocampus. Additionally, T3 treatment increased levels of the anti-apoptotic protein Bcl-2 and reduced the expression of the pro-apoptotic protein BAX in the hippocampus. Our study demonstrated that T3 could potentially protect neurons in an AD model induced by STZ.
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Affiliation(s)
- Paulina Sepúlveda
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (A.F.F.F.); (G.B.); (A.C.R.M.); (M.T.N.)
| | - Ana Flavia Fernandes Ferreira
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (A.F.F.F.); (G.B.); (A.C.R.M.); (M.T.N.)
| | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile;
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Giovanna Bergoc
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (A.F.F.F.); (G.B.); (A.C.R.M.); (M.T.N.)
| | - Ana Caroline Rippi Moreno
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (A.F.F.F.); (G.B.); (A.C.R.M.); (M.T.N.)
| | - Maria Tereza Nunes
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (A.F.F.F.); (G.B.); (A.C.R.M.); (M.T.N.)
| | - Andréa da Silva Torrão
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (A.F.F.F.); (G.B.); (A.C.R.M.); (M.T.N.)
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Liu Q, Lu C, Chen M, Feng P. Subclinical hyperthyroidism and the risk of dementia: A meta-analysis. Brain Behav 2024; 14:e70037. [PMID: 39295103 PMCID: PMC11410877 DOI: 10.1002/brb3.70037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/03/2024] [Accepted: 07/24/2024] [Indexed: 09/21/2024] Open
Abstract
BACKGROUND Accumulating evidence suggests that thyroid dysfunction may be related to the risk of dementia. However, previous studies evaluating the association between subclinical hyperthyroidism and the risk of dementia showed inconsistent results. This systematic review and meta-analysis were performed to evaluate the relationship between subclinical hyperthyroidism and the incidence of dementia in the general population. METHODS Cohort studies relevant were retrieved by searching the electronic databases including PubMed, Web of Science, and Embase. A random-effects model was used to combine the data by incorporating the influence of between-study heterogeneity. Subgroup and meta-regression analyses were performed to investigate the source of heterogeneity. RESULTS Nine cohort studies including 49,218 community-derived participants were included. Among them, 3177 (6.5%) had subclinical hyperthyroidism at baseline. During a mean follow-up of 10.2 years, 4044 participants developed dementia. The pooled results showed that compared to the participants with euthyroidism, those with subclinical hyperthyroidism had a higher incidence of dementia (risk ratio: 1.38, 95% confidence interval: 1.09 to 1.74, p = .006; I2 = 47%). Subgroup analyses according to study design, age of the participants, methods for diagnosis of dementia, or analytic model did not significantly change the results. The univariate meta-regression showed that the cutoff of thyroid-stimulating hormone for defining subclinical hyperthyroidism negatively affected the association between subclinical hyperthyroidism and dementia (coefficient: -1.44, p = .009), which completely explained the heterogeneity (residual I2 = 0%). CONCLUSION Subjects with subclinical hyperthyroidism may have a higher risk of dementia compared to those with euthyroidism.
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Affiliation(s)
- Qiao Liu
- Department of EndocrinologyTaizhou Central Hospital (Taizhou University Hospital)TaizhouChina
| | - Chaoyin Lu
- Department of EndocrinologyTaizhou Central Hospital (Taizhou University Hospital)TaizhouChina
| | - Mengdie Chen
- Department of EndocrinologyTaizhou Central Hospital (Taizhou University Hospital)TaizhouChina
| | - Ping Feng
- Department of EndocrinologyTaizhou Central Hospital (Taizhou University Hospital)TaizhouChina
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Byeon JH, Byun MS, Yi D, Jung JH, Sohn BK, Chang YY, Kong N, Jung G, Ahn H, Lee JY, Lee YS, Kim YK, Lee DY. Moderation of thyroid hormones for the relationship between amyloid and tau pathology. Alzheimers Res Ther 2024; 16:164. [PMID: 39044293 PMCID: PMC11264392 DOI: 10.1186/s13195-024-01534-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 07/16/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition. METHODS This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET. RESULTS No associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition. CONCLUSION Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.
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Affiliation(s)
- Jeong Hyeon Byeon
- Department of Neuropsychiatry, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Min Soo Byun
- Department of Neuropsychiatry, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
- Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Dahyun Yi
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Joon Hyung Jung
- Department of Psychiatry, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Bo Kyung Sohn
- Department of Psychiatry, Inje University Sanggye Paik Hospital, Seoul, Republic of Korea
| | - Yoon Young Chang
- Department of Psychiatry, Inje University Sanggye Paik Hospital, Seoul, Republic of Korea
| | - Nayeong Kong
- Department of Psychiatry, Keimyung University Hospital, Daegu, Republic of Korea
| | - Gijung Jung
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Hyejin Ahn
- Interdisciplinary Program of Cognitive Science, Seoul National University, Seoul, Republic of Korea
| | - Jun-Young Lee
- Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
- Department of Neuropsychiatry, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
| | - Yun-Sang Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yu Kyeong Kim
- Department of Nuclear Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
| | - Dong Young Lee
- Department of Neuropsychiatry, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea.
- Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea.
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
- Interdisciplinary Program of Cognitive Science, Seoul National University, Seoul, Republic of Korea.
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Wertman E. Essential New Complexity-Based Themes for Patient-Centered Diagnosis and Treatment of Dementia and Predementia in Older People: Multimorbidity and Multilevel Phenomenology. J Clin Med 2024; 13:4202. [PMID: 39064242 PMCID: PMC11277671 DOI: 10.3390/jcm13144202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/12/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Dementia is a highly prevalent condition with devastating clinical and socioeconomic sequela. It is expected to triple in prevalence by 2050. No treatment is currently known to be effective. Symptomatic late-onset dementia and predementia (SLODP) affects 95% of patients with the syndrome. In contrast to trials of pharmacological prevention, no treatment is suggested to remediate or cure these symptomatic patients. SLODP but not young onset dementia is intensely associated with multimorbidity (MUM), including brain-perturbating conditions (BPCs). Recent studies showed that MUM/BPCs have a major role in the pathogenesis of SLODP. Fortunately, most MUM/BPCs are medically treatable, and thus, their treatment may modify and improve SLODP, relieving suffering and reducing its clinical and socioeconomic threats. Regrettably, the complex system features of SLODP impede the diagnosis and treatment of the potentially remediable conditions (PRCs) associated with them, mainly due to failure of pattern recognition and a flawed diagnostic workup. We suggest incorporating two SLODP-specific conceptual themes into the diagnostic workup: MUM/BPC and multilevel phenomenological themes. By doing so, we were able to improve the diagnostic accuracy of SLODP components and optimize detecting and favorably treating PRCs. These revolutionary concepts and their implications for remediability and other parameters are discussed in the paper.
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Affiliation(s)
- Eli Wertman
- Department of Neurology, Hadassah University Hospital, The Hebrew University, Jerusalem 9190500, Israel;
- Section of Neuropsychology, Department of Psychology, The Hebrew University, Jerusalem 9190500, Israel
- Or’ad: Organization for Cognitive and Behavioral Changes in the Elderly, Jerusalem 9458118, Israel
- Merhav Neuropsychogeriatric Clinics, Nehalim 4995000, Israel
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Yu ZW, Shan ZY. Thyroid function variations within the reference range and cognitive function: A two-sample Mendelian randomization study. J Affect Disord 2024; 357:156-162. [PMID: 38703900 DOI: 10.1016/j.jad.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 04/23/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND The causal relationship between thyroid function variations within the reference range and cognitive function remains unknown. We aimed to explore this causal relationship using a Mendelian randomization (MR) approach. METHODS Summary statistics of a thyroid function genome-wide association study (GWAS) were obtained from the ThyroidOmics consortium, including reference range thyroid stimulating hormone (TSH) (N = 54,288) and reference range free thyroxine (FT4) (N = 49,269). GWAS summary statistics on cognitive function were obtained from the Social Science Genetic Association Consortium (SSGAC) and the UK Biobank, including cognitive performance (N = 257,841), prospective memory (N = 152,605), reaction time (N = 459,523), and fluid intelligence (N = 149,051). The primary method used was inverse-variance weighted (IVW), supplemented with weighted median, Mr-Egger regression, and MR-Pleiotropy Residual Sum and Outlier. Several sensitivity analyses were conducted to identify heterogeneity and pleiotropy. RESULTS An increase in genetically associated TSH within the reference range was suggestively associated with a decline in cognitive performance (β = -0.019; 95%CI: -0.034 to -0.003; P = 0.017) and significantly associated with longer reaction time (β = 0.016; 95 % CI: 0.005 to 0.027; P = 0.004). Genetically associated FT4 levels within the reference range had a significant negative relationship with reaction time (β = -0.030; 95%CI:-0.044 to -0.015; P = 4.85 × 10-5). These findings remained robust in the sensitivity analyses. CONCLUSIONS Low thyroid function within the reference range may have a negative effect on cognitive function, but further research is needed to fully understand the nature of this relationship. LIMITATIONS This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups.
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Affiliation(s)
- Zi-Wei Yu
- Department of Endocrinology and Metabolism and the Institute of Endocrinology, The NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, First Hospital of China Medical University, Shenyang 110001, China
| | - Zhong-Yan Shan
- Department of Endocrinology and Metabolism and the Institute of Endocrinology, The NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, First Hospital of China Medical University, Shenyang 110001, China.
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Ma H, Stanford D, Freeman WM, Ding XQ. Transcriptomic Analysis Reveals That Excessive Thyroid Hormone Signaling Impairs Phototransduction and Mitochondrial Bioenergetics and Induces Cellular Stress in Mouse Cone Photoreceptors. Int J Mol Sci 2024; 25:7435. [PMID: 39000540 PMCID: PMC11242393 DOI: 10.3390/ijms25137435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/01/2024] [Accepted: 07/03/2024] [Indexed: 07/16/2024] Open
Abstract
Thyroid hormone (TH) plays an essential role in cell proliferation, differentiation, and metabolism. Experimental and clinical studies have shown a potential association between TH signaling and retinal degeneration. The suppression of TH signaling protects cone photoreceptors in mouse models of retinal degeneration, whereas excessive TH signaling induces cone degeneration, manifested as reduced light response and a loss of cones. This work investigates the genes/transcriptomic alterations that might be involved in TH-induced cone degeneration in mice using single-cell RNA sequencing (scRNAseq) analysis. One-month-old C57BL/6 mice received triiodothyronine (T3, 20 µg/mL in drinking water) for 4 weeks as a model of hyperthyroidism/excessive TH signaling. At the end of the experiments, retinal cells were dissociated, and cell viability was analyzed before being subjected to scRNAseq. The resulting data were analyzed using the Seurat package and visualized using the Loupe browser. Among 155,866 single cells, we identified 14 cell clusters, representing various retinal cell types, with rod and cone clusters comprising 76% and 4.1% of the total cell population, respectively. Cone cluster transcriptomes demonstrated the most alterations after the T3 treatment, with 450 differentially expressed genes (DEGs), accounting for 38.5% of the total DEGs. Statistically significant changes in the expression of genes in the cone cluster revealed that phototransduction and oxidative phosphorylation were impaired after the T3 treatment, along with mitochondrial dysfunction. A pathway analysis also showed the activation of the sensory neuronal/photoreceptor stress pathways after the T3 treatment. Specifically, the eukaryotic initiation factor-2 signaling pathway and the cAMP response element-binding protein signaling pathway were upregulated. Thus, excessive TH signaling substantially affects cones at the transcriptomic level. The findings from this work provide an insight into how excessive TH signaling induces cone degeneration.
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Affiliation(s)
- Hongwei Ma
- Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 553, Oklahoma, OK 73104, USA;
| | - David Stanford
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA; (D.S.); (W.M.F.)
| | - Willard M. Freeman
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA; (D.S.); (W.M.F.)
| | - Xi-Qin Ding
- Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 553, Oklahoma, OK 73104, USA;
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Gong Y, Sun J, Wang X, Barrett H, Peng H. Identification of Hydrocarbon Sulfonates as Previously Overlooked Transthyretin Ligands in the Environment. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:10227-10239. [PMID: 38817092 DOI: 10.1021/acs.est.3c10973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
Incidences of thyroid disease, which has long been hypothesized to be partially caused by exposure to thyroid hormone disrupting chemicals (TDCs), have rapidly increased in recent years. However, known TDCs can only explain a small portion (∼1%) of in vitro human transthyretin (hTTR) binding activities in environmental samples, indicating the existence of unknown hTTR ligands. In this study, we aimed to identify the major environmental hTTR ligands by employing protein Affinity Purification with Nontargeted Analysis (APNA). hTTR binding activities were detected in all 11 indoor dust and 9 out of 10 sewage sludge samples by the FITC-T4 displacement assay. By using APNA, 31 putative hTTR ligands were detected including perfluorooctanesulfonate (PFOS). Two of the most abundant ligands were identified as hydrocarbon surfactants (e.g., dodecyl benzenesulfonate). Moreover, another abundant ligand was surprisingly identified as a disulfonate fluorescent brightener, 4,4'-bis(2-sulfostyryl)biphenyl sodium (CBS). CBS was validated as a nM-affinity hTTR ligand with an IC50 of 345 nM. In total, hydrocarbon surfactants and fluorescent brighteners explain 1.92-17.0 and 5.74-54.3% of hTTR binding activities in dust and sludge samples, respectively, whereas PFOS only contributed <0.0001%. Our study revealed for the first time that hydrocarbon sulfonates are previously overlooked hTTR ligands in the environment.
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Affiliation(s)
- Yufeng Gong
- Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada
| | - Jianxian Sun
- Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada
| | - Xiaoyun Wang
- Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada
| | - Holly Barrett
- Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada
| | - Hui Peng
- Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada
- School of the Environment, University of Toronto, Toronto, ON M5S 3H6, Canada
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Zhu Y, Park S, Kolady R, Zha W, Ma Y, Dias A, McGuire K, Hardi A, Lin S, Ismail Z, Adkins‐Jackson PB, Trani J, Babulal GM. A systematic review/meta-analysis of prevalence and incidence rates illustrates systemic underrepresentation of individuals racialized as Asian and/or Asian-American in ADRD research. Alzheimers Dement 2024; 20:4315-4330. [PMID: 38708587 PMCID: PMC11180860 DOI: 10.1002/alz.13820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 03/04/2024] [Accepted: 03/11/2024] [Indexed: 05/07/2024]
Abstract
We investigate Alzheimer's disease and related dementia (ADRD) prevalence, incidence rate, and risk factors in individuals racialized as Asian and/or Asian-American and assess sample representation. Prevalence, incidence rate, risk factors, and heterogeneity of samples were assessed. Random-effects meta-analysis was conducted, generating pooled estimates. Of 920 records across 14 databases, 45 studies were included. Individuals racialized as Asian and/or Asian-American were mainly from Eastern and Southern Asia, had higher education, and constituted a smaller sample relative to non-Hispanic white cohorts. The average prevalence was 10.9%, ranging from 0.4% to 46%. The average incidence rate was 20.03 (12.01-33.8) per 1000 person-years with a range of 75.19-13.59 (12.89-14.33). Risk factors included physiological, genetic, psychological, behavioral, and social factors. This review underscores the systemic underrepresentation of individuals racialized as Asian and/or Asian-American in ADRD research and the need for inclusive approaches accounting for culture, language, and immigration status. HIGHLIGHTS: There is considerable heterogeneity in the prevalence of ADRD among studies of Asian-Americans. There is limited data on group-specific risk factors for ADRD among Asian-Americans. The average prevalence of (ADRD) among Asian-Americans was found to be 7.4%, with a wide range from 0.5% to 46%.
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Affiliation(s)
- Yiqi Zhu
- School of Social WorkAdelphi UniversityGarden CityNew YorkUSA
| | - Soobin Park
- Brown SchoolWashington University in St. LouisSt. LouisMissouriUSA
| | | | - Wenqing Zha
- Department of NeurologyWashington University School of MedicineSt. LouisMissouriUSA
| | - Ying Ma
- University of Houston56B M.D. Anderson Library HoustonTexasUSA
| | - Amanda Dias
- School of Social WorkAdelphi UniversityGarden CityNew YorkUSA
| | | | - Angela Hardi
- Bernard Becker Medical LibraryWashington University School of MedicineSt. LouisMissouriUSA
| | - Sunny Lin
- Division of General Medical SciencesDepartment of MedicineWashington University School of MedicineSt. LouisMissouriUSA
| | - Zahinoor Ismail
- Departments of PsychiatryClinical Neurosciences, and Community Health SciencesHotchkiss Brain InstituteUniversity of CalgaryCalgaryAlbertaCanada
- Department of Clinical and Biomedical SciencesFaculty of Health and Life SciencesUniversity of ExeterDevonUK
| | - Paris B. Adkins‐Jackson
- Departments of Epidemiology and Sociomedical SciencesMailman School of Public HealthColumbia UniversityNew YorkNew YorkUSA
| | - Jean‐Francois Trani
- Brown SchoolWashington University in St. LouisSt. LouisMissouriUSA
- Institute of Public HealthWashington UniversitySt. LouisMissouriUSA
- Centre for Social Development in AfricaFaculty of HumanitiesUniversity of JohannesburgCnr Kingsway & University RoadsJohannesburgSouth Africa
- National Conservatory of Arts and CraftsParisFrance
| | - Ganesh M. Babulal
- Department of NeurologyWashington University School of MedicineSt. LouisMissouriUSA
- Institute of Public HealthWashington UniversitySt. LouisMissouriUSA
- National Conservatory of Arts and CraftsParisFrance
- Department of Clinical Research and LeadershipThe George Washington University School of Medicine and Health SciencesWashingtonDistrict of ColumbiaUSA
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Li Z, Liu J. Thyroid dysfunction and Alzheimer's disease, a vicious circle. Front Endocrinol (Lausanne) 2024; 15:1354372. [PMID: 38419953 PMCID: PMC10899337 DOI: 10.3389/fendo.2024.1354372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/01/2024] [Indexed: 03/02/2024] Open
Abstract
Recently, research into the link between thyroid dysfunction and Alzheimer's disease (AD) remains a current topic of interest. Previous research has primarily concentrated on examining the impact of thyroid dysfunction on the risk of developing AD, or solely explored the mechanisms of interaction between hypothyroidism and AD, a comprehensive analysis of the mechanisms linking thyroid dysfunction, including hyperthyroidism and hypothyroidism, to Alzheimer's disease (AD) still require further elucidation. Therefore, the aim of this review is to offer a thorough and comprehensive explanation of the potential mechanisms underlying the causal relationship between thyroid dysfunction and AD, highlighting the existence of a vicious circle. The effect of thyroid dysfunction on AD includes neuron death, impaired synaptic plasticity and memory, misfolded protein deposition, oxidative stress, and diffuse and global neurochemical disturbances. Conversely, AD can also contribute to thyroid dysfunction by affecting the stress repair response and disrupting pathways involved in thyroid hormone (TH) production, transport, and activation. Furthermore, this review briefly discusses the role and significance of utilizing the thyroid as a therapeutic target for cognitive recovery in AD. By exploring potential mechanisms and therapeutic avenues, this research contributes to our understanding and management of this devastating neurodegenerative disease.
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Affiliation(s)
| | - Jia Liu
- Department of Thyroid Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
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Adams R, Oh ES, Yasar S, Lyketsos CG, Mammen JS. Endogenous and Exogenous Thyrotoxicosis and Risk of Incident Cognitive Disorders in Older Adults. JAMA Intern Med 2023; 183:1324-1331. [PMID: 37870843 PMCID: PMC10594176 DOI: 10.1001/jamainternmed.2023.5619] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/15/2023] [Indexed: 10/24/2023]
Abstract
Importance Thyroid hormone is among the most common prescriptions in the US and up to 20% may be overtreated. Endogenous hyperthyroidism may be a risk factor for dementia, but data are limited for iatrogenic thyrotoxicosis. Objective To determine whether thyrotoxicosis, both endogenous and exogenous, is associated with increased risk of cognitive disorders. Design, Setting, and Participants This cohort study performed a longitudinal time-varying analysis of electronic health records for patients receiving primary care in the Johns Hopkins Community Physicians Network between January 1, 2014, and May 6, 2023. Patients 65 years and older with at least 2 visits 30 days apart to their primary care physicians were eligible. None of the 65 931 included patients had a history of low thyrotropin (TSH) level or cognitive disorder diagnoses within 6 months of their first visit. Data analysis was performed from January 1 through August 5, 2023. Exposure The exposure variable was a low TSH level, characterized based on the clinical context as due to endogenous thyrotoxicosis, exogenous thyrotoxicosis, or unknown cause, excluding those attributable to acute illness or other medical factors such as medications. Main Outcomes and Measures The outcome measure was cognitive disorders, including mild cognitive impairment and all-cause dementia, to improve sensitivity and account for the underdiagnosis of dementia in primary care. Results A total of 65 931 patients were included in the analysis (median [IQR] age at first visit, 68.0 [65.0-74.0] years; 37 208 [56%] were female; 46 106 [69.9%] were White). Patients exposed to thyrotoxicosis had cognitive disorder incidence of 11.0% (95% CI, 8.4%-14.2%) by age 75 years vs 6.4% (95% CI, 6.0%-6.8%) for those not exposed. After adjustment, all-cause thyrotoxicosis was significantly associated with risk of cognitive disorder diagnosis (adjusted hazard ratio, 1.39; 95% CI, 1.18-1.64; P < .001) across age groups. When stratified by cause and severity, exogenous thyrotoxicosis remained a significant risk factor (adjusted hazard ratio, 1.34; 95% CI, 1.10-1.63; P = .003) with point estimates suggestive of a dose response. Conclusions and Relevance In this cohort study among patients 65 years and older, a low TSH level from either endogenous or exogenous thyrotoxicosis was associated with higher risk of incident cognitive disorder. Iatrogenic thyrotoxicosis is a common result of thyroid hormone therapy. With thyroid hormone among the most common prescriptions in the US, understanding the negative effects of overtreatment is critical to help guide prescribing practice.
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Affiliation(s)
- Roy Adams
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Esther S. Oh
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sevil Yasar
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Constantine G. Lyketsos
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jennifer S. Mammen
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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15
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Sahin L, Keloglan Müsüroglu S, Selin Cevik O, Cevik K, Orekici Temel G. Hyperthyroidism leads learning and memory impairment possibly via GRIN2B expression alterations. Brain Res 2023; 1802:148209. [PMID: 36563833 DOI: 10.1016/j.brainres.2022.148209] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/23/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022]
Abstract
The hippocampus as an important structure for learning and memory functions contains a high level of thyroid hormone receptors. Although there are numerous studies investigating the effects of thyroid hormones on cognitive dysfunction and psychiatric symptoms, the underlying molecular processes of these disorders have not yet been fully elucidated. In the present study, 24 male adult rats (4 months) were divided into 3 groups: control group, sham group and hyperthyroid group. Hyperthyroid group and sham group were treated with l-thyroxine or saline for 21 days. Each group was exposed to Morris water maze testing (MWMT), measuring their performance in a hidden-platform spatial task. After learning and memory tests, intracardiac blood was taken from the rats for serum thyroxine levels. Following blood collection, the rats were decapitated to isolate hippocampal tissue. GRIN2A, GRIN2B, BDNF, cFOS, Cdk5, cdk5r1 (p35), and cdk5r2 (p39) gene expression were evaluated using quantitative reverse transcriptase-PCR. Serum thyroxine level was found to be higher in hyperthyroid rats than in the control and sham groups. According to our MWMT findings, the memory performance of the hyperthyroid group was significantly impaired compared to the control and sham groups (p < 0.05). In the hippocampus, the GRIN2A gene expression level was decreased in the sham group, and the GRIN2B gene expression level was decreased in the sham and hyperthyroid groups compared to the control group (p < 0.05). There was no significant difference in other genes (p > 0.05). Hyperthyroidism impaired hippocampus-dependent spatial memory. Hyperthyroidism caused decreased level of GRIN2B gene expression in the hippocampus.
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Affiliation(s)
- Leyla Sahin
- Mersin University, Faculty of Medicine, Physiology Department, Mersin, Turkey.
| | | | - Ozge Selin Cevik
- Mersin University, Faculty of Medicine, Physiology Department, Mersin, Turkey
| | - Kenan Cevik
- Mersin University, Health Science Institute, Mersin, Turkey
| | - Gulhan Orekici Temel
- Mersin University, Faculty of Medicine, Department of Biostatistics and Medical Informatics, Mersin, Turkey
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Alzheimer's Disease and Impaired Bone Microarchitecture, Regeneration and Potential Genetic Links. Life (Basel) 2023; 13:life13020373. [PMID: 36836731 PMCID: PMC9963274 DOI: 10.3390/life13020373] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/08/2023] [Accepted: 01/16/2023] [Indexed: 02/03/2023] Open
Abstract
Alzheimer's Disease (AD) and osteoporosis are both age-related degenerative diseases. Many studies indicate that these two diseases share common pathogenesis mechanisms. In this review, the osteoporotic phenotype of AD mouse models was discussed, and shared mechanisms such as hormonal imbalance, genetic factors, similar signaling pathways and impaired neurotransmitters were identified. Moreover, the review provides recent data associated with these two diseases. Furthermore, potential therapeutic approaches targeting both diseases were discussed. Thus, we proposed that preventing bone loss should be one of the most important treatment goals in patients with AD; treatment targeting brain disorders is also beneficial for osteoporosis.
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Yang YT, Jin S, Bai YB, Liu Y, Hogervorst E. Association of Subclinical Thyroid Dysfunction with Cognitive Impairment in Rats: The Role of Autophagy. J NIPPON MED SCH 2023; 90:372-380. [PMID: 37940558 DOI: 10.1272/jnms.jnms.2023_90-506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
BACKGROUND We investigated the effect of subclinical hyperthyroidism and subclinical hypothyroidism on cognitive function in rats and the role of autophagy in this process. METHODS Forty Wistar rats were randomized into normal control (NC), hyperthyroidism (Hyper), hypothyroidism (Hypo), subclinical hyperthyroidism (sHyper), and subclinical hypothyroidism (sHypo) groups. Cognitive function (spatial learning and memory) was tested by the Morris water maze test. Hippocampal histopathology was analyzed by H&E staining, and expression levels of caspase-3 in hippocampal CA1 neurons were measured. In addition, immunoblot analysis was performed to detect hippocampal autophagy-related proteins. RESULTS Escape latency from day 1 to day 4 was significantly longer in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). In addition, the number of rats crossing the virtual platform was significantly lower in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). Compared with the NC group, all four groups had significantly lower residence time in the target quadrant (P < 0.05). Beclin-1 and LC3-II protein expression in hippocampal tissues was significantly higher in the Hyper and sHyper groups than in the NC group (P < 0.01). Beclin-1 and LC3-II protein expression in hippocampal tissues did not significantly differ between the sHypo group and NC group (P > 0.05). CONCLUSIONS Subclinical thyroid dysfunction in rats might lead to cognitive impairment. Subclinical hyperthyroidism might be associated with excessive activation of autophagy and hippocampal neuron damage and necrosis.
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Affiliation(s)
- Yun-Tian Yang
- School of Sport, Exercise and Health Sciences, Loughborough University
- Departments of Neurology, Affiliated Hospital of Inner Mongolia Medical University
| | - Shan Jin
- School of Sport, Exercise and Health Sciences, Loughborough University
- Department of General Surgery, Affiliated Hospital of Inner Mongolia Medical University
| | - Yin-Bao Bai
- Departments of Thyroid Surgery, People's Hospital of Inner Mongolia Autonomous Region
| | - Yousheng Liu
- Department of General Surgery, Datong Third People's Hospital
| | - Eef Hogervorst
- School of Sport, Exercise and Health Sciences, Loughborough University
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Xu YX, Wang C, Li XD, Guo WL, Liu GY, Zhang HB, Sun Y, Zhu DF, Xu Q. Activation of cholinergic basal forebrain neurons improved cognitive functions in adult-onset hypothyroid mice. Biomed Pharmacother 2022; 153:113495. [DOI: 10.1016/j.biopha.2022.113495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/21/2022] [Accepted: 07/27/2022] [Indexed: 11/24/2022] Open
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Wieland DR, Wieland JR, Wang H, Chen YH, Lin CH, Wang JJ, Weng CH. Thyroid Disorders and Dementia Risk: A Nationwide Population-Based Case-Control Study. Neurology 2022; 99:e679-e687. [PMID: 35794019 DOI: 10.1212/wnl.0000000000200740] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 03/31/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Dementia has been gaining attention in aging societies and is estimated to affect 50 million adults globally in 2020, and 12% of the US population may develop a thyroid disorder in their lifetime. There have been limited studies investigating the correlation between thyroid disorder and dementia in the Asian population. METHODS Our large nationwide population-based case-control study utilized the Taiwanese National Health Insurance Research Database. 7,843 adults with newly diagnosed dementia without a previous history of dementia or neurodegenerative disease between 2006 and 2013 were identified and included in our study. 7,843 adults without dementia diagnosis prior to the index date were age and gender matched as controls. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of dementia or the same index date was identified. Results were obtained from logistic regression models and adjusted for sex, age, history of hypertension, diabetes, coronary artery disease, depression, hyperlipidemia, alcohol dependence syndrome, tinnitus, hearing loss, and radioactive iodine treatment. RESULTS A total of 15,686 patients were included in the study. Both case and control groups were slightly predominantly female (4,066 [51.8%]). The mean (SD) age for those with dementia was 74.9 (11.3) years, and for those without dementia was 74.5 (11.3) years. Among patients aged 65 years or older, a history of hypothyroidism was associated with an increased risk of being diagnosed with dementia (aOR, 1.81; 95% Cl 1.14-2.87; p=0.011), which was an association not present in patients older than 50 years but younger than 65 years. We found that this association was most significant among patients aged 65 years or older with a history of hypothyroidism who received hypothyroidism medication (aOR, 3.17; 95% Cl 1.04-9.69; p=0.043). DISCUSSION Our large-scale case-control study found that among people ≥ 65 years old, those with a history of hypothyroidism were associated with an 81% increased risk of having dementia and among those, there was an over 3-fold increased dementia risk with thyroid conditions that required thyroid hormone replacement treatment. Future well-controlled prospective longitudinal studies should be conducted to elucidate these potential mechanisms and relationships. CLASSIFICATION OF EVIDENCE This study provides Class III evidence that among patients aged 65 years or older, a history of hypothyroidism was associated with an increased risk of being diagnosed with dementia.
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Affiliation(s)
| | | | - Han Wang
- Department of Neurology, Mayo Clinic College of Medicine & Science, Rochester, Minnesota, USA.,Department of Neurology, Mayo Clinic Health System, Mankato, Minnesota, USA
| | - Yi-Huei Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, TAIWAN
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, TAIWAN
| | - Jing-Jie Wang
- Department of Otolaryngology, Taichung Veterans General Hospital, Taichung, TAIWAN.,Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chien-Hsiang Weng
- Department of Family Medicine, Brown University Warren Alpert Medical School, Providence, Rhode Island, USA .,Coastal Medical Hillside Family Medicine, Pawtucket, Rhode Island, USA
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Higher thyroid function is associated with accelerated hippocampal volume loss in Alzheimer's disease. Psychoneuroendocrinology 2022; 139:105710. [PMID: 35278981 DOI: 10.1016/j.psyneuen.2022.105710] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/02/2022] [Accepted: 03/02/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND In epidemiological studies, higher thyroid hormone (TH) levels have been associated with lower brain volume and increased risk of Alzheimer's disease (AD) in elderly individuals. However, the relationships between serum THs and hippocampal atrophy rates have previously not been investigated. METHODS A prospective study of patients with AD (n = 55), stable mild cognitive impairment (sMCI; n = 84) and healthy controls (n = 29) recruited at a single memory clinic. We investigated whether serum THs were associated with magnetic resonance imaging (MRI)-estimated hippocampal volumes at baseline and with longitudinal alterations, defined as annualized percent changes. RESULTS Serum levels of free triiodothyronine (FT3) and FT3/free thyroxine (FT4) ratio were reduced in AD and sMCI patients compared with the controls (p < 0.05). Hierarchical linear regression analyses showed that higher serum FT3/FT4 ratio was associated with greater baseline hippocampal volume in all study groups. Only in AD patients, higher serum FT4 was associated with lower baseline volume of the left hippocampus. Finally, exclusively in the AD group, higher serum levels of FT3 and FT3/FT4 ratio, and lower serum TSH levels, were associated with greater annual hippocampal volume loss. CONCLUSIONS In all study groups, FT3/FT4 ratio was related to baseline hippocampal volume. However, only in AD patients, higher levels of THs were associated with greater annual loss of hippocampal volume, suggesting that excessive TH levels exert a deleterious effect on the hippocampus in the presence of existing AD neuropathology.
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Goto M, Kimura N, Matsubara E. Association of serum thyroid hormone levels with positron emission tomography imaging in non-demented older adults. Psychogeriatrics 2022; 22:373-381. [PMID: 35293067 DOI: 10.1111/psyg.12825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/05/2022] [Accepted: 02/22/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Although increasing evidence indicates that even variations in normal range thyroid function are associated with Alzheimer's disease (AD), the association between serum thyroid hormone levels within the reference range and AD biomarkers remains unclear. This study examined whether variations in thyroid hormones within the reference range are associated with brain amyloid burden and cortical glucose metabolism in older adults without dementia. METHODS One hundred and two non-demented older adults underwent 11 C-Pittsburgh Compound B positron emission tomography (PiB-PET), 18 F-fluorodeoxyglucose (FDG)-PET, and measurement of serum thyroid-stimulating hormone (TSH), free triiodothyronine (T3), and free thyroxine (T4) levels. The discrimination between PiB-negative and PiB-positive subgroup was made on the basis of a subject's cortical uptake value ratio greater than 1.4. The association of serum thyroid hormone levels with global PiB or FDG uptake, and PiB or FDG uptake in each region of interest, including frontal and temporoparietal lobes and posterior cingulate gyrus, was analysed using a multiple regression model with adjustment for covariates, including age, gender, years of education, apolipoprotein E4 status or PiB uptake value. RESULTS In the PiB-positive subgroup, the serum TSH levels positively associated with the global FDG uptake (β = 0.471, P = 0.003) and FDG uptake in the frontal and temporoparietal lobes (β = 0.466, P = 0.003, β = 0.394, P = 0.012, respectively); the serum-free T3 levels negatively associated with the FDG uptake in the temporoparietal lobe and posterior cingulate region (β = -0.351, P = 0.033, β = -0.544, P = 0.002, respectively). The PiB-negative subgroup showed no significant associations. The serum thyroid hormone levels did not correlate with the global PiB uptake and PiB uptake in each region. CONCLUSIONS The variations in the thyroid hormones within the reference ranges are associated with glucose metabolism, particularly in the specific regions affected by the neuropathologic changes of AD, in non-demented older adults with brain amyloid burden.
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Affiliation(s)
- Megumi Goto
- Department of Neurology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Noriyuki Kimura
- Department of Neurology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Etsuro Matsubara
- Department of Neurology, Faculty of Medicine, Oita University, Yufu, Japan
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Uncontrolled Thyroid during Pregnancy Alters the Circulative and Exerted Metabolome. Int J Mol Sci 2022; 23:ijms23084248. [PMID: 35457066 PMCID: PMC9029102 DOI: 10.3390/ijms23084248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/31/2022] [Accepted: 04/07/2022] [Indexed: 02/05/2023] Open
Abstract
Normal levels of thyroid hormones (THs) are essential for a normal pregnancy outcome, fetal growth and the normal function of the central nervous system. Hypothyroidism, a common endocrine disorder during pregnancy, is a significant metabolic factor leading to cognitive impairments. It is essential to investigate whether patients with thyroid dysfunction may present an altered circulative and excreted metabolic profile, even after receiving treatment with thyroxine supplements. NMR metabolomics was employed to analyze 90 serum and corresponding colostrum samples. Parallel analyses of the two biological specimens provided a snapshot of the maternal metabolism through the excretive and circulating characteristics of mothers. The metabolomics data were analyzed by performing multivariate statistical, biomarker and pathway analyses. Our results highlight the impact of hypothyroidism on metabolites’ composition during pregnancy and lactation. Thyroid disorder causing metabolite fluctuations may lead to impaired lipid and glucose metabolic pathways as well as aberrant prenatal neurodevelopment, thus posing a background for the occurrence of metabolic syndrome or neurogenerative diseases later in life. This risk applies to not only untreated but also hypothyroid women under replacement therapy since our findings in both biofluids framed a different metabolic phenotype for the latter group, thus emphasizing the need to monitor women adequately after treatment initiation.
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Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment. Cell Death Dis 2022; 13:406. [PMID: 35468877 PMCID: PMC9039072 DOI: 10.1038/s41419-022-04858-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 11/16/2022]
Abstract
Alzheimer’s disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.
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Kim HK, Song J. Hypothyroidism and Diabetes-Related Dementia: Focused on Neuronal Dysfunction, Insulin Resistance, and Dyslipidemia. Int J Mol Sci 2022; 23:ijms23062982. [PMID: 35328405 PMCID: PMC8952212 DOI: 10.3390/ijms23062982] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 01/27/2023] Open
Abstract
The incidence of dementia is steadily increasing worldwide. The risk factors for dementia are diverse, and include genetic background, environmental factors, sex differences, and vascular abnormalities. Among the subtypes of dementia, diabetes-related dementia is emerging as a complex type of dementia related to metabolic imbalance, due to the increase in the number of patients with metabolic syndrome and dementia worldwide. Thyroid hormones are considered metabolic regulatory hormones and affect various diseases, such as liver failure, obesity, and dementia. Thyroid dysregulation affects various cellular mechanisms and is linked to multiple disease pathologies. In particular, hypothyroidism is considered a critical cause for various neurological problems-such as metabolic disease, depressive symptoms, and dementia-in the central nervous system. Recent studies have demonstrated the relationship between hypothyroidism and brain insulin resistance and dyslipidemia, leading to diabetes-related dementia. Therefore, we reviewed the relationship between hypothyroidism and diabetes-related dementia, with a focus on major features of diabetes-related dementia such as insulin resistance, neuronal dysfunction, and dyslipidemia.
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Affiliation(s)
- Hee Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonnam National University Medical School, 264 Seoyangro, Hwasun 58128, Korea;
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun 58128, Korea
- Correspondence: ; Tel.: +82-61-379-2706; Fax: +82-61-375-5834
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25
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Figueroa PBS, Ferreira AFF, Britto LR, Doussoulin AP, Torrão ADS. Association between thyroid function and Alzheimer's disease: A systematic review. Metab Brain Dis 2021; 36:1523-1543. [PMID: 34146214 DOI: 10.1007/s11011-021-00760-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 06/06/2021] [Indexed: 11/25/2022]
Abstract
Alterations in metabolic parameters have been associated with an increased risk of dementia, among which thyroid function has gained great importance in Alzheimer's disease (AD) pathology in recent years. However, it remains unclear whether thyroid dysfunctions could influence and contribute to the beginning and/or progression of AD or if it results from AD. This systematic review was conducted to examine the association between thyroid hormone (TH) levels and AD. Medline, ISI Web of Science, EMBASE, Cochrane library, Scopus, Scielo, and LILACS were searched, from January 2010 to March 2020. A total of 17 articles were selected. The studies reported alterations in TH and circadian rhythm in AD patients. Behavior, cognition, cerebral blood flow, and glucose consumption were correlated with TH deficits in AD patients. Whether thyroid dysfunctions and AD have a cause-effect relationship was inconclusive, however, the literature was able to provide enough data to corroborate a relationship between TH and AD. Although further studies are needed in this field, the current systematic review provides information that could help future investigations.
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Affiliation(s)
- Paulina Belén Sepulveda Figueroa
- Department of Preclinical Science, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile.
- Laboratory of Neuronal Communication, Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo, Av. Professor Lineu Prestes, 1524 - Cidade Universitária, São Paulo, SP, Brasil, 05508900.
| | - Ana Flávia Fernandes Ferreira
- Laboratory of Cellular Neurobiology, Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo, Av. Professor Lineu Prestes, 1524 - Cidade Universitária, São Paulo, SP, Brasil, 05508900.
| | - Luiz Roberto Britto
- Laboratory of Cellular Neurobiology, Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo, Av. Professor Lineu Prestes, 1524 - Cidade Universitária, São Paulo, SP, Brasil, 05508900
| | | | - Andréa da Silva Torrão
- Laboratory of Neuronal Communication, Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo, Av. Professor Lineu Prestes, 1524 - Cidade Universitária, São Paulo, SP, Brasil, 05508900
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26
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Ge F, Zhu D, Tian M, Shi J. The Role of Thyroid Function in Alzheimer's Disease. J Alzheimers Dis 2021; 83:1553-1562. [PMID: 34420955 DOI: 10.3233/jad-210339] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The thyroid gland is crucial for the regulation of metabolism, growth, and development of various tissues, organs, systems, including the central nervous system. Recent studies have implicated the role of thyroid dysfunction in the etiology of Alzheimer's disease (AD), while AD leads to a significant increase in the prevalence of thyroid dysfunction. In this review, we have analyzed the role of thyroid function in the pathophysiology of AD as well as its biomarkers. The present review aims to provide encouraging targets for early screening of AD risk factors and intervention strategies.
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Affiliation(s)
- Feifei Ge
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Donglin Zhu
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Minjie Tian
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Jingping Shi
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
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27
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Szlejf C, Suemoto CK, Janovsky CCPS, Bertola L, Barreto SM, Lotufo PA, Benseñor IM. Subtle Thyroid Dysfunction Is Not Associated with Cognitive Decline: Results from the ELSA-Brasil. J Alzheimers Dis 2021; 81:1529-1540. [PMID: 33967048 DOI: 10.3233/jad-210018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Subtle thyroid alterations have a controversial role in cognition. OBJECTIVE We investigated the longitudinal association of baseline thyroid function, thyrotropin (TSH), and thyroxine (FT4) levels with cognitive performance after 4 years of follow-up in middle-aged and older adults without overt thyroid dysfunction. METHODS We included 4,473 individuals, age≥55 years at the second study wave, without overt thyroid dysfunction at baseline. Individuals were divided according to thyroid function and TSH and FT4 tertiles. Cognition was assessed at baseline and after 4 years of follow-up by the word recall (DWR), semantic verbal fluency (SVF), and trail making (TMT) tests. The longitudinal association of thyroid function and TSH and FT4 tertiles with cognitive performance was investigated using generalized estimating equations adjusted for sociodemographic characteristics, lifestyle, cardiovascular risk factors and depression. RESULTS There was no longitudinal association of thyroid function and TSH and FT4 baseline levels with performance on the cognitive tests. However, there was a baseline cross-sectional U-shaped association of FT4 tertiles with poorer performance in the SVF (first FT4 tertile: β= -0.11, 95% CI = -0.17; -0.04; third FT4 tertile: β= -0.10, 95% CI = -0.17; -0.04) and of the third FT4 tertile with poorer performance in the DWR (β= -0.09, 95% CI = -0.16; -0.02). CONCLUSION Thyroid function and hormone levels were not associated with cognitive decline during 4 years of follow-up in middle-aged and older adults without overt thyroid dysfunction. Future studies with longer follow-up could clarify the implications of subtle thyroid alterations in cognition.
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Affiliation(s)
- Claudia Szlejf
- Center for Clinical and Epidemiological Research, Hospital Universitario, University of Sao Paulo, Sao Paulo, Brazil
| | - Claudia Kimie Suemoto
- Center for Clinical and Epidemiological Research, Hospital Universitario, University of Sao Paulo, Sao Paulo, Brazil.,Division of Geriatrics, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | | | - Laiss Bertola
- Center for Clinical and Epidemiological Research, Hospital Universitario, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Paulo Andrade Lotufo
- Center for Clinical and Epidemiological Research, Hospital Universitario, University of Sao Paulo, Sao Paulo, Brazil.,Department of Internal Medicine, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Isabela Martins Benseñor
- Center for Clinical and Epidemiological Research, Hospital Universitario, University of Sao Paulo, Sao Paulo, Brazil.,Department of Internal Medicine, University of Sao Paulo Medical School, Sao Paulo, Brazil
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28
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Tang X, Song ZH, Wang D, Yang J, Augusto Cardoso M, Zhou JB, Simó R. Spectrum of thyroid dysfunction and dementia: a dose-response meta-analysis of 344,248 individuals from cohort studies. Endocr Connect 2021; 10:410-421. [PMID: 33875615 PMCID: PMC8111311 DOI: 10.1530/ec-21-0047] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/19/2021] [Indexed: 12/21/2022]
Abstract
Thyroid hormone, as a modifiable risk factor for dementia, promotes neurocognitive function and regulates metabolic processes. Various studies have defined different thyroid-stimulating hormone cutoffs, but the safest thyroid-stimulating hormone concentration was absent. A dose-response meta-analysis describing the overall functional relation and identifying exposure intervals associated with a higher or lower disease risk is thus desirable. Therefore, our current analysis was conducted to understand the influence of thyroid dysfunction on dementia risk. We searched PubMed, Embase, and Web of Science before May 1, 2020 for human studies published in English. Studies were considered for inclusion if they used a cohort study design to measure the risk of dementia in different thyroid function status groups, diagnosed thyroid functional status and all-cause dementia, included participants aged >18 years, and provided quantitative measures of data. The analysis contained 17 articles with 344,248 individuals with a 7.8-year mean follow-up. Ten studies with 329,287 participants indicated that only subclinical hyperthyroidism was associated with an increased risk of dementia. In contrast, subclinical hypothyroidism, clinical hyperthyroidism, and clinical hypothyroidism did not affect dementia. In the dose-response meta-analysis with 46,417 samples from 11 studies, the association of thyroid-stimulating hormone with the risk of dementia exhibited a U-shaped curve. Our study indicated that subclinical hyperthyroidism was associated with the risk of dementia and the thyroid-stimulating hormone concentration at around 1.55-1.60 mU/L as the optimum range for the risk of dementia.
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Affiliation(s)
- Xingyao Tang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Zhi-Hui Song
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Dawei Wang
- General Practice Department, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jinkui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Marly Augusto Cardoso
- Department of Nutrition, School of Public Health, University of Sao Paulo, Sao Paulo, Brazil
| | - Jian-Bo Zhou
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Rafael Simó
- Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron, Diabetes and Metabolism Research Unit, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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29
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Anzai T, Grandinetti A, Katz AR, Hurwitz EL, Wu YY, Masaki K. Paradoxical association between atrial fibrillation/flutter and high cholesterol over age 75 years: The Kuakini Honolulu Heart Program and Honolulu-Asia Aging Study. J Electrocardiol 2021; 65:37-44. [PMID: 33482619 DOI: 10.1016/j.jelectrocard.2020.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/06/2020] [Accepted: 12/14/2020] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Several studies have indicated high cholesterol is paradoxically associated with low prevalence of atrial fibrillation/flutter (AF). However, the etiology is uncertain. One potential explanation might be the confounding effect of age exemplifying prevalence-incidence (Neyman's) bias. However, this bias has not often been discussed in depth in the literature. Therefore, we conducted a cross-sectional analysis to test the hypothesis that there is a paradoxical association between lipid profile and AF prevalence. METHODS This is a cross-sectional study design, using data from the Kuakini Honolulu Heart Program. Participants were 3741 Japanese-American men between 71 and 93 years old living in Hawaii. Serum total cholesterol (TC) level was measured and categorized into quartiles. AF was diagnosed by 12‑lead Electrocardiogram. We categorized age into quartiles (71-74, 75-77, 78-80 and 81+ years). RESULTS We observed opposite associations between AF and TC among different age groups. For participants age ≥75, higher TC levels were paradoxically associated with lower prevalence of AF after multivariable adjustment, i.e. the odds ratios of AF comparing the highest TC quartile with the lowest TC quartile for age 75-77, 78-80 and 81+ years were 0.17 (95% confidence interval [CI], 0.06-0.52), 0.28 (95% CI, 0.07-1.09) and 0.14 (95% CI, 0.03-0.62), respectively. Conversely, for those who were 71-74 years old, the odds ratio of AF was 2.09 (95% CI, 0.76-5.75) between the highest and the lowest TC quartiles. CONCLUSIONS There is a paradoxical association of TC with AF in Japanese-American men age ≥75, but not <75 years. The paradox might be explained by Neyman's bias.
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Affiliation(s)
- Tagayasu Anzai
- Office of Public Health Studies, University of Hawai'i at Mānoa, 1960 East-West Road, Honolulu, HI, USA.
| | - Andrew Grandinetti
- Office of Public Health Studies, University of Hawai'i at Mānoa, 1960 East-West Road, Honolulu, HI, USA.
| | - Alan R Katz
- Office of Public Health Studies, University of Hawai'i at Mānoa, 1960 East-West Road, Honolulu, HI, USA.
| | - Eric L Hurwitz
- Office of Public Health Studies, University of Hawai'i at Mānoa, 1960 East-West Road, Honolulu, HI, USA.
| | - Yan Yan Wu
- Office of Public Health Studies, University of Hawai'i at Mānoa, 1960 East-West Road, Honolulu, HI, USA.
| | - Kamal Masaki
- Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawai'i at Mānoa, 347 N Kuakini St, Honolulu, HI, USA; Kuakini Medical Center, 347 N Kuakini St, Honolulu, HI, USA.
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30
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Eslami-Amirabadi M, Sajjadi SA. The relation between thyroid dysregulation and impaired cognition/behaviour: An integrative review. J Neuroendocrinol 2021; 33:e12948. [PMID: 33655583 PMCID: PMC8087167 DOI: 10.1111/jne.12948] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 12/19/2020] [Accepted: 01/29/2021] [Indexed: 12/20/2022]
Abstract
Despite decades of research on the relation between thyroid diseases and cognition, the nature of this relationship remains elusive. An increasing prevalence of cognitive impairment and thyroid dysfunction has been consistently observed with ageing. Also, there appears to be an association between thyroid disorders and cognitive decline. Given the increasing global burden of dementia, elucidating the relationship between thyroid disorders as a potentially modifiable risk factor of cognitive impairment was the main goal of this review. We summarise the current literature examining the relationship between thyroid hormonal dysregulation and cognition or behaviour. We present the available imaging and pathological findings related to structural and functional brain changes related to thyroid hormonal dysregulation. We also propose potential mechanisms of interaction between thyroid hormones, autoantibodies and cognition/behaviour. Effects of gender, ethnicity and environmental factors are also briefly discussed. This review highlights the need for long-term prospective studies to capture the course of brain functional changes associated with the incidence and progression of thyroid dysregulations along with the confounding effects of non-modifiable risk factors such as gender and ethnicity. Moreover, double-blind controlled clinical trials are necessary to devise appropriate treatment plans to prevent cognitive consequences of over or undertreatment of thyroid disorders.
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31
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Niiyama T, Kuroiwa M, Yoshioka Y, Kitahara Y, Shuto T, Kakuma T, Ohta K, Nakamura KI, Nishi A, Noda M. Sex Differences in Dendritic Spine Formation in the Hippocampus and Animal Behaviors in a Mouse Model of Hyperthyroidism. Front Cell Neurosci 2020; 14:268. [PMID: 33192304 PMCID: PMC7533561 DOI: 10.3389/fncel.2020.00268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/31/2020] [Indexed: 12/30/2022] Open
Abstract
Thyroid hormones are critical for the regulation of development and differentiation of neurons and glial cells in the central nervous system (CNS). We have previously reported the sex-dependent changes of glial morphology in the brain under the state of hyperthyroidism. Here, we examined sex-dependent changes in spine structure of granule neurons in the dentate gyrus of hippocampus in male and female mice with hyperthyroidism. Using FIB/SEM (focused ion beam/scanning electron microscopy), three-dimensional reconstructed structures of dendritic spines in dentate granule cells were analyzed. Dendritic spine density in granule cells increased significantly in both male and female mice with hyperthyroidism. The decrease in spine volume was observed only in female mice. These findings suggest that hyperthyroidism induces the formation of spines with normal size in male mice but the formation of spines with small size in female mice. To evaluate an outcome of neuronal and previously observed glial changes, behavioral tests were performed. Male mice with hyperthyroidism showed increased locomotor activity in the open field test, while female mice showed elevated immobility time in the tail suspension test, reflecting depression-like behavior. Although direct link between changes in spine and behavioral modifications requires further analysis, our results may help to understand gender-dependent neurological and psychological symptoms observed in patients with hyperthyroidism.
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Affiliation(s)
- Tetsushi Niiyama
- Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Mahomi Kuroiwa
- Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
| | - Yusaku Yoshioka
- Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Yosuke Kitahara
- Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
| | - Takahide Shuto
- Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
| | | | - Keisuke Ohta
- Department of Anatomy, Kurume University School of Medicine, Kurume, Japan
| | | | - Akinori Nishi
- Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
| | - Mami Noda
- Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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32
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Choi BW, Kim S, Kang S, Won KS, Yi HA, Kim HW. Relationship Between Thyroid Hormone Levels and the Pathology of Alzheimer's Disease in Euthyroid Subjects. Thyroid 2020; 30:1547-1555. [PMID: 32438896 DOI: 10.1089/thy.2019.0727] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background: Although several studies have reported an association between thyroid dysfunction and Alzheimer's disease (AD), the effect of mild thyroid dysfunction within the normal range of thyrotropin (TSH) on the development of AD remains unclear. The aim of this study was to evaluate the association between thyroid hormones and the pathology of AD in euthyroid subjects. Methods: Sixty-nine subjects with a TSH level between 0.5 and 4.5 μIU/L who underwent 18F-florbetaben positron emission tomography were included in this prospective cross-sectional study. The levels of serum free thyroxine (fT4) and TSH were quantified using radioimmunoassay. Neuropsychological tests were performed to assess cognitive function. Differences in cerebral amyloid-β (Aβ) burden were compared between high-normal TSH (TSH ≥2.5 μIU/mL) and low-normal TSH (TSH <2.5 μIU/mL) groups. Multiple linear regression analyses, adjusted for age, sex, education level, and Neuropsychiatric Inventory scores, were performed to evaluate relationships between thyroid hormone levels and both cerebral Aβ burden and cognitive function. Results: The cerebral Aβ burden in the high-normal TSH group was significantly higher than in the low-normal TSH group (1.53 ± 0.31 vs. 1.35 ± 0.22, p = 0.009). The fT4 levels were negatively correlated with cerebral Aβ burden (β = -0.240, p = 0.035), and TSH levels were positively correlated with cerebral Aβ burden (β = 0.267, p = 0.020). The fT4 level was also positively associated with cognitive function, as inferred from neuropsychological test scores. Conclusions: Thyroid hormone concentrations were associated with AD pathology in euthyroid subjects. Our findings suggest that AD is likely to occur even in individuals with high-normal TSH levels.
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Affiliation(s)
- Byung Wook Choi
- Department of Nuclear Medicine, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Shin Kim
- Department of Immunology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Sungmin Kang
- Department of Nuclear Medicine, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Kyoung Sook Won
- Department of Nuclear Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hyon-Ah Yi
- Department of Neurology, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hae Won Kim
- Department of Nuclear Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
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Quinlan P, Horvath A, Eckerström C, Wallin A, Svensson J. Altered thyroid hormone profile in patients with Alzheimer's disease. Psychoneuroendocrinology 2020; 121:104844. [PMID: 32889491 DOI: 10.1016/j.psyneuen.2020.104844] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 08/05/2020] [Accepted: 08/11/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Epidemiological studies have linked higher levels of thyroid hormones (THs) to increased risk of Alzheimer's disease (AD), whereas in advanced AD, THs have been unchanged or even decreased. In early AD dementia, little is known whether THs are related to AD neuropathology or brain morphology. METHODS This was a cross-sectional study of 36 euthyroid AD patients and 34 healthy controls recruited at a single memory clinic. Levels of THs were measured in serum and cerebrospinal fluid (CSF). In addition, we determined AD biomarkers (amyloid-β1-42, total tau and phosphorylated tau) in CSF and hippocampal and amygdalar volumes using magnetic resonance imaging. RESULTS Serum free thyroxine (FT4) levels were elevated, whereas serum free triiodothyronine (FT3)/FT4 and total T3 (TT3)/total T4 (TT4) ratios were decreased, in AD patients compared to controls. In addition, serum TT4 was marginally higher in AD (p = 0.05 vs. the controls). Other TH levels in serum as well as CSF concentrations of THs were similar in both groups, and there were no correlations between THs and CSF AD biomarkers. However, serum FT3 correlated positively with left amygdalar volume in AD patients and serum TT3 correlated positively with left and right hippocampal volume in controls. CONCLUSIONS Thyroid hormones were moderately altered in mild AD dementia with increased serum FT4, and in addition, the reduced T3/T4 ratios may suggest decreased peripheral conversion of T4 to T3. Furthermore, serum T3 levels were related to brain structures involved in AD development.
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Affiliation(s)
- Patrick Quinlan
- Institute of Medicine, Department of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Alexandra Horvath
- Institute of Medicine, Department of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carl Eckerström
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Wallin
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Johan Svensson
- Institute of Medicine, Department of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Ge YJ, Xu W, Tan CC, Tan L. Blood-based biomarkers in hypothalamic-pituitary axes for the risk of dementia or cognitive decline: a systematic review and meta-analysis. Aging (Albany NY) 2020; 12:20350-20365. [PMID: 33104518 PMCID: PMC7655197 DOI: 10.18632/aging.103813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022]
Abstract
Blood-based biomarkers are ideal candidates for dementia prediction. This systematic review and meta-analysis aimed to evaluate longitudinal relationships of blood hormones and hormone-binding proteins in hypothalamic-pituitary (HP) axes with dementia or cognitive decline. PubMed, MEDLINE, EMBASE, PsycINFO, and BIOSIS were systematically searched from 1919 to June 2020. Fifteen types of hormones and four types of hormone-binding proteins were measured in 48 prospective studies. Increased risk of dementia or cognitive decline could be predicted by elevated blood concentrations of free-thyroxine (free-T4, RR = 1.06, p = 0.001) and sex hormone-binding globulin (SHBG, RR = 1.10, p = 0.025). Lower thyroid-stimulating hormone (TSH) levels within (RR = 1.28, p < 0.001) and below (RR = 1.27, p = 0.004) the normal range were both risky. Current evidence suggests the alterations of multiple blood molecules in HP axes, especially TSH, free-T4, and SHBG precede the incidence of dementia or cognitive decline. The underpinning etiology remains to be elucidated in the future.
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Affiliation(s)
- Yi-Jun Ge
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Wei Xu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Chen-Chen Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
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Li LX, Yang T, Guo L, Wang DY, Tang CH, Li Q, Yang HM, Zhu J, Zhang LL. Serum tau levels are increased in patients with hyperthyroidism. Neurosci Lett 2020; 729:135003. [PMID: 32335219 DOI: 10.1016/j.neulet.2020.135003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 04/16/2020] [Accepted: 04/18/2020] [Indexed: 12/19/2022]
Abstract
Hyperthyroidism may cause cognitive decline and increases the risk of Alzheimer's disease (AD), the major form of dementia; however, the underlying mechanism of this relationship is unclear. AD is associated with increased serum levels of tau. In this study, we investigated the relationship between serum thyroid hormones (THs) and tau. Fifty participants diagnosed with hyperthyroidism and fifty euthyroid counterparts were included and received clinical examinations. Serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3) and tau protein were assessed. The total tau protein level was significantly higher in hyperthyroidism participants than in their euthyroid counterparts. The level of circulating total tau had a significant positive association with the serum concentrations of FT3 and FT4. Total tau level was increased in the low TSH group and the serum THs decreased with the increase of age. These findings reveal that peripheral THs are associated with the serum concentration of tau, which may be involved in the pathogenesis of AD, suggesting a potential therapeutic target of AD via hyperthyroidism therapy.
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Affiliation(s)
- Lun-Xi Li
- Department of Neurology, Army Medical University Daping Hospital, China
| | - Tong Yang
- Department of Neurology, Army Medical University Daping Hospital, China
| | - Lu Guo
- Department of Neurology, Army Medical University Daping Hospital, China
| | - Da-Yan Wang
- Department of Neurology, the Seventh Affiliated Hospital, Sun Yat-sen University, China
| | - Chun-Hua Tang
- Department of Neurology, Army Medical University Daping Hospital, China
| | - Qiong Li
- Department of Neurology, Army Medical University Daping Hospital, China
| | - Hai-Mei Yang
- Department of Neurology, Army Medical University Daping Hospital, China
| | - Jie Zhu
- Department of Neurology, Army Medical University Daping Hospital, China.
| | - Li-Li Zhang
- Department of Neurology, Army Medical University Daping Hospital, China
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Garrett MD. Multiple Causes of Dementia as Engineered Senescence. EUROPEAN JOURNAL OF MEDICAL AND HEALTH SCIENCES 2020; 2. [DOI: 10.24018/ejmed.2020.2.2.227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
All traumas—cranial, cardiovascular, hormone, viral, bacterial, fungi, parasites, misfolded protein, genetic, behavior, environmental and medication—affect the brain. This paper itemizes studies showing the many different causes of dementia including Alzheimer’s disease. Causes interact with each other, act sequentially by preparing the optimal conditions for its successor, initiate other diseases, allow for other traumas to accumulate and degrade protective features of the brain. Since such age-related cognitive impairment is not exclusively a human attribute there might be support for an evolutionary theory of dementia. Relying on theories of antagonistic pleiotropy and polymorphism, the brain has been designed to sequester trauma. Because of increased longevity, the short-term tactic of sequestering trauma becomes a long-term liability. We are engineered to sequester these insults until a tipping point is reached. Dementia is an evolutionary trade-off for longevity. We cannot cure dementia without understanding the overall biology of aging.
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Lim S, Mohaimin S, Min D, Roberts T, Sohn YJ, Wong J, Sivanesathurai R, Kwon SC, Trinh-Shevrin C. Alzheimer's Disease and its Related Dementias among Asian Americans, Native Hawaiians, and Pacific Islanders: A Scoping Review. J Alzheimers Dis 2020; 77:523-537. [PMID: 32675416 PMCID: PMC8638681 DOI: 10.3233/jad-200509] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) aging population is rapidly growing and the burden of Alzheimer's disease and its related dementias (ADRD) will likely mirror this demographic growth. AANHPIs face significant barriers in obtaining timely ADRD diagnosis and services; yet little is known about ADRD in this population. OBJECTIVE The study objective is to conduct a systematic review on the published literature on ADRD among AANHPIs to identify gaps and priorities to inform future research and action plans. METHODS The systematic review was conducted following the PRISMA Protocol for Systematic Reviews. Co-author (TR), an experienced Medical Librarian, searched PubMed, EMBASE, PsycINFO, Cochrane Central of Clinical Trials, Ageline, and Web of Science for peer-reviewed articles describing ADRD among AANHPIs. The search was not limited by language or publication date. Each citation was reviewed by two trained independent reviewers. Conflicts were resolved through consensus. RESULTS The title/abstract and full texts of 1,447 unique articles were screened for inclusion, yielding 168 articles for analysis. Major research topics included prevalence, risk factors, comorbidities, interventions and outreach, knowledge and attitudes, caregiving, and detection tools. A limited number of studies reported on national data, on NHPI communities generally, and on efficacy of interventions targeting AANHPI communities. CONCLUSION To our knowledge, this is the first systematic review on ADRD among AANHPI populations. Our review provides a first step in mapping the extant literature on ADRD among this underserved and under-researched population and will serve as a guide for future research, policy, and intervention.
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Affiliation(s)
- Sahnah Lim
- Department of Population Health, New York University Grossman School of Medicine
| | - Sadia Mohaimin
- Department of Population Health, New York University Grossman School of Medicine
| | - Deborah Min
- Department of Population Health, New York University Grossman School of Medicine
| | - Timothy Roberts
- Health Science Library, New York University Grossman School of Medicine
| | - Young-Jin Sohn
- Department of Population Health, New York University Grossman School of Medicine
| | - Jazmine Wong
- Department of Population Health, New York University Grossman School of Medicine
| | | | - Simona C. Kwon
- Department of Population Health, New York University Grossman School of Medicine
| | - Chau Trinh-Shevrin
- Department of Population Health, New York University Grossman School of Medicine
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Wood T, Nance E. Disease-directed engineering for physiology-driven treatment interventions in neurological disorders. APL Bioeng 2019; 3:040901. [PMID: 31673672 PMCID: PMC6811362 DOI: 10.1063/1.5117299] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023] Open
Abstract
Neurological disease is killing us. While there have long been attempts to develop therapies for both acute and chronic neurological diseases, no current treatments are curative. Additionally, therapeutic development for neurological disease takes 15 years and often costs several billion dollars. More than 96% of these therapies will fail in late stage clinical trials. Engineering novel treatment interventions for neurological disease can improve outcomes and quality of life for millions; however, therapeutics should be designed with the underlying physiology and pathology in mind. In this perspective, we aim to unpack the importance of, and need to understand, the physiology of neurological disease. We first dive into the normal physiological considerations that should guide experimental design, and then assess the pathophysiological factors of acute and chronic neurological disease that should direct treatment design. We provide an analysis of a nanobased therapeutic intervention that proved successful in translation due to incorporation of physiology at all stages of the research process. We also provide an opinion on the importance of keeping a high-level view to designing and administering treatment interventions. Finally, we close with an implementation strategy for applying a disease-directed engineering approach. Our assessment encourages embracing the complexity of neurological disease, as well as increasing efforts to provide system-level thinking in our development of therapeutics for neurological disease.
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Li J, Abe K, Milanesi A, Liu YY, Brent GA. Thyroid Hormone Protects Primary Cortical Neurons Exposed to Hypoxia by Reducing DNA Methylation and Apoptosis. Endocrinology 2019; 160:2243-2256. [PMID: 31095291 DOI: 10.1210/en.2019-00125] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 05/10/2019] [Indexed: 02/03/2023]
Abstract
Traumatic brain injury (TBI) is associated with disruption of cerebral blood flow leading to localized brain hypoxia. Thyroid hormone (TH) treatment, administered shortly after injury, has been shown to promote neural protection in rodent TBI models. The mechanism of TH protection, however, is not established. We used mouse primary cortical neurons to investigate the effectiveness and possible pathways of T3-promoted cell survival after exposure to hypoxic injury. Cultured primary cortical neurons were exposed to hypoxia (0.2% oxygen) for 7 hours with or without T3 (5 nM). T3 treatment enhanced DNA 5-hydroxymethylcytosine levels and attenuated the hypoxia-induced increase in DNA 5-methylcytosine (5-mc). In the presence of T3, mRNA expression of Tet family genes was increased and DNA methyltransferase (Dnmt) 3a and Dnmt3b were downregulated, compared with conditions in the absence of T3. These T3-induced changes decreased hypoxia-induced DNA de novo methylation, which reduced hypoxia-induced neuronal damage and apoptosis. We used RNA sequencing to characterize T3-regulated genes in cortical neurons under hypoxic conditions and identified 22 genes that were upregulated and 15 genes that were downregulated. Krüppel-like factor 9 (KLF9), a multifunctional transcription factor that plays a key role in central nervous system development, was highly upregulated by T3 treatment in hypoxic conditions. Knockdown of the KLF9 gene resulted in early apoptosis and abolished the beneficial role of T3 in neuronal survival. KLF9 mediates, in part, the neuronal protective role of T3. T3 treatment reduces hypoxic damage, although pathways that reduce DNA methylation and apoptosis remain to be elucidated.
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Affiliation(s)
- Jianrong Li
- Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Endocrinology Division, Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Kiyomi Abe
- Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Endocrinology Division, Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Anna Milanesi
- Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Endocrinology Division, Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Yan-Yun Liu
- Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Endocrinology Division, Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Gregory A Brent
- Molecular Endocrinology Laboratory, VA Greater Los Angeles Healthcare System, Endocrinology Division, Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
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George KM, Lutsey PL, Selvin E, Palta P, Windham BG, Folsom AR. Association Between Thyroid Dysfunction and Incident Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study. JOURNAL OF ENDOCRINOLOGY AND METABOLISM 2019; 9:82-89. [PMID: 32411312 PMCID: PMC7223793 DOI: 10.14740/jem588] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Abnormal thyroid hormone levels (high or low) and autoimmunity from autoimmune thyroid disease (AITD) may increase dementia risk. METHODS We examined the associations of thyroid dysfunction or possible AITD in 1990 - 1992 with dementia through 2017 in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. Thyroid dysfunction (subclinical and overt hypo- or hyperthyroidism and euthyroidism) was categorized from serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) cut-points and AITD from anti-thyroid peroxidase (anti-TPO) antibody positivity. Dementia was identified primarily based on cognitive test performance, neuropsychological examinations and clinician review of suspected cases. Additional cases of dementia were ascertained through telephone interviews or relevant hospital and death certificate codes. Cox regression with multivariable adjustment was used for analysis. RESULTS After exclusions for missing data, 12,481 participants were included in the analysis (mean index exam age 57 ± 5.7 (44% male, 25% black)), and 2,235 incident dementia cases were identified. AITD was not significantly associated with dementia. Subclinical hypothyroidism was associated with a lower risk of dementia (hazard ratio (HR) (95% confidence interval (CI)): 0.74 (0.60 - 0.92)), while overt hyperthyroidism was associated with a higher risk of dementia (HR (95% CI): 1.40 (1.02 - 1.92)) compared to euthyroid participants. Participants with serum FT4 concentrations above the 95th percentile were at an increased risk of dementia compared to those in the middle 90% of FT4 (HR (95% CI): 1.23 (1.02 - 1.48)). CONCLUSIONS Subclinical hypothyroidism was associated with reduced risk of dementia, whereas overt hyperthyroidism, particularly very elevated FT4, was associated with increased risk of dementia. The association between subclinical hypothyroidism and reduced risk of dementia cannot be explained, but may have been an artifact due to change. By extrapolation, effective treatment of overt hyperthyroidism may modestly reduce dementia risk in older adults.
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Affiliation(s)
- Kristen M. George
- University of Minnesota School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN, USA
| | - Pamela L. Lutsey
- University of Minnesota School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN, USA
| | - Elizabeth Selvin
- Johns Hopkins University Bloomberg School of Public Health, Department of Epidemiology, Baltimore, MD, USA
| | - Priya Palta
- Columbia University Department of Medicine, Division of General Medicine, New York, NY, USA
| | - Beverly Gwen Windham
- University of Mississippi Medical Center, Department of Medicine, Jackson, MS, USA
| | - Aaron R. Folsom
- University of Minnesota School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN, USA
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Toro CA, Zhang L, Cao J, Cai D. Sex differences in Alzheimer's disease: Understanding the molecular impact. Brain Res 2019; 1719:194-207. [PMID: 31129153 DOI: 10.1016/j.brainres.2019.05.031] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 04/10/2019] [Accepted: 05/22/2019] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disorder that presents with cognitive impairment and behavioral disturbance. Approximately 5.5 million people in the United States live with AD, most of whom are over the age of 65 with two-thirds being woman. There have been major advancements over the last decade or so in the understanding of AD neuropathological changes and genetic involvement. However, studies of sex impact in AD have not been adequately integrated into the investigation of disease development and progression. It becomes indispensable to acknowledge in both basic science and clinical research studies the importance of understanding sex-specific differences in AD pathophysiology and pathogenesis, which could guide future effort in the discovery of novel targets for AD. Here, we review the latest and most relevant literature on this topic, highlighting the importance of understanding sex dimorphism from a molecular perspective and its association to clinical trial design and development in AD research field.
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Affiliation(s)
- Carlos A Toro
- National Center for the Medical Consequences of Spinal Cord Injury, James J Peters VA Medical Center, Bronx, NY 10468, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
| | - Larry Zhang
- Research and Development, James J Peters VA Medical Center, Bronx, NY 10468, United States; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Jiqing Cao
- Research and Development, James J Peters VA Medical Center, Bronx, NY 10468, United States; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
| | - Dongming Cai
- Research and Development, James J Peters VA Medical Center, Bronx, NY 10468, United States; Neurology Section, James J Peters VA Medical Center, Bronx, NY 10468, United States; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
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Nomoto S, Kinno R, Ochiai H, Kubota S, Mori Y, Futamura A, Sugimoto A, Kuroda T, Yano S, Murakami H, Shirasawa T, Yoshimoto T, Minoura A, Kokaze A, Ono K. The relationship between thyroid function and cerebral blood flow in mild cognitive impairment and Alzheimer's disease. PLoS One 2019; 14:e0214676. [PMID: 30943231 PMCID: PMC6447192 DOI: 10.1371/journal.pone.0214676] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 03/18/2019] [Indexed: 11/18/2022] Open
Abstract
The thyroid hormones have been reported to be associated with cognitive decline and Alzheimer’s disease. The relationship between thyroid function within the normal range and cerebral blood flow in Alzheimer’s disease patients has been shown in a recent study. Mild cognitive impairment is often the first stage of Alzheimer’s disease; thus, early diagnosis is important. The present study investigated the relationship between thyroid function and regional cerebral blood flow in patients with mild cognitive impairment and Alzheimer’s disease. A total of 122 memory clinic outpatients who underwent thyroid function testing and single photon emission computed tomography were divided into mild cognitive impairment, Alzheimer’s disease, and Normal groups. Regional cerebral blood flow was calculated using a three-dimensional stereotactic region of interest template in an automated cerebral perfusion single photon emission computed tomography analysis system. Multiple regression analysis adjusted for age and sex was conducted to examine the relationships between thyroid hormones and regional cerebral blood flow. Thyroid stimulating hormone was significantly associated with regional cerebral blood flow in the bilateral temporal, bilateral pericallosal, and bilateral hippocampal regions in the mild cognitive impairment group. In the Alzheimer’s disease group, free triiodothyronine was significantly associated with regional cerebral blood flow in the bilateral parietal, right temporal, and bilateral pericallosal regions. The present study showed the association of thyroid stimulating hormone with regional cerebral blood flow in the mild cognitive impairment group and the association of free triiodothyronine with regional cerebral blood flow in the Alzheimer’s disease group. These study findings could contribute to the early diagnosis of mild cognitive impairment at general memory clinics and the prevention of subsequent progression to Alzheimer’s disease.
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Affiliation(s)
- Shohei Nomoto
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
- Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Ryuta Kinno
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hirotaka Ochiai
- Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Satomi Kubota
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yukiko Mori
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Akinori Futamura
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Azusa Sugimoto
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Takeshi Kuroda
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Satoshi Yano
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hidetomo Murakami
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Takako Shirasawa
- Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Takahiko Yoshimoto
- Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Akira Minoura
- Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Akatsuki Kokaze
- Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kenjiro Ono
- Division of Neurology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
- * E-mail:
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Tigano V, Cascini GL, Sanchez-Castañeda C, Péran P, Sabatini U. Neuroimaging and Neurolaw: Drawing the Future of Aging. Front Endocrinol (Lausanne) 2019; 10:217. [PMID: 31024455 PMCID: PMC6463811 DOI: 10.3389/fendo.2019.00217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/18/2019] [Indexed: 11/13/2022] Open
Abstract
Human brain-aging is a complex, multidimensional phenomenon. Knowledge of the numerous aspects that revolve around it is therefore essential if not only the medical issues, but also the social, psychological, and legal issues related to this phenomenon are to be managed correctly. In the coming decades, it will be necessary to find solutions to the management of the progressive aging of the population so as to increase the number of individuals that achieve successful aging. The aim of this article is to provide a current overview of the physiopathology of brain aging and of the role and perspectives of neuroimaging in this context. The progressive development of neuroimaging has opened new perspectives in clinical and basic research and it has modified the concept of brain aging. Neuroimaging will play an increasingly important role in the definition of the individual's brain aging in every phase of the physiological and pathological process. However, when the process involved in age-related brain cognitive diseases is being investigated, factors that might affect this process on a clinical and behavioral level (genetic susceptibility, risks factors, endocrine changes) cannot be ignored but must, on the contrary, be integrated into a neuroimaging evaluation to ensure a correct and global management, and they are therefore discussed in this article. Neuroimaging appears important to the correct management of age-related brain cognitive diseases not only within a medical perspective, but also legal, according to a wider approach based on development of relationship between neuroscience and law. The term neurolaw, the neologism born from the relationship between these two disciplines, is an emerging field of study, that deals with various issues in the impact of neurosciences on individual rights. Neuroimaging, enhancing the detection of physiological and pathological brain aging, could give an important contribution to the field of neurolaw in elderly where the full control of cognitive and volitional functions is necessary to maintain a whole series of rights linked to legal capacity. For this reason, in order to provide the clinician and researcher with a broad view of the brain-aging process, the role of neurolaw will be introduced into the brain-aging context.
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Affiliation(s)
- Vincenzo Tigano
- Department of Juridical, Historical, Economic and Social Sciences, University of Magna Graecia, Catanzaro, Italy
| | - Giuseppe Lucio Cascini
- Department of Experimental and Clinical Medicine, University of Magna Graecia, Catanzaro, Italy
| | | | - Patrice Péran
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, Toulouse, France
| | - Umberto Sabatini
- Department of Medical and Surgical Sciences, University of Magna Graecia, Catanzaro, Italy
- *Correspondence: Umberto Sabatini
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Quinlan P, Horvath A, Wallin A, Svensson J. Low serum concentration of free triiodothyronine (FT3) is associated with increased risk of Alzheimer's disease. Psychoneuroendocrinology 2019; 99:112-119. [PMID: 30223192 DOI: 10.1016/j.psyneuen.2018.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 07/31/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND In epidemiological studies, thyroid hormones (THs) have been associated with the risk of dementia. However, little is known of the relation between THs and risk of Alzheimer's disease (AD) or vascular dementia (VaD) in a memory clinic population. METHODS In a mono-center study, serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were assessed in 302 patients. All patients had subjective or objective mild cognitive impairment and none received treatment with THs. Cox proportional hazards regression analyses was used to determine whether THs at baseline were associated with the risk of conversion to all-cause dementia, AD or VaD. RESULTS During the follow-up (mean 2.8 years), 82 (28%) of the patients progressed to dementia [AD, n = 55 (18%) and VaD, n = 17 (6%)]. Serum concentrations of TSH, FT4, and FT3 did not associate with all-cause dementia or VaD. Higher serum FT3 was associated with lower risk of conversion to AD [hazard ratio (HR) = 054; 95% confidence interval (CI): 0.32-0.92 per 1 pmol/L increase]. Furthermore, patients in the lowest serum FT3 quartile had a twofold increased risk of AD compared to those in the highest quartile (HR = 2.63; 95% CI: 1.06-6.47). These associations remained after adjustment for multiple covariates. CONCLUSIONS In a memory clinic population, there was an inverse, linear association between serum FT3 and risk of AD whereas THs did not associate with all-cause dementia or VaD. Further studies are needed to determine the underlying mechanisms as well as the clinical significance of these findings.
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Affiliation(s)
- Patrick Quinlan
- Institute of Medicine, Department of Internal Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
| | - Alexandra Horvath
- Institute of Medicine, Department of Internal Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Anders Wallin
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Johan Svensson
- Institute of Medicine, Department of Internal Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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Park S, Kim DK, Myung W, Yoo JH, Shin SJ, Na DL, Kim SY, Lee JH, Kim SY, Han SH, Choi SH, Shin J. Risk Factors of Behavioral and Psychological Symptoms in Patients with Alzheimer Disease: The Clinical Research of Dementia of South Korea Study. Korean J Fam Med 2018; 40:16-21. [PMID: 30369216 PMCID: PMC6351791 DOI: 10.4082/kjfm.17.0061] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 07/11/2017] [Indexed: 11/04/2022] Open
Abstract
Background Few studies have evaluated risk factors for behavioral and psychological symptoms of dementia at the initial assessment for Alzheimer disease in large patient samples. In this study, the factors influencing Alzheimer disease were examined using the Clinical Research of Dementia of South Korea data. Methods This cross-sectional study was conducted using data of 1,128 patients with Alzheimer disease. The behavioral and psychological symptoms of dementia were examined using the Korean version of the Neuropsychiatric Inventory. Demographic characteristics, health-related behavior, neuropsychological tests, comorbidities, blood test results, and caregiver characteristics were assessed. Median logistic regression analysis with adjustment for covariates was conducted. Results The behavioral and psychological symptoms of dementia were negatively associated with memory (P=0.022) and frontal/executive (P<0.001) function in the Seoul Neuropsychological Screening Battery-dementia, Barthel Index for Activities of Daily Living (P<0.001), Korean version of the Mini-Mental State Examination score (P=0.003), and caregiver age (P=0.005) after adjustment for confounding factors, and positively associated with the Seoul-Instrumental Activities of Daily Living score (P<0.001), Clinical Dementia Rating Sum of Box (P<0.001), Global Deterioration Scale score (P<0.001), abnormality of free T4 level (P<0.001), anemia (P<0.001), and family history of stroke (P=0.001). Patients with female caregivers exhibited more severe behavioral and psychological symptoms of dementia than those with male caregivers. Conclusion Behavioral and psychological symptoms of dementia in Alzheimer disease patients were associated with various risk factors including the inability to live independently and Alzheimer disease severity. These findings suggest that prevention and treatment strategies for the behavioral and psychological symptoms of dementia should be comprehensive.
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Affiliation(s)
- Sunyoung Park
- Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Doh Kwan Kim
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woojae Myung
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jun Hyun Yoo
- Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Su Jeong Shin
- Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Duk L Na
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Kim
- Department of Neurology, Seoul National University Bundang Hospital, Seoul, Korea
| | - Jae-Hong Lee
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seong Yoon Kim
- Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seol-Heui Han
- Department of Neurology, Konkuk University School of Medicine, Seoul, Korea
| | - Seong Hye Choi
- Department of Neurology, Inha University School of Medicine, Seoul, Korea
| | - Jinyoung Shin
- Department of Family Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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Abstract
As the worldwide prevalence of dementia increases, there is a greater and more urgent need for all health care providers to understand how to evaluate and manage cognitive impairment. Many people presenting with a dementing illness have one or more reversible underlying conditions that worsen prognosis and, if treated, can improve cognitive function. This article reviews the major potentially reversible dementias, including the basic workup and management of each condition.
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Affiliation(s)
- Milta O Little
- Division of Geriatric Medicine, Department of Internal Medicine, Saint Louis University Health Center, 1402 South Grand Boulevard Room M238, St Louis, MO 63104, USA.
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Delitala AP, Manzocco M, Sinibaldi FG, Fanciulli G. Thyroid function in elderly people: The role of subclinical thyroid disorders in cognitive function and mood alterations. Int J Clin Pract 2018; 72:e13254. [PMID: 30216651 DOI: 10.1111/ijcp.13254] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 08/01/2018] [Accepted: 08/04/2018] [Indexed: 01/06/2023] Open
Affiliation(s)
- Alessandro P Delitala
- U.O.C. di Medicina Interna 2 (Clinica Medica), Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy
| | - Marta Manzocco
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Federico G Sinibaldi
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Giuseppe Fanciulli
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
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Brenowitz WD, Han F, Kukull WA, Nelson PT. Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 2018; 62:64-71. [PMID: 29107848 PMCID: PMC5743774 DOI: 10.1016/j.neurobiolaging.2017.10.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/02/2017] [Accepted: 10/02/2017] [Indexed: 01/01/2023]
Abstract
Thyroid hormone disease is common among older adults and is associated with cognitive impairment. However, pathologic correlates are not well understood. We studied pathologic and clinical factors associated with hypothyroidism, the most common manifestation of thyroid disease, in research subjects seen annually for clinical evaluations at U.S. Alzheimer's Disease Centers. Thyroid disease and treatment status were assessed during clinician interviews. Among autopsied subjects, there were 555 participants with treated hypothyroidism and 2146 without known thyroid disease; hypothyroidism was associated with severe atherosclerosis (odds ratio: 1.35; 95% confidence interval: 1.02, 1.79) but not Alzheimer's disease pathologies (amyloid plaques or neurofibrillary tangles). Among participants who did not undergo autopsy (4598 with treated hypothyroidism and 20,945 without known thyroid hormone disease), hypercholesterolemia and cerebrovascular disease (stroke and/or transient ischemic attack) were associated with hypothyroidism, complementing findings in the smaller autopsy sample. This is the first large-scale evaluation of neuropathologic concomitants of hypothyroidism in aged individuals. Clinical hypothyroidism was prevalent (>20% of individuals studied) and was associated with cerebrovascular disease but not Alzheimer's disease-type neuropathology.
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Affiliation(s)
- Willa D Brenowitz
- National Alzheimer's Coordinating Center (NACC), Department of Epidemiology, University of Washington, Seattle, WA, USA.
| | - Fang Han
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Walter A Kukull
- National Alzheimer's Coordinating Center (NACC), Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Peter T Nelson
- Division of Neuropathology, Department of Pathology, University of Kentucky, Lexington, KY, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
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Bojar I, Stasiak M, Cyniak-Magierska A, Raczkiewicz D, Lewiński A. Cognitive Function, APOE Gene Polymorphisms, and Thyroid Status Associations in Postmenopausal Women in Poland. Dement Geriatr Cogn Disord 2018; 42:169-185. [PMID: 27649316 DOI: 10.1159/000449373] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The objective of the study was to analyze a potential association between cognitive functions and thyroid status in postmenopausal women with different polymorphisms of the apolipoprotein E gene (APOE). METHODS The examined population included 402 postmenopausal women from south-eastern Poland. The evaluation of cognitive functions was made with the use of the diagnostic Central Nervous System-Vital Signs equipment (Polish version). Multiplex polymerase chain reactions were performed to assess APOE polymorphisms. The thyroid hormone tests were assessed by an accredited laboratory. RESULTS AND CONCLUSION Lower results of cognitive functions were associated with the presence of the ε4 APOE allele in postmenopausal women. The ε4 APOE polymorphism was associated with a higher concentration of thyroid-stimulating hormone and lower concentrations of free triiodothyronine and total triiodothyronine.
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Affiliation(s)
- Iwona Bojar
- Department for Health Problems of Ageing, Institute of Rural Health, Lublin, Poland
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Low-frequency stimulation induces a durable long-term depression in young adult hyperthyroid rats: the role of p38 mitogen-activated protein kinase and protein phosphatase 1. Neuroreport 2018; 27:640-6. [PMID: 27128724 DOI: 10.1097/wnr.0000000000000589] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Long-term potentiation and long-term depression (LTD) are cellular mechanisms of learning and memory in the mammalian brain. We have previously shown that adult hyperthyroid rats showed a delay in the acquisition of a place learning task and attenuated long-term potentiation. However, changes in LTD in hyperthyroidism remain unclear. Rats were administered 0.2 mg/kg/day of L-thyroxine for 21 days starting at postnatal day 40 to induce hyperthyroidism. LTD was induced in the dentate gyrus using low-frequency stimulation (LFS) of the perforant pathway. The mRNA expressions of p38 mitogen-activated protein kinase (p38-MAPK) and protein phosphatase 1 (PP1) were evaluated using a quantitative reverse transcriptase PCR. In control rats, a standard LFS protocol induced a slight depression of the population spike (PS) amplitude during the induction phase of LTD (76±13% vs. baseline), but a small potentiation of the PS amplitude was observed in the early (107±18%) and late (111±20%) phases of LTD. Interestingly, in the hyperthyroid rats, the same LFS protocol induced a reliable LTD in the dentate gyrus of the hippocampus as evidenced by a marked depression in the PS amplitude during the induction (54±6% vs. baseline) and the early phases (56±8%) of LTD. Elevated mRNA levels of p38-MAPK and PP1 were observed in the hippocampus of the LFS-treated hyperthyroid rats compared with the hippocampus of the vehicle-treated hyperthyroid rats. No significant change in p38-MAPK or PP1 mRNA expression was observed in the euthyroid rats. The present study shows that a standard LFS protocol can induce a durable depression of synaptic strength and an upregulation of PP1 and p38-MAPK mRNA in hyperthyroid rats. We conclude that hyperthyroidism can induce molecular changes associated with degeneration of the hippocampus. The relationship between the levels of thyroid hormone and dementia requires further investigation.
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