Patients with mutations in the thyroid hormone (TH) cell transporter monocarboxylate transporter 8 ( MCT8 ) gene develop severe neuropsychomotor retardation known as Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired triiodothyronine (T3) transport in developing neural cells, as assessed through deiodinase-3–mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3 inducibility of TH-regulated genes. In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3′,5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for patients with AHDS.

N-methyl-D-aspartate receptors (NMDARs) are glutamate receptors with key roles in synaptic communication and plasticity. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs can promote cell death underlying a potential mechanism of neurodegeneration occurring in Alzheimer’s disease (AD). The distribution of synaptic versus extrasynaptic NMDARs has emerged as an important parameter contributing to neuronal dysfunction in neurodegenerative diseases including AD. Here, we review the concept of extrasynaptic NMDARs, as this population is present in numerous neuronal cell membranes but also in the membranes of various non-neuronal cells. Previous evidence regarding the membranal distribution of synaptic versus extrasynaptic NMDRs in relation to AD mice models and in the brains of AD patients will also be reviewed.

Maternal low thyroxine (T4) serum levels during the first trimester of pregnancy correlate with cerebral cortex volume and mental development of the progeny, but why neural cells during early fetal brain development are vulnerable to maternal T4 levels remains unknown. In this study, using iPSCs obtained from a boy with a loss-of-function mutation in MCT8 — a transporter previously identified as critical for thyroid hormone uptake and action in neural cells — we demonstrate that thyroid hormone induces transcriptional changes that promote the progression of human neural precursor cells along the dorsal projection trajectory. Consistent with these findings, single-cell, spatial, and bulk transcriptomics from MCT8-deficient cerebral organoids and cultures of human neural precursor cells underscored the necessity for optimal thyroid hormone levels for these cells to differentiate into neurons. The controlled intracellular activation of T4 signaling occurs through the transient expression of the enzyme type 2 deiodinase, which converts T4 into its active form, T3, alongside the coordinated expression of thyroid hormone nuclear receptors. The intracellular activation of T4 in neural precursor cells results in transcriptional changes important for their division mode and cell cycle progression. Thus, T4 is essential for fetal neurogenesis, highlighting the importance of adequate treatment for mothers with hypothyroidism.

The identification of critical factors that can worsen the mechanisms contributing to the pathophysiology of Alzheimer’s is paramount. Thyroid hormones (TH) fit this criterion. Epidemiological studies have identified an association between altered circulating TH levels and Alzheimer’s. The study of human and animal models indicates that TH can affect all the main cellular, molecular, and genetic mechanisms known as hallmarks of Alzheimer’s. This is true not only for the excessive production in the brain of protein aggregates leading to amyloid plaques and neurofibrillary tangles but also for the clearance of these molecules from the brain parenchyma via the blood-brain barrier and for the escalated process of neuroinflammation–and even for the effects of carrying Alzheimer’s-associated genetic variants. Suboptimal TH levels result in a greater accumulation of protein aggregates in the brain. The direct TH regulation of critical genes involved in amyloid beta production and clearance is remarkable, affecting the expression of multiple genes, including APP (related to amyloid beta production), APOE, LRP1, TREM2, AQP4, and ABCB1 (related to amyloid beta clearance). TH also affects microglia by increasing their migration and function and directly regulating the immunosuppressor gene CD73, impacting the immune response of these cells. Studies aiming to understand the mechanisms that could explain how changes in TH levels can contribute to the brain alterations seen in patients with Alzheimer’s are ongoing. These studies have potential implications for the management of patients with Alzheimer’s and ultimately can contribute to devising new interventions for these conditions.

Background: Alzheimer’s disease (AD) affects tens of millions of individuals and their families in the world. As AD progresses, the effectiveness of treatment declines, making a timely diagnosis crucial. One promising approach for timely diagnosis is testing biofluid biomarkers in patients’ blood and cerebrospinal fluid (CSF). However, a comprehensive evaluation of whether these tests are cost-effective is missing. Here, we conducted a systematic review to assess the cost-effectiveness of testing biofluid biomarkers to diagnose AD. Method: We searched PubMed, Embase, Cochrane Library, and Web of Science for studies published until October 2024. Studies were included if published in English, conducted an economic evaluation of CSF or blood biomarker testing to diagnose AD, and provided economic outcomes. We assessed the quality of studies using the CHEERS 2022 criteria. Results: Nine studies were included: six evaluated CSF biomarker tests and three on blood biomarker tests. All studies used model-based simulations (decision trees or Markov models) rather than trial-based evaluations. CSF biomarker tests were mostly cost-effective compared to neurocognitive assessments or neuroimaging, while blood biomarker tests showed mixed results. Key cost-effectiveness contributors included AD prevalence, diagnostic accuracy, and treatment effectiveness. Studies met ~ 80% of the CHEERS criteria, with missing information on patient engagement. Conclusion: Our review supports that biofluid biomarker testing could be cost-effective to diagnose AD. Given the lack of trial-based economic evaluations, model-based studies are a valuable starting point. Future evaluations should incorporate patient-centered outcomes and consider the emotional value and other socio-economic factors that affect patients and families suffering from AD.

SUMMARY: Maternal low thyroxine (T4) serum levels during the first trimester of pregnancy correlate with cerebral cortex volume and mental development of the progeny, but why neural cells during early fetal brain development are vulnerable to maternal T4 levels remains unknown. In this study, using iPSCs obtained from a boy with a loss-of-function mutation in MCT8—a transporter previously identified as critical for thyroid hormone uptake and action in neural cells—we demonstrate that thyroid hormones induce transcriptional changes that promote the progression of human neural precursor cells along the dorsal projection trajectory. Consistent with these findings, single-cell, spatial, and bulk transcriptomics from MCT8-deficient cerebral organoids and cultures of human neural precursor cells underscore the necessity for optimal thyroid hormone levels for these cells to differentiate into neurons. The controlled intracellular activation of T4 signaling occurs through the transient expression of the enzyme type 2 deiodinase, which converts T4 into its active form, T3, alongside the coordinated expression of thyroid hormone nuclear receptors. The intracellular activation of T4 in NPCs results in transcriptional changes important for their division mode and cell cycle progression. Thus, T4 is essential for fetal neurogenesis, highlighting the importance of adequate treatment for mothers with hypothyroidism.