Increased NLRP1 mRNA and Protein Expression Suggests Inflammasome Activation in the Dorsolateral Prefrontal and Medial Orbitofrontal Cortex in Schizophrenia.

Schizophrenia is a complex mental condition, with key symptoms marked for diagnosis including delusions, hallucinations, disorganized thinking, reduced emotional expression, and social dysfunction. In the context of major developmental hypotheses of schizophrenia, notably those concerning maternal immune activation and neuroinflammation, we studied NLRP1 expression and content in the postmortem brain tissue of 10 schizophrenia and 10 control subjects. In the medial orbitofrontal cortex (Brodmann's area 11/12) and dorsolateral prefrontal cortex (area 46) from both hemispheres of six schizophrenia subjects, the NLRP1 mRNA expression was significantly higher than in six control brains (p < 0.05). As the expression difference was highest for the medial orbitofrontal cortex in the right hemisphere, we assessed NLRP1-immunoreactive pyramidal neurons in layers III, V, and VI in the medial orbitofrontal cortex in the right hemisphere of seven schizophrenia and five control brains. Compared to controls, we quantified a significantly higher number of NLRP1-positive pyramidal neurons in the schizophrenia brains (p < 0.01), suggesting NLRP1 inflammasome activation in schizophrenia subjects. Layer III pyramidal neuron dysfunction aligns with working memory deficits, while impairments of pyramidal neurons in layers V and VI likely disrupt predictive processing. We propose NLRP1 inflammasome as a potential biomarker and therapeutic target in schizophrenia.

Role of ST6GAL1 in Thyroid Cancers: Insights from Tissue Analysis and Genomic Datasets.

Thyroid cancer is the predominant endocrine-related malignancy. ST6 ß-galactoside α2,6-sialyltransferase 1 (ST6GAL1) has been studied in various types of cancers; however, the expression and function of ST6GAL1 in thyroid cancer has not been investigated so far. Previously, we conducted two genome-wide association studies and have identified the association of the ST6GAL1 gene with plasma thyroglobulin (Tg) levels. Since Tg levels are altered in thyroid pathologies, in the current study, we wanted to evaluate the expression of ST6GAL1 in thyroid cancer tissues. We performed an immunohistochemical analysis using human thyroid tissue from 89 patients and analyzed ST6GAL1 protein expression in papillary thyroid cancer (including follicular variant and microcarcinoma) and follicular thyroid cancer in comparison to normal thyroid tissue. Additionally, ST6GAL1 mRNA levels from The Cancer Genome Atlas (TCGA, n = 572) and the Genotype-Tissue Expression (GTEx) project (n = 279) were examined. The immunohistochemical analysis revealed higher ST6GAL1 protein expression in all thyroid tumors compared to normal thyroid tissue. TCGA data revealed increased ST6GAL1 mRNA levels in both primary and metastatic tumors versus controls. Notably, the follicular variant of papillary thyroid cancer exhibited significantly higher ST6GAL1 mRNA levels than classic papillary thyroid cancer. High ST6GAL1 mRNA levels significantly correlated with lymph node metastasis status, clinical stage, and reduced survival rate. ST6GAL1 emerges as a potential cancer-associated glycosyltransferase in thyroid malignancies, offering valuable insights into its diagnostic and prognostic significance.

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a progressive degenerative illness that affects 1 in every 6 to 11,000 live births. This autosomal recessive disorder is caused by homozygous deletion or mutation of the SMN1 gene (survival motor neuron). As a backup, the SMN1 gene has the SMN2 gene, which produces only 10% of the functional SMN protein. Nusinersen and risdiplam, the first FDA-approved medications, act as SMN2 pre-mRNA splicing modifiers and enhance the quantity of SMN protein produced by this gene. The emergence of new therapies for SMA has increased the demand for good prognostic and pharmacodynamic (response) biomarkers in SMA. This article discusses current molecular diagnostic, prognostic, and pharmacodynamic biomarkers that could be assessed in SMA patients' body fluids. Although various proteomic, genetic, and epigenetic biomarkers have been explored in SMA patients, more research is needed to uncover new prognostic and pharmacodynamic biomarkers (or a combination of biomarkers).

Soluble TREM2 Concentrations in the Cerebrospinal Fluid Correlate with the Severity of Neurofibrillary Degeneration, Cognitive Impairment, and Inflammasome Activation in Alzheimer's Disease.

BACKGROUND: Individuals with specific TREM2 gene variants that encode for a Triggering Receptor Expressed on Myeloid cells 2 have a higher prevalence of Alzheimer's disease (AD). By interacting with amyloid and apolipoproteins, the TREM2 receptor regulates the number of myeloid cells, phagocytosis, and the inflammatory response. Higher TREM2 expression has been suggested to protect against AD. However, it is extremely difficult to comprehend TREM2 signaling in the context of AD. Previous results are variable and show distinct effects on diverse pathological changes in AD, differences between soluble and membrane isoform signaling, and inconsistency between animal models and humans. In addition, the relationship between TREM2 and inflammasome activation pathways is not yet entirely understood. OBJECTIVE: This study aimed to determine the relationship between soluble TREM2 (sTREM2) levels in cerebrospinal fluid (CSF) and plasma samples and other indicators of AD pathology. METHODS: Using the Enzyme-Linked Immunosorbent Assay (ELISA), we analyzed 98 samples of AD plasma, 35 samples of plasma from individuals with mild cognitive impairment (MCI), and 11 samples of plasma from healthy controls (HC), as well as 155 samples of AD CSF, 90 samples of MCI CSF, and 50 samples of HC CSF. RESULTS: CSF sTREM2 levels were significantly correlated with neurofibrillary degeneration, cognitive decline, and inflammasome activity in AD patients. In contrast to plasma sTREM2, CSF sTREM2 levels in the AD group were higher than those in the MCI and HC groups. Moreover, concentrations of sTREM2 in CSF were substantially higher in the MCI group than in the HC group, indicating that CSF sTREM2 levels could be used not only to distinguish between HC and AD patients but also as a biomarker to detect earlier changes in the MCI stage. CONCLUSIONS: The results indicate CSF sTREM2 levels reliably predict neurofibrillary degeneration, cognitive decline, and inflammasome activation, and also have a high diagnostic potential for distinguishing diseased from healthy individuals. To add sTREM2 to the list of required AD biomarkers, future studies will need to include a larger number of patients and utilize a standardized methodology.

Thyroid Function and Metabolic Syndrome: A Two-Sample Bidirectional Mendelian Randomization Study.

CONTEXT: Thyroid function has been associated with metabolic syndrome (MetS) in a number of observational studies but the direction of effects and the exact causal mechanism of this relationship is still unknown. OBJECTIVE: To examine genetically predicted effects of thyroid function on MetS risk and its components, and vice versa, using large-scale summary genetic association data. METHODS: We performed a two-sample bidirectional Mendelian randomization (MR) study using summary statistics from the most comprehensive genome-wide association studies (GWAS) of thyroid-stimulating hormone (TSH, n = 119 715), free thyroxine (fT4, n = 49 269), MetS (n = 291 107), and components of MetS: waist circumference (n = 462 166), fasting blood glucose (n = 281 416), hypertension (n = 463 010), triglycerides (TG, n = 441 016) and high-density lipoprotein cholesterol (HDL-C, n = 403 943). We chose the multiplicative random effects inverse variance weighted (IVW) method as the main analysis. Sensitivity analysis included weighted median and mode analysis, as well as MR-Egger and Causal Analysis Using Summary Effect estimates (CAUSE). RESULTS: Our results suggest that higher fT4 levels lower the risk of developing MetS (OR = 0.96, P = .037). Genetically predicted fT4 was also positively associated with HDL-C (ß = 0.02, P = .008), while genetically predicted TSH was positively associated with TG (ß = 0.01, P = .044). These effects were consistent across different MR analyses and confirmed with the CAUSE analysis. In the reverse direction MR analysis, genetically predicted HDL-C was negatively associated with TSH (ß = -0.03, P = .046) in the main IVW analysis. CONCLUSION: Our study suggests that variations in normal-range thyroid function are causally associated with the diagnosis of MetS and with lipid profile, while in the reverse direction, HDL-C has a plausible causal effect on reference-range TSH levels.

Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model.

The tauopathy of Alzheimer's disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human MAPT (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3-4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correlate with presumed cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at 3 days and 4, 8, and 11 months post-injection using antibodies AT8 and MC1, which reveal early phosphorylation and aberrant conformation of tau, respectively, HT7, anti-synaptophysin, and the Gallyas silver staining method. Human tau oligomers and tau fibrils exhibited some similarities and some differences in their ability to seed and propagate tau-related changes. Both human tau fibrils and tau oligomers rapidly propagated from the mEC anterogradely into the hippocampus and various parts of the neocortex. However, using a human tau-specific HT7 antibody, 3 days post-injection we found inoculated human tau oligomers in the red nucleus, primary motor, and primary somatosensory cortex, a finding not seen in animals inoculated with human tau fibrils. In animals inoculated with human tau fibrils, 3 days post-injection the HT7 antibody showed fibrils in the pontine reticular nucleus, a finding explained only by uptake of human tau fibrils by incoming presynaptic fibers to the mEC and retrograde transport of inoculated human tau fibrils to the brainstem. Rats inoculated with human tau fibrils showed as early as 4 months after inoculation a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain, dramatically faster propagation of neurofibrillary changes than with human tau oligomers. The overall severity of tau protein changes 4, 8, and 11 months after inoculation of human tau oligomers and tau fibrils correlated well with spatial working memory and cognition impairments, as measured by the T-maze spontaneous alternation, novel object recognition, and object location tests. We concluded that this non-trangenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons, synapses, and identifiable pathways together with cognitive and behavioral changes, through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising model for future experimental studies of primary and secondary tauopathies, especially AD.

Metals in Alzheimer's Disease.

The role of metals in the pathogenesis of Alzheimer's disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies that (1) compared the metal concentrations between AD patients and healthy controls, (2) correlated concentrations of AD cerebrospinal fluid (CSF) biomarkers with metal concentrations, and (3) used Mendelian randomization (MR) to assess the potential metal contributions to AD risk. Although many studies have examined various metals in dementia patients, understanding the dynamics of metals in these patients remains difficult due to considerable inconsistencies among the results of individual studies. The most consistent findings were for Zn and Cu, with most studies observing a decrease in Zn levels and an increase in Cu levels in AD patients. However, several studies found no such relation. Because few studies have compared metal levels with biomarker levels in the CSF of AD patients, more research of this type is required. Given that MR is revolutionizing epidemiologic research, additional MR studies that include participants from diverse ethnic backgrounds to assess the causal relationship between metals and AD risk are critical.

Vitamin D and the Thyroid: A Critical Review of the Current Evidence.

Vitamin D is necessary for the normal functioning of many organs, including the thyroid gland. It is, therefore, not surprising that vitamin D deficiency is considered a risk factor for the development of many thyroid disorders, including autoimmune thyroid diseases and thyroid cancer. However, the interaction between vitamin D and thyroid function is still not fully understood. This review discusses studies involving human subjects that (1) compared vitamin D status (primarily determined by serum calcidiol (25-hydroxyvitamin D [25(OH)D]) levels) with thyroid function assessed by thyroid stimulating hormone (TSH), thyroid hormones, and anti-thyroid antibody levels; and (2) evaluated the effect of vitamin D supplementation on thyroid function. Due to the many inconsistencies in the results between the studies, it is still difficult to draw a definite conclusion on how vitamin D status affects thyroid function. Studies in healthy participants observed either a negative correlation or no association between TSH and 25(OH)D levels, while the results for thyroid hormones showed high variability. Many studies have observed a negative association between anti-thyroid antibodies and 25(OH)D levels, but equally many studies have failed to observe such an association. Regarding the studies that examined the effect of vitamin D supplementation on thyroid function, almost all observed a decrease in anti-thyroid antibody levels after vitamin D supplementation. Factors that could contribute to the high variability between the studies are the use of different assays for the measurement of serum 25(OH)D levels and the confounding effects of sex, age, body-mass index, dietary habits, smoking, and the time of year when the samples were collected. In conclusion, additional studies with larger numbers of participants are needed to fully understand the effect of vitamin D on thyroid function.

Serotonin Receptor Gene Polymorphisms Are Associated with Cerebrospinal Fluid, Genetic, and Neuropsychological Biomarkers of Alzheimer's Disease.

A decrease in serotonergic transmission throughout the brain is among the earliest pathological changes in Alzheimer's disease (AD). Serotonergic receptors are also affected in AD. Polymorphisms in genes of serotonin (5HT) receptors have been mostly associated with behavioral and psychological symptoms of dementia (BPSD). In this study, we examined if AD patients carrying different genotypes in 5HTR1B rs13212041, 5HTR2A rs6313 (T102C), 5HTR2C rs3813929 (-759C/T), and 5HTR6 rs1805054 (C267T) polymorphisms have a higher risk of faster disease progression (assessed by neuropsychological testing), are more prone to develop AD-related pathology (reflected by levels of cerebrospinal fluid [CSF] AD biomarkers), or have an association with an apolipoprotein E (APOE) haplotype. This study included 115 patients with AD, 53 patients with mild cognitive impairment (MCI), and 2701 healthy controls. AD biomarkers were determined in the CSF of AD and MCI patients using enzyme-linked immunosorbent assays (ELISA), while polymorphisms were determined using either TaqMan SNP Genotyping Assays or Illumina genotyping platforms. We detected a significant decrease in the CSF amyloid ß1-42 (Aß1-42) and an increase in p-tau181/Aß1-42 ratio in carriers of the T allele in the 5HTR2C rs3813929 (-759C/T) polymorphism. A significantly higher number of APOE ε4 allele carriers was observed among individuals carrying a TT genotype within the 5HTR2A T102C polymorphism, a C allele within the 5HTR1B rs13212041 polymorphism, and a T allele within the 5HTR6 rs1805054 (C267T) polymorphism. Additionally, individuals carrying the C allele within the 5HTR1B rs13212041 polymorphism were significantly more represented among AD patients and had poorer performances on the Rey-Osterrieth test. Carriers of the T allele within the 5HTR6 rs1805054 had poorer performances on the MMSE and ADAS-Cog. As all four analyzed polymorphisms of serotonin receptor genes showed an association with either genetic, CSF, or neuropsychological biomarkers of AD, they deserve further investigation as potential early genetic biomarkers of AD.

Association between Thyroid Function and Ocular Parameters.

During development, thyroid hormones play an important role in eye development, while in adults, some pathological thyroid conditions can affect the normal functioning of the eyes. Thyroid eye disease is the most well-known eye pathology caused by a pathological thyroid condition. Few studies have investigated the association between ocular parameters and thyroid function. Thus, in this study, we aimed to examine whether thyroid activity affects ocular parameters. This cross-sectional study included 4633 healthy adults recruited within the 10,001 Dalmatians project of the Croatian Biobank. The plasma levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), thyroglobulin (Tg), thyroglobulin antibodies (TgAb), and thyroid peroxidase antibodies (TPOAb) were measured by an immunoassay. We determined 20 ocular parameters for each participant (10 for each eye, including corneal radius, corneal thickness, anterior chamber depth, anterior chamber angle, lens thickness, posterior chamber length, axial length, intraocular lens power (IOL), spherical power, and cylinder power). Patients with hyperthyroidism had thicker corneas compared to euthyroid individuals. Corneal thickness was also negatively associated with plasma TSH levels. Intra-ocular lens power was higher in patients with clinical hypothyroidism, while spherical power was higher in euthyroid individuals with positive antibodies compared to euthyroid individuals. Intra-ocular lens power negatively correlated with fT4 levels, while spherical power positively correlated with TgAb, TPOAb, and Tg levels and negatively correlated with TSH levels. The anterior chamber angle was positively associated with plasma TSH levels and TPOAb levels and negatively associated with plasma fT4 levels. These findings suggest an interesting interplay between ophthalmic measures and thyroid status, detectable even in the general adult population.

Thyroid Hormones Are Not Associated with Plasma Osteocalcin Levels in Adult Population with Normal Thyroid Function.

Thyroid hormones (THs) play an indispensable role in skeletal development and bone remodeling. Some studies have reported associations of THs with serum osteocalcin (OC) levels, but the results are quite inconsistent and the molecular mechanism of their simultaneous or interdependent activity on bone is almost unknown. Therefore, the aim of this study was to determine the possible associations of plasma THs with plasma OC levels and the possible mediating effect of OC on the relationship between THs and bone mineral density (BMD). For this purpose, out of the initial 1981 participants, we selected healthy euthyroid participants controlled for available confounding factors that can affect thyroid function and bone metabolism (N = 694). Given our results, we could not confirm any associations of THs with plasma OC levels nor the mediating effect of OC on the relationship between THs and BMD in euthyroid population. In the group of women controlled for menopause status (N = 396), we found a significant negative association of body mass index (BMI) with OC levels (ß = −0.14, p = 0.03). We also found a negative association of free triiodothyronine (fT3) (ß = −0.01, p = 0.02) and age (ß = −0.003, p < 0.001) with BMD, and a positive association of BMI (ß = 0.004, p < 0.001) and male gender (ß = 0.1, p < 0.001) with BMD. In addition, we found significantly higher plasma OC levels and lower values of BMD in postmenopausal euthyroid women compared with premenopausal euthyroid women. In our opinion, the results of previous studies suggesting an association between circulating THs and serum OC levels may be influenced by an inconsistent selection of participants and the influence of confounding factors.

Epidemiology of Hypothyroidism, Hyperthyroidism and Positive Thyroid Antibodies in the Croatian Population.

Thyroid dysfunction appears to be the leading endocrine disorder. We conducted a cross-sectional study on 4402 individuals from three Croatian cohorts. The aim of this study was to analyse the prevalence of diagnosed and undiagnosed hypothyroidism, hyperthyroidism (subclinical and clinical) and positive thyroid antibodies in the Croatian population. The results of the study indicated that 17.6% of participants were euthyroid with positive antibodies. The prevalence of clinical and subclinical hypothyroidism was 3% and 7.4%, respectively, while the prevalence of clinical and subclinical hyperthyroidism was 0.2% and 1.1%, respectively. Among them, 92.6% subclinical hypothyroid, 93.9% clinical hypothyroid, 83% subclinical hyperthyroid and 71.4% clinical hyperthyroid participants were undiagnosed. Finally, the prevalence of undiagnosed subclinical and clinical hypothyroidism in our population was 6.9% and 2.8%, respectively, while the prevalence of undiagnosed subclinical and clinical hyperthyroidism was 0.9% and 0.1%, respectively. Women showed a higher prevalence of thyroid disorders; 1.57 times higher odds of euthyroidism with positive antibodies, 2.1 times higher odds of subclinical hyperthyroidism, 2.37 times higher odds of clinical hypothyroidism and 1.58 times higher odds of subclinical hypothyroidism than men. These results indicate an extremely high proportion of undiagnosed cases, and therefore require investments in a prevention programme.

Genome-Wide Association Analysis and Genomic Prediction of Thyroglobulin Plasma Levels.

Thyroglobulin (Tg) is an iodoglycoprotein produced by thyroid follicular cells which acts as an essential substrate for thyroid hormone synthesis. To date, only one genome-wide association study (GWAS) of plasma Tg levels has been performed by our research group. Utilizing recent advancements in computation and modeling, we apply a Bayesian approach to the probabilistic inference of the genetic architecture of Tg. We fitted a Bayesian sparse linear mixed model (BSLMM) and a frequentist linear mixed model (LMM) of 7,289,083 variants in 1096 healthy European-ancestry participants of the Croatian Biobank. Meta-analysis with two independent cohorts (total n = 2109) identified 83 genome-wide significant single nucleotide polymorphisms (SNPs) within the ST6GAL1 gene (p<5×10-8). BSLMM revealed additional association signals on chromosomes 1, 8, 10, and 14. For ST6GAL1 and the newly uncovered genes, we provide physiological and pathophysiological explanations of how their expression could be associated with variations in plasma Tg levels. We found that the SNP-heritability of Tg is 17% and that 52% of this variation is due to a small number of 16 variants that have a major effect on Tg levels. Our results suggest that the genetic architecture of plasma Tg is not polygenic, but influenced by a few genes with major effects.

Heavy Metals and Essential Metals Are Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease.

Various metals have been associated with the pathogenesis of Alzheimer's disease (AD), principally heavy metals that are environmental pollutants (such as As, Cd, Hg, and Pb) and essential metals whose homeostasis is disturbed in AD (such as Cu, Fe, and Zn). Although there is evidence of the involvement of these metals in AD, further research is needed on their mechanisms of toxicity. To further assess the involvement of heavy and essential metals in AD pathogenesis, we compared cerebrospinal fluid (CSF) AD biomarkers to macro- and microelements measured in CSF and plasma. We tested if macro- and microelements' concentrations (heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Na, Mg, K, Ca, Fe, Co, Mn, Cu, Zn, and Mo), essential non-metals (B, P, S, and Se), and other non-essential metals (Al, Ba, Li, and Sr)) are associated with CSF AD biomarkers that reflect pathological changes in the AD brain (amyloid ß1-42, total tau, phosphorylated tau isoforms, NFL, S100B, VILIP-1, YKL-40, PAPP-A, and albumin). We used inductively coupled plasma mass spectroscopy (ICP-MS) to determine macro- and microelements in CSF and plasma, and enzyme-linked immunosorbent assays (ELISA) to determine protein biomarkers of AD in CSF. This study included 193 participants (124 with AD, 50 with mild cognitive impairment, and 19 healthy controls). Simple correlation, as well as machine learning algorithms (redescription mining and principal component analysis (PCA)), demonstrated that levels of heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Ca, Co, Cu, Fe, Mg, Mn, Mo, Na, K, and Zn), and essential non-metals (P, S, and Se) are positively associated with CSF phosphorylated tau isoforms, VILIP-1, S100B, NFL, and YKL-40 in AD.

Association of the MAOB rs1799836 Single Nucleotide Polymorphism and APOE ε4 Allele in Alzheimer's Disease.

BACKGROUND: The dopaminergic system is functionally compromised in Alzheimer's Disease (AD). The activity of Monoamine Oxidase B (MAOB), the enzyme involved in the degradation of dopamine, is increased during AD. Also, increased expression of MAOB occurs in the postmortem hippocampus and neocortex of patients with AD. The MAOB rs1799836 polymorphism modulates MAOB transcription, consequently influencing protein translation and MAOB activity. We recently showed that cerebrospinal fluid levels of amyloid ß1-42 are decreased in patients carrying the A allele in MAOB rs1799836 polymorphism. OBJECTIVE: The present study compares MAOB rs1799836 polymorphism and APOE, the only confirmed genetic risk factor for sporadic AD. METHODS: We included 253 participants, 127 of whom had AD, 57 had mild cognitive impairment, 11 were healthy controls, and 58 suffered from other primary causes of dementia. MAOB and APOE polymorphisms were determined using TaqMan SNP Genotyping Assays. RESULTS: We observed that the frequency of APOE ε4/ε4 homozygotes and APOE ε4 carriers is significantly increased among patients carrying the AA MAOB rs1799836 genotype. CONCLUSION: These results indicate that the MAOB rs1799836 polymorphism is a potential genetic biomarker of AD and a potential target for the treatment of decreased dopaminergic transmission and cognitive deterioration in AD.

Environmental Factors Affecting Thyroid-Stimulating Hormone and Thyroid Hormone Levels.

Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that alters the levels of thyroid-stimulating hormone (TSH) and thyroid hormones is crucial. Genetic factors contribute up to 65% of interindividual variations in TSH and thyroid hormone levels, but many environmental factors can also affect thyroid function. This review discusses studies that have analyzed the impact of environmental factors on TSH and thyroid hormone levels in healthy adults. We included lifestyle factors (smoking, alcohol consumption, diet and exercise) and pollutants (chemicals and heavy metals). Many inconsistencies in the results have been observed between studies, making it difficult to draw a general conclusion about how a particular environmental factor influences TSH and thyroid hormone levels. However, lifestyle factors that showed the clearest association with TSH and thyroid hormones were smoking, body mass index (BMI) and iodine (micronutrient taken from the diet). Smoking mainly led to a decrease in TSH levels and an increase in triiodothyronine (T3) and thyroxine (T4) levels, while BMI levels were positively correlated with TSH and free T3 levels. Excess iodine led to an increase in TSH levels and a decrease in thyroid hormone levels. Among the pollutants analyzed, most studies observed a decrease in thyroid hormone levels after exposure to perchlorate. Future studies should continue to analyze the impact of environmental factors on thyroid function as they could contribute to understanding the complex background of gene-environment interactions underlying the pathology of thyroid diseases.

The Association of Essential Metals with APOE Genotype in Alzheimer's Disease.

BACKGROUND: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer's disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. OBJECTIVE: To test the association of essential metals with APOE genotype. METHODS: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. RESULTS: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. CONCLUSION: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

Alterations and interactions of subcortical modulatory systems in Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) is not fully understood. Here we summarize current knowledge on the involvement of the serotonergic, noradrenergic, dopaminergic, cholinergic, and opioid systems in AD, emphasizing the importance of interactions between the serotonergic and the other subcortical modulatory systems during the progression of AD. In physiological conditions, all neurotransmitter systems function in concert and are interdependent at both the neuroanatomical and molecular levels. Through their early involvement in AD, cognitive and behavioral abilities that rely on their interactions also become disrupted. Considering that serotonin (5HT) regulates the release of noradrenaline (NA), dopamine (DA) and acetylcholine (ACh), any alteration in 5HT levels leads to disturbance of NA, DA, and ACh homeostasis in the brain. One of the earliest pathological changes during the prodromal phase of AD is a decrease of serotonergic transmission throughout the brain, with serotonergic receptors being also affected. Additionally, serotonergic and noradrenergic as well as serotonergic and dopaminergic nuclei are reciprocally interconnected. As the serotonergic dorsal raphe nucleus (DRN) is affected by pathological changes early in AD, and the noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental area (VTA) exhibit AD-related pathological changes, their connectivity also becomes altered in AD. Such disrupted interactions among neurotransmitter systems in AD can be used in the development of multi-target drugs. Some of the potential AD therapeutics (such as ASS234, RS67333, tropisetron) target multiple neurotransmitter systems to achieve the best possible improvement of cognitive and behavioral deficits observed in AD. Here, we review how serotonergic system interacts with other subcortical modulatory systems (noradrenergic, dopaminergic, cholinergic, and opioid systems) during AD.

Environmental Factors That Affect Parathyroid Hormone and Calcitonin Levels.

Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate homeostasis in the body. Therefore, an understanding of environmental and genetic factors influencing PTH and calcitonin levels is crucial. Genetic factors are estimated to account for 60% of variations in PTH levels, while the genetic background of interindividual calcitonin variations has not yet been studied. In this review, we analyzed the literature discussing the influence of environmental factors (lifestyle factors and pollutants) on PTH and calcitonin levels. Among lifestyle factors, smoking, body mass index (BMI), diet, alcohol, and exercise were analyzed; among pollutants, heavy metals and chemicals were analyzed. Lifestyle factors that showed the clearest association with PTH levels were smoking, BMI, exercise, and micronutrients taken from the diet (vitamin D and calcium). Smoking, vitamin D, and calcium intake led to a decrease in PTH levels, while higher BMI and exercise led to an increase in PTH levels. In terms of pollutants, exposure to cadmium led to a decrease in PTH levels, while exposure to lead increased PTH levels. Several studies have investigated the effect of chemicals on PTH levels in humans. Compared to PTH studies, a smaller number of studies analyzed the influence of environmental factors on calcitonin levels, which gives great variability in results. Only a few studies have analyzed the influence of pollutants on calcitonin levels in humans. The lifestyle factor with the clearest relationship with calcitonin was smoking (smokers had increased calcitonin levels). Given the importance of PTH and calcitonin in maintaining calcium and phosphate homeostasis and bone mineral metabolism, additional studies on the influence of environmental factors that could affect PTH and calcitonin levels are crucial.