methimazole and Cognition-Disorders

Serum thyroid stimulating hormone (TSH) levels increase with age. This elevation has been associated with better outcomes in very elderly subjects; however, little is known about the relationship between TSH below the lower limit of the reference range and health-related outcomes. Here, we investigated the association between cognitive impairment or depressive symptoms and low-normal serum TSH (<1.0 μIU/mL, in the reference range) in elderly subjects and whether the use of methimazole in subjects without dementia but with low-normal TSH could affect cognition or depressive symptoms. From 293 healthy adults ≥65 years old with normal TSH included in the sectional phase, only subjects without dementia were prospectively analyzed: 1) TSH ≥1.0 μIU/mL (observation; untreated); 2) TSH <1.0 μIU/mL (observation; untreated); and 3) TSH <1.0 μIU/mL (methimazole therapy). Cognition was assessed, using the Mini Mental State Examination (MMSE) and depressive symptoms (at MMSE ≥ 13) by the Geriatric Depression Scale (GDS). Age >80 years was the sole independent factor associated with dementia (OR=2.89; confidence interval [CI] 1.72-4.86; p<0.01). Prospectively, 93 completed follow-up, with 7.5% (7) receiving methimazole intervention. Untreated subjects with lower TSH showed the greatest declines in MMSE scores during follow-up that was not observed in those with serum TSH ≥1.0 μIU/mL. Lower MMSE score reductions were associated with elderly subjects receiving methimazole. There were no significant changes in depressive symptoms and GDS scores among those with serum TSH <1.0 μIU/mL. In this study, low-normal TSH was not associated with higher prevalence of dementia. However, in elderly subjects without dementia, low TSH was associated with worsening cognition.

Topics: Aged; Aged, 80 and over; Aging; Cognition; Cognition Disorders; Cross-Sectional Studies; Depression; Female; Geriatric Assessment; Humans; Longitudinal Studies; Male; Methimazole; Pilot Projects; Reference Values; Thyroid Function Tests; Thyrotropin

Methimazole (MMI) is a first-line therapy used to manage hyperthyroidism and Graves' disease. Despite its therapeutic benefit, chronic MMI administration can lead to hypothyroidism and perturb brain homeostasis in patients, resulting in neuropsychiatric disorders such as depression and cognitive dysfunction. We recently developed the spiroimidazopyridine derivative SAK3 as cognitive enhancer; however, mechanisms underlying its activity remained unclear. Here, we show that SAK3 potentially improves cognitive impairment seen following MMI-induced hypothyroidism. Twenty-four hours after MMI (75 mg/kg, i.p.) treatment, we administered SAK3 (0.1, 0.5 and 1 mg/kg, p.o.) to mice daily for 7 days. MMI treatment alone disrupted olfactory bulb (OB) glomerular structure, as assessed by staining with the olfactory marker protein (OMP), reduced the number of choline acetyl transferase (ChAT)-immunoreactive neurons in medial septum (MS), and significantly impaired cognition. SAK3 (0.5 and 1 mg/kg, p.o.) administration significantly restored the number of cholinergic MS neurons in MMI-treated mice, and SAK3 treatment at a higher dose significantly improved cognitive deficits seen in MMI-treated control mice. Overall, our study suggests that SAK3 treatment could antagonize such impairment in patients with hypothyroidism.

Topics: Animals; Cognition Disorders; Dose-Response Relationship, Drug; Female; Hypothyroidism; Imidazoles; Maze Learning; Methimazole; Mice; Pyridines; Random Allocation; Spiro Compounds

Neurological deficits in the offspring caused by human maternal hypothyroxinemia are thought to be irreversible. To understand the mechanism responsible for these neurological alterations, we induced maternal hypothyroxinemia in pregnant rats. Behavior and synapse function were evaluated in the offspring of thyroid hormone-deficient rats. Our data indicate that, when compared with controls, hypothyroxinemic mothers bear litters that, in adulthood, show prolonged latencies during the learning process in the water maze test. Impaired learning capacity caused by hypothyroxinemia was consistent with cellular and molecular alterations, including: 1) lack of increase of phosphorylated c-fos on the second day of the water maze test; 2) impaired induction of long-term potentiation in response to theta-burst stimulation to the Schaffer collateral pathway in the area 1 of the hippocampus Ammon's horn stratum radiatum, despite normal responses for input/output experiments; 3) increase of postsynaptic density protein 95 (PSD-95), N-methyl-D-aspartic acid receptor subunit 1, and tyrosine receptor kinase B levels in brain extracts; and 4) significant increase of PSD-95 at the PSDs and failure of this molecule to colocalize with N-methyl-D-aspartic acid receptor subunit 1, as it was shown by control rats. Our findings suggest that maternal hypothyroxinemia is a harmful condition for the offspring that can affect key molecular components for synaptic function and spatial learning.

Topics: Age Factors; Animals; Cognition Disorders; Disks Large Homolog 4 Protein; Female; Hypothyroidism; Imidazoles; Intracellular Signaling Peptides and Proteins; Long-Term Potentiation; Male; Maze Learning; Membrane Proteins; Phosphorylation; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Space Perception; Synapses; Thyroxine