Epidemiological profile of myasthenia gravis in South Korea using the national health insurance database.

OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigue. Our objective was to investigate the incidence of MG using the National Health Insurance database of South Korea. MATERIALS AND METHODS: We conducted a retrospective cohort analysis of patients with the G70.0 code designated as MG and administered with MG medications for >3 months from 2007 to 2018 using nationwide data from South Korea. RESULTS: A total of 8,376 patients with MG during the period of 2010-2018 were identified. There were 3,862 (46.1%) male and 4,517 (53.9%) female patients. The standardized incidence rate was 1.18/100,000 in 2010, and increased to 1.81/100,000 in 2018. The standardized prevalence was 7.50/100,000 in 2010, and changed to 11.15/100,000 in 2018. Pyridostigmine was used to treat 82.3 ± 1.2% of patients with MG during 2010-2018. Among MG patients, 85.7 ± 0.9% used steroids, 31.6 ± 4.8% used azathioprine, 12.9 ± 9.5% used tacrolimus, 7.2 ± 2.1% used cyclosporine, 6.2 ± 1.8% used mycophenolate mofetil, and 0.4 ± 0.1% used methotrexate. Thymectomy was performed in 1,130 MG patients, and the time from MG diagnosis to thymectomy decreased from 2010 to 2018. CONCLUSION: Based on the national registry data from 2010 to 2018, the incidence and prevalence rate in South Korea has increased. Whereas the use of IVIG has remained stable, thymectomy is performed earlier than before, and the distribution of immunosuppressant therapies has changed over the years with an increase in tacrolimus and mycophenolate mofetil. We expect that this study will serve as a basis for future South Korean MG epidemiological studies.

Cytoreductive Pleurectomy and Intrathoracic Chemohyperthermia for Pleural Relapse of Thymomas.

Several surgical procedures, from debulking to extrapleural pneumonectomy, may be applied for stage IVa Masaoka thymomas, but their efficiency is still controversial. Case studies have favored R0 resection as the cornerstone of multimodal therapy for locoregional metastatic extension. This report describes a standardized procedure combining a cytoreductive surgical procedure and intrathoracic chemohyperthermia on a 46-year-old patient presenting with B2 thymoma and synchronous unilateral pleural metastasis.

Is thymomectomy equivalent to complete thymectomy in non-myasthenic patients with early-stage thymoma?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed is whether thymomectomy can be equivalent to thymectomy for non-myasthenic early-stage thymoma in terms of recurrence and survival. Ten papers were chosen to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. All studies included in this analysis are retrospective; most of them are small and from single-institution experiences, and only 3 used propensity-matched analysis to minimize the patients' selection bias. The choice of performing thymectomy or thymomectomy was based on surgeons' preference rather than on a standardized surgical approach. Most papers found that thymectomy was equivalent to thymomectomy in terms of outcomes, but these results could be affected by the intergroup differences in terms of follow-up length, administration of induction or adjuvant therapy, histological subtypes distribution and tumour size. Conversely, the studies of the Japanese Association for Research on the Thymus and the Chinese Alliance for Research in Thymoma found a higher rate of local recurrence in the thymomectomy group than in the thymectomy group. The National Comprehensive Cancer Network, National Cancer Institute and International Thymic Malignancy Interest Group recommend complete thymectomy in non-myasthenic patients with early thymoma; therefore, the identified studies in this review are not strong enough to change this recommendation.

The Effect of Immunonutrition on the Postoperative Complications in Thymoma with Myasthenia Gravis.

Object. To test whether preoperative immunonutrition is efficacious in reducing postoperative complications in patients of thymoma with myasthenia gravis (MG). Material and Methods. A total of 244 patients operated on for thymoma with myasthenia gravis were prospectively assigned to two groups, each receiving seven-day preoperative and seven-day postoperative nutrition. The patients in immunonutrition group were given oral immunonutrition (IN). The patients in control group received oral standard nutrition. Immunonutritional and inflammatory biomarkers (IgA, IgG, IgM, CD3t, CD4t, CD8t, CD4t/CD8t ratio, NK-cell, prealbumin, albumin, white blood cells counts, and C-reactive protein) and clinical variables (age, gender, BMI, performance status, type of thymoma, type of MG, operative time, pathology, operative approach, postoperative complications, quantity of drainage, hospital stays) were examined. Results. A significant reduction in the length of hospital stay, quantity of drainage, and postoperative complications was observed in the IN group (p < 0.05). An increase in the level of IgA, IgG, IgM, CD3+T, CD4+T, CD4+T/CD8+T, WBC, CRP, and NK-cell in the IN group was observed after thymectomy, while a decrease was seen with regard to prealbumin and albumin (p < 0.05). Conclusion. Preoperative immunonutrition support is effective in reducing postoperative complications in patients of thymoma with MG. It helps to lower the risk of postoperative infectious complications and hospital stays.

Thymic uptake after high-dose I-131 treatment in patients with differentiated thyroid carcinoma: a brief review of possible causes and management.

PURPOSE: To report five cases of patients diagnosed with differentiated thyroid carcinoma (DTC) with uptake in the thymic area after high-dose treatment with I-131 and to evaluate the potential causes and therapeutic management. METHODS: Five cases of young female patients with a mean age of 36.6 years (24-43) who had been treated with a mean dose of 106 mCi of I-131 (100-150 mCi) showing tracer uptake in the thymic area are reported. An I-131 whole-body scan (131I-WBS) was performed 7 days after therapeutic dose administration to each patient. Anterior and posterior planar images, followed by SPECT/CT of the head, neck and superior mediastinum were acquired in all patients. Thyroglobulin levels were measured with and without hormone replacement therapy in all cases. Samples taken from the superior mediastinum were sent to pathology for analysis, which confirmed the presence of thymic tissue. RESULTS: Two patients underwent elective total thymectomy due to the gross characteristics of the gland, local 131-I uptake, and high thyroglobulin levels. The remaining three patients had already undergone thymectomy as part of neck dissection during initial surgery, and no further invasive interventions were therefore performed. Pathological examination revealed no metastases in these five patients. CONCLUSIONS: Thymus visualization in young patients after administration of therapeutic doses of I-131 seems to be a more common finding than usually thought. Absence of metastasis in the thymus despite high thyroglobulin levels was confirmed in all cases. Based on these results, we suggest that a more expectant and less aggressive therapeutic approach could be used. We also suggest that I-131 therapy for DTC should be considered in classification of the potential causes of true thymic hyperplasia in the subgroup of patients recovering from a stressor.

Introducing corticosteroids therapy from 1969 to 1990 at the Centre/Institute for Neuromuscular Diseases, KBC Rebro, Zagreb, Croatia.

The author presents the chronological development of therapy by corticosteroids in myasthenia gravis (MG), as well as dilemmas connected to this kind of treatment at the Centre/Institute Zagreb, she founded. The improvement of postoperative prognosis of thymectomy with corticosteroids is described and transfer of positive experiences to other neurological diseases. The side effects can be reduced significantly by respecting the basic rules: the choice of corticosteroids (fluocortolone, methyprednisolone, no dexamethasone), single dose administered in the morning, not later than 8 a.m. (respecting the circadian rhythm of concentration of cortisol in blood). Initially, the high dose is administered daily, until the stabilisation of signs and symptoms improvement. Then, in my early modification, the initial dose, administered every other day, becames gradually lowered. The diet is similar to diabetic, with the potassium added. In the period from 1973 to 1990, 212 myasthenia gravis and 37 polymyositis patients were treated that way.We recommend to continue endocrinological research, on which we already reported, now with contemporary methods. The value of the "pulse therapy" should be analysed in more details, with peroral corticosteroids added afterwards.

[Extended thymectomy and intraoperative-intrapleural perfusion hyperthermo-chemotherapy for stage IVa invasive thymoma with myasthenia gravis].

A 37-year-old woman diagnosed with ocular myasthenia gravis was referred to our department. Chest computed tomography (CT) showed anterior mediastinal tumor and right pleural dissemination. Extended thymectomy and right intraoperative-intrapleural perfusion hyperthermo-chemothrapy (IPHC) were performed. Pathological diagnosis was invasive thymoma type B2 and stage IVa based on Masaoka's classification. The post operative course was uneventful. The patient underwent 4 cycles of adjuvant chemotherapy with doxorubicin, cisplatin, vincristine, and cyclophosphamide (ADOC), and is free from recurrence at 12 months postoperatively.

[Successful treatment with rituximab in a patient with primary thymic MALT lymphoma complicated with acquired von Willebrand syndrome and Sjögren syndrome].

A 53-year-old female developed epigastric discomfort and back pain in 2007. Diagnostic imaging studies demonstrated a soft tissue tumor with heterogeneous enhancement in the anterior mediastinum and multiple nodules in the right lung. She underwent expanded thymectomy with subtotal resection of the right lung. The pathological diagnosis was primary thymic mucosa-associated lymphoid tissue (MALT) lymphoma. The patient complained of ocular discomfort, oral dryness and continuous nasal bleeding in 2007. Detailed examination led to a diagnosis of Sjögren syndrome and acquired von Willebrand syndrome. Rituximab treatment for residual disease achieved not only a reduction of the lung MALT lymphoma but also clinical and hematological remission of both syndromes. This is, to our knowledge, the first reported case of primary thymic MALT lymphoma accompanied by Sjögren and acquired von Willebrand syndromes.

Induction chemotherapy, cytoreductive surgery and intraoperative hyperthermic pleural irrigation in patients with stage IVA thymoma.

The optimal treatment for Masaoka stage IVA thymoma remains controversial. Whilst extrapleural pneumonectomy (EPP) has been proposed, we sought to examine the results of our institutional preference for induction chemotherapy, cytoreductive surgery and intraoperative hyperthermic pleural irrigation. We undertook a retrospective study of patients undergoing surgery for Masaoka stage IVA thymoma following induction chemotherapy over a three-year period at our institution. Between February 2007 and February 2010, 42 patients underwent surgery for thymoma. Six patients underwent surgery with intent to perform cytoreductive surgery and intraoperative hyperthermic pleural irrigation. Complete cytoreductive surgery was not feasible in one patient and thymectomy only was performed. One patient had re-operation for recurrent disease 24 months after the first operation and there were therefore seven procedures undertaken in six patients during the study period. There were no in-hospital deaths. Median follow-up was 18.8 months (range 1.5-31.9 months). One patient died 14 months postoperatively from an acute cardiovascular event. The four remaining patients are alive and well with no evidence of disease recurrence. Multimodality therapy consisting of induction chemotherapy and cytoreductive surgery is a safe, feasible treatment for stage IVA thymoma. Our experience suggest that full pleurectomy is an alternative to EPP.

The estrogen-injected female mouse: new insight into the etiology of PCOS.

BACKGROUND: Female mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland. METHODS, RESULTS AND CONCLUSION: A putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS) was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 microg estrogen at 5-7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naïve mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We propose that in utero exposure to excessive levels of steroids such as estrogen has a long-term effect on the ability of the thymus to produce regulatory T cells. In female offspring this can lead to PCOS.

Regulatory T cells participate in 4-1BB-mediated suppression of experimental allergic conjunctivitis.

BACKGROUND: We showed previously that treatment with an agonistic anti-4-1BB Ab during the induction phase of murine experimental allergic conjunctivitis (EC) suppresses the development of this model disease. It was reported that 4-1BB promotes the expansion of regulatory T cells. Here we asked whether the suppression of EC by agonistic anti-4-1BB Ab treatment is mediated by regulatory T cells. METHODS: Neonatal BALB/c mice were thymectomized and intraperitoneally injected with anti-CD25 Ab. At 6 weeks of age, these mice were immunized with ragweed (RW) in alum. As a control, immunocompetent BALB/c mice were immunized. Ten days later, the mice were challenged with RW in eye drops and 24 h later, the conjunctivas and spleens were harvested for histological and flow-cytometric analyses, respectively. The agonistic anti-4-1BB Ab or control normal rat IgG was injected intraperitoneally during the induction phase of EC. RESULTS: With regard to immunocompetent mice, anti-4-1BB Ab treatment significantly suppressed the severity of EC as evaluated by conjunctival eosinophil numbers. In contrast, in thymectomized and anti-CD25 Ab-treated mice in which CD4+CD25+ regulatory T cells were efficiently depleted, anti-4-1BB Ab treatment did not affect the severity of EC. CONCLUSIONS: These results indicate that CD4+CD25+ regulatory T cells play a critical role in the suppression of EC by anti-4-1BB Ab treatment.

The History of Myasthenia Gravis

Since Willis described 'fatigable weakness' in 1672, most physicians consider it as a kind of hysteria due to the inconsistent fluctuation of symptoms. Erb presented three cases of 'bulbal palsy' in the 1870s, and Oppenheim and Hopper considered myasthenia gravis as a disease similar to curare poisoning and as a disease induced by attack of the motor centers by intrinsic toxins, respectively. In 1903, Elliot suggested that a 'chemical substance' mediates the nerve impulses at synapse. However, it was not until 1921 that this was demonstrated by Loewi, who provided evidence from the famous two-frog-hearts experiment. Dale later revealed the substance to be acetylcholine, and he also suggested that myasthenia gravis is due to a problem with the motor end plate. In 1934, Walker was prompted by the resemblance between myasthenia gravis and curare poisoning to apply physostigmine, a curare-poisoning antidote, to a patient, which produced a dramatic result. Since then the use of anticholinesterase inhibitors has been adopted for standard therapeutic modality. Some prominent surgeons have also applied thymectomy as a surgical modality. The most recent focus of myasthenia gravis has been immunological. In 1960, Simpson proposed the autoimmune hypothesis, and Chang et al. showed that snake venom contained a selective antagonist of the nicotinic acetylcholine receptor, alpha-bungarotoxin. The immunization of rabbits with acetylcholine receptor purified from the electrical organs of electric eels by Patrick et al. induced myasthenic symptoms and signs, and these were reversed by acetylcholinesterase inhibitors. The role of the autoimmune system has led to the introduction of an immunosuppressive modality and plasma exchange to the field of clinical neurology.

[The history of thymus surgery]. / Die Geschichte der Thymuschirurgie.

Thymus surgery was initially dominated by the erroneous interpretation of the organs' pathogenicity and associated thymus diseases. Misleadingly, the thymus gland was made responsible for dyspnoea in children and a transcervical ektropexia was performed in a child suffering from dyspnoea in 1896. After F. Sauerbruch's thymectomy in a patient with myasthenia gravis syndrome (MG), A. Blalock established thymectomy in the 1940s for the treatment of MG. At the same time, the drug treatment initiated by M.B. Walker increased in significance. Despite progress in surgical techniques and the molecular understanding of MG pathogenesis, randomized controlled trials, which would increase the evidence for surgical access and indications for surgery compared to immunosuppressive treatment in MG, are lacking.

Metallothioneins (I+II) and thyroid-thymus axis efficiency in old mice: role of corticosterone and zinc supply.

Thymic atrophy or thymus absence causes depressed thyroid-thymus axis (TTA) efficiency in old, young propyl-thiouracil (PTU) (experimental hypothyroidism) and in young-adult thymectomised (Tx) mice, respectively. Altered zinc turnover may be also involved in depressed TTA efficiency. Zinc turnover is under the control of zinc-bound metallothioneins (Zn-MTs) synthesis. Thyroid hormones, corticosterone and nutritional zinc affect Zn-MT induction. Zn-MT releases zinc in young-adult age during transient oxidative stress for prompt immune response. In constant oxidative stress (ageing and liver regeneration after partial hepatectomy), high liver Zn-MTs, low zinc ion bioavailability and depressed TTA efficiency appear. This last finding suggested that MT might not release zinc during constant oxidative stress leading to impaired TTA efficiency. The aim of this work/study is to clarify the role of Zn-MTs (I+II) in TTA efficiency during development and ageing. The main results are (1) Old and PTU mice display high corticosterone, enhanced liver MTmRNA, low zinc and depressed TTA efficiency restored by zinc supply. Increased survival and no significant increments in basal liver Zn-MTs proteins occur in old and PTU mice after zinc supply. (2) Lot of zinc ions bound with MT in the liver from old mice than young (HPLC). (3) Young-adult Tx mice, evaluated at 15 days from thymectomy, display high MTmRNA and nutritional-endocrine-immune damage restored by zinc supply or by thymus grafts from old zinc-treated mice. (4) Young-adult Tx mice, but evaluated at 40 days from thymectomy, display natural normalisation in MTmRNA and nutritional-endocrine-immune profile with survival similar to normal mice. (5) Stressed (constant dark for 10 days) mice overexpressing MT display low zinc, depressed immunity, reduced thymic cortex, high corticosterone, altered thyroid hormones turnover showing a likeness with old mice. These findings, taken altogether, show that corticosterone is pivotal in MTs induction under stress. MTs bind preferentially zinc ions in constant oxidative stress, but with no release of zinc from MT leading to impaired TTA efficiency. Zinc supply restores the defect because zinc has no interference in affecting pre-existing Zn-MTs protein concentrations in old and PTU mice. Therefore, free zinc ions are available for TTA efficiency after zinc supply. Thymus from old zinc-treated mice induces the same restoring effect when transplanted in Tx recipients. However, Tx mice display natural normalisation in MTmRNA and in nutritional-endocrine-immune profile in the long run. Therefore, Zn-MTs (I+II) are crucial in zinc homeostasis for endocrine-immune efficiency during the entire life assuming a role of potential and novel 'biological clock of ageing'.

Resection and perfusion thermochemotherapy: a new approach for the treatment of thymic malignancies with pleural spread.

BACKGROUND: Thymoma and thymic carcinoma with pleural spread have a high rate of locoregional recurrence and poor prognosis. Maximal debulking coupled with aggressive local treatment could offer a chance for cure. This study evaluates the early and midterm results of operation and hyperthermic pleural perfusion with cisplatinum for thymic malignancies. METHODS: Fifteen patients (11 men), 20 to 67 years old (10 thymoma, 4 thymic carcinoma, 1 carcinoma in thymic cyst) underwent resection and hyperthermic pleural perfusion between 1995 to 2000. All had pleural spread proven before or intraoperatively. Six of the thymoma cases were recurrent. Current operation included resection without pleurectomy (9 patients), resection with pleurectomy (5), and extrapleural pneumonectomy (1 patient) with intraoperative hyperthermic pleural perfusion in all. Intrapleural temperature reached 40.3 degrees C to 43 degrees C. The total dose of cisplatinum was 150 mg or more in 14 patients. RESULTS: Complete resection (R0) was achieved in 10 patients, subtotal (R1) in 3, and partial (R2) in 2. There was no operative mortality, no hemodynamic or respiratory disturbances during perfusion, and no hematologic, neurologic, or renal complications. Complications consisted of significant bleeding (2 patients), fever (2), and air leak (1 patient). Two patients with thymic carcinoma died after 27 and 34 months, and 1 is alive with no evidence of disease at 54 months. Two patients with thymoma died after 7 and 36 months. Eight are alive after 9 to 70 months. Four patients (all R0) are alive without local recurrence more than 60 months after operation and hyperthermic pleural perfusion. CONCLUSIONS: Operation and thermochemotherpy is feasible and safe in patients with thymic tumors. This method seems to offer excellent local control for patients with stage IV-a thymic malignancies. Midterm results suggest that operation plus hyperthermic pleural perfusion may lengthen survival in stage IV-a thymoma.

Thymectomy-induced deterioration of learning and memory.

Age-associated immunodeficiency and cognitive deterioration are two predominant features of the aging process, but the mutual influences between them are not clear yet. Research on the neuroendocrine immunomodulation (NIM) network indicate reciprocal interactions between the neuroendocrine and the immune systems mediated by neurotransmitters, neuropeptides, hormones and cytokines, which form an integrated network to maintain normal physiological functions of the body. An imbalance in the NIM network is believed to accelerate the aging process, in which the thymus plays an important role. We recently discovered that thymectomy in mice not only reduces the immune response, but also deteriorates learning performances. Cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor, and corticosterone affect the induction of hippocampal long-term potentiation, a synaptic model of memory. Clinical studies have demonstrated that Alzheimer's patients show disordered immune function in addition to cognitive deficit, and the brain lesions of Alzheimer's patients may be associated with abnormal immune reactions occurring in the brain. With these findings, it is speculated that the disordered immune function may induce an imbalance in the NIM network, which consequently influences central cognitive function.

Effects of Mivacurium in the Patients with Myasthenia Gravis / 대한마취과학회지

BACKGROUND: Myasthenia gravis is an autoimmune neuromuscular disorder that shows increased sensitivity to nondepolarizing muscle relaxants. Mivacurium chloride is a short acting nondepolarizing neuromuscular blocker and a benzylisoquinolin diester that is hydrolized rapidly to inactive metabolites by plasma pseudocholinesterase. The onset and duration of mivacurium in patients undergoing a thymectomy with myasthenia gravis was studied. METHODS: Fifteen patients undergoing a thymectomy for myasthenia gravis and fifteen patients of ASA class I, II without liver, kidney or neuromuscular disease undergoing orthopedic surgical procedures were included in this study. Anesthesia was induced with thiopental 4 5 mg/kg and maintained with inhalation of N2O:O2 (1:1) and enflurane 1.0 2.0 vol%. Mivacurium 0.2 mg/kg was given as a muscle relaxant and then intubation performed after the twitch response was depressed more than 90%. Neuromuscular relaxation was assessed by TOF (T1) at the adductor pollicis with supramaximal stimulation of the ulnar nerve at 2 Hz every 12 seconds. The onset and duration of 5%, 25%, 50%, 75%, and 95% recovery time of T1 and recovery index were recorded. RESULTS: Onset of block was shortened but recovery time of 5%, 25%, 50%, 75%, 95% and recovery index were prolonged in patients with myasthenia gravis. CONCLUSIONS: In patients with myasthenia gravis, mivacurium induced rapid onset time and prolonged recovery time of 5%, 25%, 50%, 75%, 95% and recovery index.

A role of the thymus and thymosin-alpha1 in brain NGF levels and NGF receptor expression.

Using neonatal rats we investigated the role of the thymus and thymosin-alpha1 (T-alpha1) in brain NGF levels, NGF receptor (p75NGFr) expression, as well as the activity of choline acetyl-transferase, a cholinergic enzyme regulated by NGF. It is shown that early postnatal thymectomy causes a decrease in NGF in the hippocampus and cortex and p75NGFr distribution in the basal forebrain cholinergic neurons (FBCN). Intracerebral T-alpha1 injection in thymectomized animals induces a recovery, albeit not complete, of both NGF and p75NGFr. These findings indicate that thymectomy affects both the brain NGF producing and responding cells and that T-alpha1 may be one of the thymic hormones involved in the regulation of cerebral NGF synthesis.

Functional relationship between age-related immunodeficiency and learning deterioration.

Disordered immune responses are supposed to alter the function of the central nervous system through the neuroendocrine immunomodulation network. In this paper, we studied the influence of the immune function on learning performances from the angle of pharmacology using aged garlic extract (AGE), an immunomodulator. Splenocyte proliferation, induced by concanavalin A or lipopolysaccharide, and the antibody production response were declined in senescence accelerated mouse-prone 8 (SAMP8) aged 12 months compared with age-matched SAMR1 (SAM-resistant 1). Chronic oral administration of AGE-containing food (2%, w/w) significantly enhanced the immune responses of both SAMP8 and SAMR1. Male ddY mice were thymectomized 4 weeks after birth and fed AGE-containing food after the operation until the experiments were finished. Learning performances, brain monoamine content and choline acetyltransferase (ChAT) activity, as well as the immune response were evaluated 10 months after the operation. Thymectomy resulted in not only immunodeficiency, but also deteriorated learning ability. AGE treatment prevented the reduction of the antibody production response induced by thymectomy and improved the thymectomy-induced deterioration of learning behaviours in passive avoidance performance and in a spatial memory task. The contents of hypothalamic noradrenaline, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and the hypothalamic ChAT activity were increased in thymectomized mice compared to those of sham-operated control, while AGE treatment restored them to the control levels. These results suggest that the improvement of immune function is closely related to the amelioration of age-associated deterioration of learning and memory.