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Recovery of Dementia Syndrome following Treatment of Brain Inflammation

Aim/Background This research aims to prevent progression from mild cognitive impairment (MCI) to Alzheimer's disease. A Japanese study of leprosy patients revealed that the incidence of dementia in leprosy patients was lower than that in patients taking dapsone who had never been treated. But a similar study the following year refuted the finding of less dementia in leprosy patients taking dapsone. According to conflicting reports, Mycobacterium leprae was a factor in reducing the incidence of Alzheimer's disease. Thus, we formed a hypothesis that if dapsone is administered to patients without leprosy but with MCI and the prophylactic effect of dementia syndrome is observed over a long period of time, we can determine whether dapsone can prevent the progression of MCI to dementia syndrome. If dementia does not occur after treating inflammation in brain cells while dementia develops after a certain long-term period (usually within 2–3 years), brain cell inflammation can be demonstrated as the cause of dementia. Methods This is a prospective cohort research. We report on an elderly patient diagnosed with MCI from February 2008 to January 2019. The patient took dapsone 100 mg once a day from 2010 to 2015 for the treatment of MCI. Since 2016, the production of dapsone has ceased in Korea. In June 2018, the patient was diagnosed with Alzheimer's disease. The patient took Aricept for the treatment of Alzheimer's disease but complained of serious side effects. And dapsone was re-administered to the patient from November 2018. Results The patient recovered to MCI and improved her daily life owing to the treatment with dapsone. The drug controls the inflammatory response in the brain, irrespective of whether proteins are deposited in neurons. Conclusions This finding means that dementia syndrome is an inflammatory disease. This research suggests that diagnostic criteria for Alzheimer's disease should be based on the presence or absence of inflammation in neurons. Because inflammation in neurons can occur in middle age due to various causes, we can treat inflammation in neurons and prevent and treat dementia syndrome, including Alzheimer's disease.


Introduction
Since 2011, the diagnosis of Alzheimer's disease has included amyloid beta protein or tau protein deposits in brain cells, even if dementia symptoms are absent [1]. Dementia refers to a state in which cognitive function is generally deteriorated by various causes, causing significant disruption to daily life.
Dementia is a "syndrome" that is a set of specific symptoms with cognitive impairment. More than 70 cases of the disease that causes the clinical syndrome of dementia are classified. Alzheimer's disease belongs to dementia syndrome with cognitive impairment, but it is a degenerative brain disease in which amyloid beta protein or tau protein is deposited in brain cells even in the absence of cognitive impairment (Fig. 1).
The first hypothesis of this study is that we can prevent or cure cognitive disorders by treating brain cell inflammation in patients with dementia syndrome (Alzheimer's disease).
In the 1990s, a Japanese epidemiological survey study of leprosy patients aged 65 years or older revealed that the incidence of dementia in leprosy patients who had been treated with dapsone and related medications was lower than that in patients taking the drug who had never been treated [2,3]. A neuropathological case series of leprosy patients detected the absence of senile plaques but detected the expected levels of neurofibrillary tangles compared to those in the general population [3,4]. A similar study the following year showed no difference in the discovery of senile plaques between the patient and control groups, thus refuting the finding of less dementia in leprosy patients taking dapsone [3,5].
According to conflicting reports by the Japanese Sanatorium for leprosy patients, Hansen's disease was a factor in reducing the incidence of Alzheimer's disease [6]. In addition, the Japanese researchers tested dapsone-containing medicines for leprosy patients, but they were unable to find the effect of removing amyloid beta protein; thus, they proposed that Mycobacterium leprae is a major causative factor of Hansen's disease [7]. Worldwide, M. leprae is considered responsible for reducing the incidence of Alzheimer's disease based on these two papers [6,7].
However, the study [6] by the Japanese Sanatorium for leprosy patients selected the target group from the 65-84 age category. When comparing and analyzing two traits, patients with lepromatous leprosy and those with tuberculosis, the leprosy patients in the 80-95 age group with the high incidence of dementia should be selected as the target group with which to compare the occurrence of dementia. In other words, the incidence of dementia is not relatively high in the 65-75 age groups. Importantly, dementia incidence should have been compared in the 80-95 age groups with a high incidence of dementia. Potential selection bias was identified in data processing. There were also a number of leprosy patients who stopped taking dapsone due to Hansen's inactivation. When analyzing the preventive effect of dementia, we compared the period in which leprosy patients were taking dapsone continuously with the period in which these patients stopped taking dapsone. Notably, the pharmacological effect of dapsone is to control inflammation in brain cells, not to remove amyloid beta protein [7]. M. leprae was posited as the major cause of dementia reduction by studying the amyloid beta protein removal function of dapsone, which is a null hypothesis.
The null hypothesis can be proved if dapsone is administered to patients without leprosy but with mild cognitive impairment (MCI) and the prophylactic effect of dementia syndrome is observed over a long period of time. Through long-term observation, we can determine whether dapsone can prevent the progression of MCI to dementia syndrome when brain cell inflammation is controlled. If dementia does not occur after treating inflammation in brain cells while dementia develops after a certain long-term period (a period of transition from MCI to dementia within 2-3 years), brain cell inflammation can be demonstrated as the cause of dementia.
The second hypothesis of this study is that the following represents the null hypothesis: M. leprae, which induces leprosy, is the cause of the low incidence of Alzheimer's disease in patients with Hansen's disease.

Methods
This Seoul study was a prospective cohort study of patients diagnosed with MCI from February 2008 to January 2019. Dapsone was administered to patients from 2010 to 2015 for the treatment of MCI. SNU institute of Aging in Seoul National University approved the clinical study of patients based on The Nuremberg Code (1947) and FDA guidelines ethically in accordance with the World Medical Association Declaration of Helsinki. All methods were carried out in accordance with relevant guidelines and regulations. The subjects (or their parents or guardians) gave written informed consent, and the study protocol was approved by the committee on human research of SNU Institute of Aging, Seoul National University. We administered medicines in compliance with medical and pharmacist laws under the informed consent of the patient.  [1]. Alzheimer's disease belongs to dementia syndrome with cognitive impairment, but it is a degenerative brain disease in which the amyloid beta protein or tau protein is deposited in brain cells even in the absence of cognitive impairment [1]. In this study, we suggest that the diagnosis criteria and treatment plan of Alzheimer's disease should be changed. Whether inflammatory reactions are persistent is important when diagnosing and treating Alzheimer's disease.
Dapsone is an antibiotic similar to other sulfonamides and blocks bacterial synthesis of dihydrofolic acid via competition with p-aminobenzoic acid for the active site of dihydropteroate synthetase [8]. Dapsone is a common treatment for leprosy and is also used as an important drug in many other skin diseases [9].
Dapsone binds with hemoglobin, which decreases oxygen transport capacity, causes methemoglobinemia, and induces hemolytic anemia [10]. In addition to hemoglobin, dapsone can affect biochemical metabolism by binding to various constituents, such as human enzymes [11]. Dapsone is a substance with allosteric regulation of structure and function.
Immune cells such as leukocyte neutrophils produce hypochlorite to attack foreign bodies to defend cells when a foreign substance attacks the cells. Myeloperoxidase is a kind of oxidoreductase that catalyzes the chemical reaction of the following reaction: H 2 O 2 + Cl − = H 2 O + OCl − . Dapsone binds to myeloperoxidase and regulates the production of hypochlorite, thereby reducing the inflammatory response of cells [12][13][14].
Myeloperoxidase is a hemoprotein. Dapsone reduces the inflammatory response of neutrophils and preserves cells by regulating the production of hypochlorous acid. The ability of dapsone to exert its anti-inflammatory and immunomodulatory effects reduces the inflammatory response by binding to myeloperoxidase contained in leukocytes.
Therefore, we prepared a prospective cohort Seoul study for patients with MCI who underwent precise neuropsychiatry and MRI examinations for the elderly with short-term memory impairment in 2008; this study was performed in accordance with the Korean In this study, we hypothesized that the deterioration of MCI to Alzheimer's disease could be prevented by the inflammation control effect of dapsone. The patient was dosed once daily with 50-100 mg dapsone. The patient is the second daughter, a pharmacist graduated from Seoul National University College of Pharmacy (online suppl. 5 [page 1]). The patient took the dapsone from the Najin pharmacy. The dapsone tablets were produced by Taegeuk Pharmaceutical Company ( Table 1).
The symptoms of the patient's memory impairment disappeared after dosing. The patient continued her daily life, including taking care of grandchildren, paying bills, shopping, washing clothes, preparing meals, and managing savings. The patient visited her youngest daughter at Gyeong Hee Lee's house (online suppl. 5 [page 3]) every day.
However, after the prescription of dapsone on March 2, 2015, Taegeuk Pharmaceutical Co., which produced dapsone in Korea, stopped the production of dapsone. Since then, the  For Alzheimer's disease treatment, this patient took Aricept, one of the four currently available Alzheimer's drugs in May 2019, according to a prescription from Hyeong-gil Lee, a neurologist at Kyunghee Neulfureun Geriatric Hospital. However, the patient experienced serious adverse drug reactions ( The patient's son (as a physician) prescribed dapsone to the patient, who had taken the drug in the MCI state. Domestic production was discontinued, but the Korea Orphan & Essential Drug Center designated dapsone as an essential medicinal product and imported it from Riemser Pharma GmbH (Germany). The Korea Orphan and Essential Drug Center Dapsone had no side effects, and the patient's dementia syndrome improved significantly. The patient became able to live everyday life. On December 20, 2018, the patient received an outpatient medical examination by Dr. Soh-hyun Ahn, a neurologist at Seoul National University Hospital, for an objective examination. Dr. Jong-hoon Lee explained to Dr. Soh-hyun Ahn that the patient stopped taking Aricept due to severe side effects and that he administered dapsone; thereafter, the side effects caused by Aricept were eliminated, and the patient became able to live everyday life. On January 14, 2019 Dr. Soh-hyun Ahn proposed to re-examine the test for cognitive impairment and compare the results (online suppl. 2 [page 2]).
On January 18, 2019, the patient received outpatient medical care from Prof. Kyung-min Lee of the Department of Neurology at Seoul National University Hospital (online suppl. 2 [page 3]) and received a second test to determine the presence or absence of cognitive impairment (online suppl. 1 [page 3]). The duration of this test was also 1.5 h. Patient received a medical record, a report on the examination for the presence of cognitive impairment, etc., and a medical certificate for the current patient status from Seoul National University Hospital (online suppl. 1 [5 page]).

Results
The patient was examined twice by the Neurology Department of Seoul National University Hospital for cognitive impairment (online suppl. 1 (pages 1-4); for all online suppl. material, see www.karger.com/doi/10.1159/000504880). On November 6, 2018, the patient was taking Aricept (online suppl. 2), and on January 14, 2019, the patient was taking dapsone (online suppl. 3). Since there were no side effects after taking dapsone, the patient was able to take it steadily, and the results were comparable. The results of the examination are shown in the comparison table (Table 3).
The patient's memory and cognitive function were measured; there was no significant difference in these factors between Aricept and dapsone. However, with dapsone, the NPI-Q and K-IADL items were normalized, abnormal behavior disappeared, and the patient returned to daily life. Additionally, the patient's personality was restored (Fig. 2).
Our observations suggest that reducing inflammation to treat dementia syndrome, including Alzheimer's disease, is important. In addition, the cause of dementia syndrome, including Alzheimer's disease, is due to the inflammatory reaction. Moreover, we can deduce that amyloid beta protein and tau protein accumulate if the inflammatory reaction is not treated. Therefore, the onset of Alzheimer's disease is due to an untreated inflammatory response. Now, we need to find a trigger that determines that DNA and RNA produce amyloid beta proteins in response to an inflammatory response in neurons.  In the 1990s, a Japanese epidemiological survey study of leprosy patients aged 65 years or older revealed the incidence of dementia in leprosy patients [2]. A neuropathological case series of leprosy patients detected the absence of senile plaques [4]. But a similar study the following year showed no difference in the discovery of senile plaques between the patient and control groups [5]. Seoul study: a patient diagnosed with MCI through MRI and mental neurological examination in 2008 continued to take dapsone regularly until 2016 and lived a normal routine (online suppl. [4][5][6]. However, after discontinuation, the patient was diagnosed with Alzheimer's disease in 2018, but lives with MCI as of November 2019 after taking dapsone (online suppl. 1, 2).

Discussion
Hemoglobin is a human constituent used in studies on structure and function, such as changes in hemoglobin oxygen transport ability and changes in the structure of hemoglobin in the blood. Dapsone binds to hemoglobin and causes cyanosis [10]. When dapsone binds to the molecules and structures of myeloperoxidase contained in leukocytes, it exerts antiinflammatory and immunomodulatory effects [12][13][14]. These findings mean that dapsone can bind to various constituents of the body, such as various enzymes, and affect cell physiology [10]. Considering the structure of dapsone and the allosteric regulation of the molecular unit, dapsone can be presumed to preserve cells by decreasing the inflammatory response of neutrophils and can regulate the production of hypochlorous acid. This response is associated with myeloperoxidase, a kind of reductase enzyme, and has the effect of reducing inflammatory reactions. Myeloperoxidase is also a hemoprotein [15]. Dapsone inhibits myeloperoxidase, a mechanism that protects neurons. Moreover, dapsone is effective in Alzheimer's disease or stroke, a neurodegenerative disease caused by inflammation [16][17][18].
As a result, patients with Alzheimer's disease were able to return to their normal lives when dapsone stopped the inflammation and protected the brain cells. These findings suggest that the cause of dementia syndrome, including Alzheimer's disease, is probably due to an inflammatory response. The NPI-Q and K-IADL items in the test for the presence of cognitive impairment can be checked by examining whether the patient has returned to his/her daily life.
Inflammatory reactions are intensified by various causes in brain cells, and these cells are attacked by hypochlorite. Various foreign substances and intracellular components accumulate and cause brain cells to die. Here, dapsone was used as a prophylactic material for stopping neuronal death. One experiment demonstrated the function of dapsone in neurons in mice that experienced neuron injury by temporary cerebral ischemia followed by cerebral blood flow recovery after dapsone was administered [19].
Therefore, in this study, we suggest that the diagnostic criteria and treatment plan of Alzheimer's disease should be changed. Whether inflammatory reactions are persistent is important when diagnosing and treating Alzheimer's disease. There have been reports that most epidemiological studies are ineffective in examining a variety of issues, such as the effects of NSAIDs, MCI, and Alzheimer's disease [20]. Other results are expected if the evaluation of the effects of dapsone and MCI or Alzheimer's disease is based on NPI-Q and K-IADL items.
In the future, we will be able to prevent the development of a broad spectrum of dementia syndrome [21].