The Preventive and Treatment of the Neuro-Inflammasome in Sorokdo National Hospital

doi:10.21203/rs.3.rs-243831/v2

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The Preventive and Treatment of the Neuro-Inflammasome in Sorokdo National Hospital

https://doi.org/10.21203/rs.3.rs-243831/v2

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Aim/Background: This study investigated leprosy patients with Alzheimer's disease (AD) treated with 4,4’-diaminodiphenyl sulfone (DDS) as a neuroinflammasome competitor.

Method: We searched all medical records of the National Health Insurance Service (NHIS) in Korea and the Sorokdo National Hospital from the time when the Korean government computerized the International Classification of Diseases (ICD)-9 code and Electronic Data Interchange (EDI). The Seoul study analyzed statistically AD, and anti-AD drugs (AADs) in the Sorokdo National Hospital's EDI database archived from January 2005 to June 2020 through the ICD-9 and -10 codes with National Health Insurance System.

Result: The relation between DDS and AD each year was analysed using the chi-square test. P value was significant from 2007 to 2020 when P-value < 0.05 was considered significant. The AD (+/-) Group was rearranged based on the DDS (+/-) Group. DDS’s effect as a neuro-inflammasome competitor was statistically proved with T-Test Calculator by comparing the prevalence of AD in patients who had been prescribed DDS and those who had not.

Conclusion: Our study is the first to prove the association between dapsone and AD through observational studies. This study suggests the use of neuroinflammasome therapy as a preventive and therapeutic method for AD.

Neurology

Neurobiology of Disease

Obstetrics & Gynecology

Neuroinflammasome

Alzheimer's disease

Dapsone

In 1992, an Alzheimer's disease (AD) research team published a method of preventing and treating human AD dementia with 4,4’-diaminodiphenyl sulfone (DDS, dapsone), its didextrose sulfonate derivative, and other closely related sulfones (sulfetrone and thiazolsulfone)^1-3. However, further investigations did not detect any differences in AD prevalence among leprosy patients treated with DDS and failed to demonstrate that it had any protective effects against Aβ neurotoxicity⁴. There have been various claims in autopsy findings and AD interpretations in leprosy patients. Population studies varied in their specific neuropathological findings, but all observed some abnormal neuropathology characteristic of AD despite DDS treatment^5-8.

The Seoul study originated from the Seoul Longitudinal Study of Aging⁹ had investigated five patients diagnosed with MCI from February 2008 to December 2020. The production of dapsone was ceased from 2016 to2018 in South Korea. The reason is that pharmaceutical companies gave up the production of dapsone because the maximum allowance price of National Health Insurance System was too low. Patients were diagnosed with Alzheimer's disease on June 2018. The patient suffered from severe side effects after taking anti-AD drugs (AADs)^10,11. We have found that taking dapsone and stopping it leads to the development of AD. So, we reviewed the studies on AD and dapsone^1-8. So it was possible to estimate that whether or not leprosy patients have been taking dapsone consistently is a key point in AD and dapsone research. Because dapsone is a drug with side effects, doctors closely monitor the condition of leprosy patients and prescribe dapsone.

The Sorok island as a Japanese 'leper colony' was established in May 1916 to quarantine leprosy patients. It was not easy for them to see a doctor. So they have been taking the prescribed leprosy remedy steadily. From our survey, there were a number of people living on The Sorok Island for 79 years and taking dapsone for more than 50 years. After graduating from her nursing school at the University of Innsbruck Nursing School in Tyrol, Western Austria, Marianne, who worked at a hospital in Innsbruck, joined Sorok Island in February 1962. Sister Margaret entered Sorok Island in October 1967 and they left Sorok island on November 21st, 2005, returned to their homeland. Since this study was conducted from 2005 to 2020 based on the medical records of Sorokdo National Hospital, the patient research was initiated by Sister Marianne Stoeger and Sister Margaritha Pissarek from 1962 as a kind of control group.

The Seoul study analyzed the AD prevalence with dapsone in leprosy patients.

From 2010 to June 2020, the diagnosis of patients with MCI and AD in Korea increased dramatically. From 2010 to June 2019, the Dementia Management Act increased the diagnosis of patients with mild cognitive impairment or AD by 3.26 times and AAD prescription by 4.65 times in South Korea. From 2010 to June 2019. Through rapid diagnosis and prescription changes over 10 years, it is possible to clearly monitor how AAD affects dementia. (Table 1) (Fig. 1)

Table 1. Numbers of drug prescriptions for dementia patients in Korea from 2010 to 2019

Year	Total billed quantity of drugs	Total amount billed for drugs (US dollar)	Total number of patients
2010	56,258,246	109,447,004.94	257,385
2011	72,339,833	134,113,060.88	319,327
2012	88,533,271	140,102,940.12	376,126
2013	106,422,008	160,202,046.28	435,538
2014	127,120,294	187,253,891.03	497,676
2015	154,734,543	215,276,823.70	562,844
2016	181,226,560	240,267,890.56	627,823
2017	207,303,641	265,949,723.52	692,531
2018	234,480,000	296,443,092.12	767,282
2019	261,621,750	328,425,770.98	839,413

(Currency data provided by Morningstar on 07 February, 12:58 AM UTC)

Korean leprosy patients continue to take DDS throughout their lives. Based on the relative prevalence of AD in patients who have been prescribed DDS and those who have not, dapsone has a preventive effect against AD. AD diagnosed (+) Group has increased DDS non-prescription (-) Group and has the lower prevalence in the DDS (-) group from January 2005 to June 2020. (Fig. 2) The proportion of DDS prescription (+) group has been increased and the proportion of DDS (-) group has been decreased significantly in the AD no (-) group. There are significant relationship between DDS and the differential prevalence proportion of AD in patients. (Fig. 3)

The relation between DDS and AD each year was analysed using the chi-square test. P value was significant from 2007 to 2020 when P-value < 0.05 was considered significant. The AD (+/-) Group was rearranged based on the DDS (+/-) Group. (Table 2)

Table 2. Alzheimer’s Disease Prevalence rate in the DDS (+/-) group from January 2005 to June 2020

Year	DDS (+)	DDS (-)	AD (+) Total	DDS (+)	DDS (-)	AD (-) Total	P-value*	DDS(+)/AD(+)total	DDS(+)/AD (-)total	DDS(-)/AD (+)total	DDS (-)/AD (-)total
2005	18	19	37	290	417	707	.3583	0.4865	0.4102	0.5135	0.5898
2006	20	37	57	302	363	665	.1324	0.3509	0.4541	0.6491	0.5459
2007	22	51	73	317	332	649	.0024**	0.3014	0.4884	0.6986	0.5116
2008	22	58	80	310	312	622	.00028**	0.2750	0.4984	0.7250	0.5016
2009	19	66	85	300	283	583	< .00001**	0.2235	0.5146	0.7765	0.4854
2010	25	82	107	270	286	556	< .00001**	0.2336	0.4856	0.7664	0.5144
2011	35	98	133	255	268	523	< .00001**	0.2632	0.4876	0.7368	0.5124
2012	39	135	174	238	241	479	< .00001**	0.2241	0.4969	0.7759	0.5031
2013	34	172	206	195	248	443	< .00001**	0.1650	0.4402	0.8350	0.5598
2014	25	190	215	172	236	408	< .00001**	0.1163	0.4216	0.8837	0.5784
2015	26	242	268	167	168	335	< .00001**	0.0970	0.4985	0.9030	0.5015
2016	33	255	288	154	149	303	< .00001**	0.1146	0.5083	0.8854	0.4917
2017	37	268	305	143	115	258	< .00001**	0.1213	0.5543	0.8787	0.4457
2018	45	292	337	132	87	219	< .00001**	0.1335	0.6027	0.8665	0.3973
2019	46	334	380	114	40	154	< .00001**	0.1211	0.7403	0.8789	0.2597
2020	32	352	384	109	4	113	< .00001**	0.0833	0.9646	0.9167	0.0354

*The relation between DDS and Alzheimer’s Disease each year was analyzed using the chi-square test. A P-value < 0.05 was considered significant. ** indicates a P-value < 0.05.

The values of f and p were calculated using a one-way ANOVA calculator. Four groups were defined: Treatment 1: DDS (+) AD (+), Treatment 2: DDS (+) AD (-), Treatment 3: DDS (-) AD (+), Treatment 4: DDS (-) AD (-). The The f-ratio value is 59.27206. The p-value is < .00001. The results are all significant at p < .05 with T-Test Calculator between Treatment 1, 2, 3 and 4. (Supplement Section 1)

Fewer people suffer from Alzheimer's disease in the group who regularly took DDS from 2005 to 2020 in the DDS (+) Group. There are far more people in the group taking DDS who do not develop Alzheimer's disease. (Fig. 4)

DDS (-) Group shows a steady increase in the number of people with AD. It suggests that an increase in Alzheimer's disease is associated with an increased prescription for AAD in addition to not taking DDS because very few people who do not take DDS do not get developed to AD. (Fig. 5)

DDS's action as a neuroinflammasome competitor¹² can be conjectured by comparing the AD prevalence in leprosy patients who have been prescribed DDS and those who have not. Thus, DDS is a neuroinflammasome competitor because of low AD prevalence.

Because of the Dementia Management Act in Korea, the Sorokdo National Hospital strengthened the diagnosis of dementia for old leprosy patients. Korean doctors perform standard treatment according to AD diagnosis and neuropsychiatric examinations results for leprosy patients. They strengthened the prescription of AADs and discontinued DDS in patients with inactive leprosy. As a result, it became possible to separate the group taking DDS from the group not taking DDS in among AD patients. The relationship between AD and dapsone become clear for 15 years. If any study does not differentiate groups who have been prescribed from the other groups discontinued to take dapsone in the statistical data, the effects of dapsone as an inflammasome competitor are mixed in the pathology findings like previous confused pathologic findings^4-8.

The results of many epidemiologic studies and limited clinical evidence suggest that NSAIDs should delay the onset and hinder AD's progression¹³ ¹⁴. The results of long-term clinical trials were negative. Still, these drugs affect the periphery of the inflammatory reaction¹⁵. The components of the neurovascular unit harmoniously working influence the BBB's properties. The brain capillary phenotypes have differences in a lack of fenestration and low pinocytotic activity. They mostly have the presence of tight junctions with low permeability between cells. Since most central nervous system (CNS) diseases are caused by inflammation and oxidative stress, the efficiency of drugs acting on CNS is essential¹⁶. DDS passes through the BBB, and high-dose sulfadiazine results in an effective CSF concentration in humans¹⁷. DDS appears to have more significant anti-inflammatory effects than NSAIDs. Moreover, DDS does not have the side effects of NSAIDs, such as gastrointestinal disorders; therefore, it is possible to administer adequate doses of DDS (100-300 mg/day) while monitoring other side effects.

DDS can regulate the production of hypochlorous acid. This response is associated with myeloperoxidase, a kind of reductase enzyme, and reduces inflammatory reactions¹⁸. DDS may regulate NLRP3 inflammasome activators and a common signalling pathway. However, the specific NLRP3 target may act through a competitive therapeutic mechanism to counter the progression of MCI to AD. Our work corroborates a finding reported in 1994: antibodies could inhibit this activation against complement receptors in the nanomolar range. DDS and indomethacin are weakly inhibitory (10^-4M range) therapeutic agents in AD³.

The National Agency approved this study for Management of Life-sustaining Treatment, which certified that the life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006). The KoNIBP approved the observational study of patients ethically based on FDA guidelines following the World Medical Association Declaration of Helsinki. We carried out all methods following relevant ethical guidelines, regulations.

4.1. Inclusion and exclusion criteria

According to the Official Information Disclosure Act in Korea, the Seoul study analyzed AD and AAD use in Hansen subjects. We searched all medical records of the National Health Insurance Service (NHIS) in Korea and the Sorokdo National Hospital from the time when the Korean government computerized the International Classification of Diseases (ICD)-9 code and Electronic Data Interchange (EDI). We connected to the medical record database of the Sorokdo National Hospital and archived it from January 2005 to June 2020. With the ICD-9 and -10 codes, we then analyzed medical data on the correlation between DDS and AD. We used the software programs Object-Relational DBMS and SPSS. According to the Official Information Disclosure Act in Korea, we also requested and analyzed the entire ICD 9 and 10 code data of AD and AAD from the Health Insurance Review & Assessment system.

The total number of leprosy patients living in Sorok Island as a control group was investigated. After diagnosis and examination, all of the leprosy patients diagnosed with AD were examined for drugs being administered. All data was computerized.

4.2. Korean Standard Classification of Diseases (KCD) disease code for "Alzheimer's disease."

(1) Mental and behavioural disorders, F00-F09, G30

[F00 code Dementia in Alzheimer's disease (G30.-+)]

[F01 code Vascular dementia]

[F02 code Dementia in other diseases classified elsewhere]

[F03 code Unspecified dementia]

[F04 code Organic amnesic syndrome, not induced by alcohol and other psychoactive substances ]

[F05 code - Delirium, not induced by alcohol and other psychoactive substances]

[F06 code - Other mental disorders due to brain damage and dysfunction and to physical disease]

[F07 code - Personality and behavioural disorders due to brain disease, damage and dysfunction]

[F09 code - Unspecified organic or symptomatic mental disorder]

[G30 Alzheimer's disease]

(2) For symptomatic relief of Alzheimer's disease

First Group: For symptomatic relief of Alzheimer’s disease

[donepezil hydrochloride]

148603ATB 148602ATD 148602ATB 148601ATD 148601ATB 643401ATD 643402ATD

[rivastigmine]

224501ACH 224503ACH 224504ACH 224505ACH 224506CPC 224507CPC 224508CPC

[galantamine]

385203ACR 385203ATR 385204ACR 385204ATR 385205ACR 385205ATR

[N-methyl-D-aspartate (NMDA) receptor antagonist]

190031ALQ 190001ATB 190003ATD 190004ATB 190004ATD

Second Group: For psychologic symptoms of Alzheimer’s disease

[haloperidol]

167903ATB 167904ATB 167905ATB 167906ATB 167908ATB 167908ATB 168030BIJ

[Risperidone]

224201ATB 224201ATD 224202ATB 224202ATD 224203ATB 224204ATB 224205BIJ 224206BIJ

[Quetiapine]

378601ATB 378602ATB 378603ATB 378604ATB 378605ATB 378605ATR 378606ATR 378607ATR 378608ATR 378608ATR 378610ATB

[Olanzapine]

204001ATB 204001ATD 204002ATB 204002ATD 204004ATB 204005ATB

[Aripiprazole]

451501ATB 451501ATD 451502ATB 451502ATD 451503ATB 451504ATB 451505ATB 451506BIJ 451507BIJ

[Oxcarbazepine]

206330ASS 206301ATB 206302ATB 206303ATB

[fluvoxamine]

162501ATB 162502ATB

[Escitalopram]

474801ATB 474802ATB 474803ATB 474804ATB

[Trazodone]

242901ACH 242901ATB 242902ATB 242903ATR

[sertraline]

227001ATB 227002ATB 227003ATB

[Escitalopram]

474801ATB 474802ATB 474803ATB 474804ATB

[Fluoxetine]

161501ACH 161501ATB 161502ACH 161502ATB 161502ATD

Our study is the first to prove the association between dapsone and AD through observational studies. Dapsone is a drug that is not easy to take consistently. There is a group that has been taking dapsone consistently for a long time in Korea, and the results of this study were derived. Efforts to reduce the incidence of AD should continue through very meticulous further research.

Data availability

According to the Official Information Disclosure Act in Korea, it is possible to provide public access to a dataset based on the linkage of data from nationwide public registries. Access to the National Health Insurance Service (NHIS) in Korea and the Sorokdo National Hospital and the Health Insurance Review & Assessment system's registry data can be granted to individual researchers only upon seeking approval according to the Official Information Disclosure Act in Korea the National Agency for Data Protection. We, therefore, cannot place the dataset in a public repository. However, pooling of aggregated data is possible and would be of interest to the research group.

Acknowledgements

Soon Joe (09-12-1931 ~ 03-01-2021) contributed to making treatment method for MCI & AD, SARS-CoV-2 ARDS. So naming is Soon, Joe's treatment³¹. Dapsone may also be used to prevent, treat AD and COVID-19 ARDS^12,31.

Author contributions

JL designed and performed this study and wrote the manuscript. CJL analyzed the medical data statistically and examined the HD patients with MCI and AD in Sorokdo National Hospital. JP analyzed intractable AD symptoms and the use of the AAD (D). SJL analyzed the MCI patient.

Competing interests

The author(s) declare no competing interests.

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No competing interests reported.

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The Preventive and Treatment of the Neuro-Inflammasome in Sorokdo National Hospital

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Abstract

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1. Introduction

2. Results

3. Discussion

4. Methods

5. Conclusion

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