4.1. The Alzheimer's continuum (A + T + (N) +) (D)
For clinical research, the Alzheimer's continuum (A + T + (N) +) was selected based on biomarkers. Before AD progressed, biomarkers were changed. Therefore, clinical symptoms and biomarkers were separated from AD diagnosis, and AD was defined only by changes in biomarkers [7]. The AD criteria biologically classify cognitive impairments separately as symptoms/signs caused by these diseases. AD problems may include the following: depression, apathy, social withdrawal, mood swings, distrust in others, irritability and aggressiveness, changes in sleeping habits, wandering, loss of inhibitions, and delusions, such as believing something has been stolen [25]. As of mid-2019, several AD drugs were available worldwide: donepezil, galantamine, rivastigmine and memantine [26]. Aripiprazole, olanzapine, risperidone, quetiapine, haloperidol, selective serotonin reuptake inhibitors, and carbamazepine are used to control the psychiatric symptoms associated with dementia [27-32]. However, it was challenging to differentiate whether AAD caused symptoms because of the Korea Dementia Act and the health insurance system. Biomarker (D) can be used as a biomarker to distinguish the symptoms caused by AAD. Since the side effects of AAD have been reported [33, 34], it is necessary to record the biomarker (D).
The FDA warned that dementia-related antipsychotic drugs increase mortality. The boxed warning reads as follows: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [33]. More recent studies from many countries confirm that antipsychotic drugs should not be prescribed for dementia patients, as they significantly increase the risk of seizures and all-cause mortality [34]. Therefore, to distinguish the symptoms caused by AAD or AD, it is necessary to stop taking AAD and observe clinical progress. In this study, when acetylcholine precursor was administered to the patient, the patient state changed to NCS 6 stage. Medical staff must label the AAD as a biomarker (D) and monitor the patient's condition for changes.
4.2. DDS as the preventive of AD and Aβ neurotoxicity
In the first review [35], DDS was a therapeutic, preventive agent in AD, according to reports [36-38]. However, in the second review [39], DDS was not a therapeutic, preventive agent in AD [38, 40]. There were different interpretations of the commonly cited 'Decreased Aβ and Increased Abnormal Tau Deposition in the Brain of Aged Patients with Leprosy’. It has been reported that amyloid-beta protein (Aβ) depositions were significantly lower in the temporal cortex and hippocampal formation of aged HD and that patients with T-type leprosy (who did not take DDS) exhibited slightly more Aβ deposition than L-type leprosy. The brains of HD show high abnormal tau deposition in neurons and neural threads despite the low levels of Aβ deposition [38]. Mycobacterium leprae, which induces leprosy, was assumed to cause a low incidence of AD in HD [41]. However, the next researchers hypothesized a null hypothesis because the Aβ removal function of DDS and the dementia reduction by M. leprae are irrelevant [1].
The inflammasome competitor model of DDS shows a reaction pattern that is a typical molecular model of electronic clouds. Therefore, in vitro or in vivo, it can show pathological findings that can be this or that. The autopsy findings of leprosy's brain pathology of the sanatorium in Japan are sometimes like this and sometimes like that. The pathologic findings in the previous review are consistent with those of a typical inflammasome competitor. An alternative way science can help us prevent or treat AD is to use an inflammasome competitor and reduce the prevalence rate.
The molecular properties of DDSs, including electron density and its Laplacian delocalization index, have been elucidated to shed light on the chemical bonding and atomic and molecular details [42, 43]. The redox properties of DDS are dependent on amine and sulfone moieties explain the oxidation mechanism of DDS by electron transfer. The aniline ring is the nucleophilic moiety conferring potential biological properties via a redox mechanism, mainly electron transfer or oxidation for DDS‒NHOH formation [44]. We can understand the various neuropathological findings of HD, including its mysterious sensory manifestations [45].
DDS regulates NLRP3 inflammasome activators and a common signaling pathway of SARS-CoV-2 inflammasome activators in the medulla oblongata [46]. It acts through the same competitive therapeutic mechanism to counter the progression of MCI to AD. Korean HD on Sorokdo (an island for HD patients) continues to take DDS throughout their lives. This drug appears to have a preventive effect against AD, according to the study of HD patients who have lived only all their lives [47]
4.3. Neuroimmunity & neuroprotection for Stroke patients
Hypertension causes blood-brain barrier breakdown by mechanisms involving inflammation, oxidative stress, and circulating vasoactive molecules. It exposes neurons to cytotoxic molecules, leading to neuronal loss, cognitive decline, and impaired recovery from ischemia [48]. Active treatment for elevated blood pressure can decrease perfusion at the cerebral infarction area, thus extending the cerebral infarction area [49]. However, there is no evidence that high blood pressure that develops after a stroke indicates Stroke's severity or is intended to provide collateral blood flow to maintain blood flow to the ischemia area (penumbra) [49-51]. Instead, in 2004, there was a report that patients with stroke had a high mortality rate when hospitalized with high or low blood pressure [51]. There are only reviews reporting that starting treatment for severe hypertension within a few hours of stroke onset can cause a decrease in cerebral blood flow and may be problematic [52]. There is no medical evidence that neglecting high blood pressure can increase a patient's survival rate. However, it has been reported that the stress of being admitted to the hospital is the main factor causing high blood pressure in stroke patients [50].
Markedly low RBC cholesterol and markedly high RBC lipoperoxides may pathologically aggravate cerebral hemorrhage patients and lead to oxidative and lipoperoxidation damage [53]. These factors are positively correlated with erythrocyte deformability [54]. Considering that there are disturbances in the function of erythrocyte membranes and free radicals in acute cerebral infarction, erythrocyte deformity and membrane Na+-K+-ATPase activity in acute cerebral infarction patients were lower than those in healthy persons [55, 56]. Antioxidants such as DDS attenuate microvascular changes in the early phase of experimental pneumococcal meningitis [57]. DDS increases the viability of brain cells in acute stroke. Clinical trials were already conducted in 2013, and statistics were significant [58]. In 2014, an analysis was published that was very effective and economical in treating acute ischemic stroke patients [59]. In 2016, MRI results were published to compensate for functional loss after brain cell damage [60]. Additionally, studies have been reported to protect brain cells and increase viability in various experiments [61]. In particular, the paper that DDS increased Parkin's concentration in old rats was a study that was precisely consistent with the patient (Supplement_7.pdf (page 1-4, Koh) (online suppl. 7 [4])) in the Seoul cohort, who improved Parkinson's symptoms [62].
Astrocytes play a crucial role in regulating homeostasis within the CNS. Furthermore, hypoxia-induced changes in pathological conditions associated with the immune response and manipulation of mitochondrial function and metabolism are mediated. The transcriptomic profile of astrocytes in an in vitro study was used to perform a detailed characterization of hypoxia-induced changes. Analysis of the significant differentially expressed transcripts identified an increase in immune response pathways, dysregulation of signaling pathways, and metabolism, including glycolysis [63]. After administering DDS at 7 pm on 15 September and 18:53 on 16 September, the patient recovered consciousness. Except for taking DDS, the patient’s treatment did not change but improved to stable states of infective endocarditis. DDS also reduced doxorubicin's cardiac toxicity due to its production of free radicals and inflammatory cytokines [64].
DDS has already been used as a substitute for colchicine. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by the DDS may be responsible for its observed preventive effects on MCI [1], functioning as a competitor for the SARS-CoV-2 inflammasome [14].