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Multimer Detection System-Oligomerized Amyloid Beta (MDS-OAβ): A Plasma-Based Biomarker Differentiates Alzheimer’s Disease from Other Etiologies of Dementia

Multimer Detection System-Oligomerized Amyloid Beta (MDS-OAβ): A Plasma-Based Biomarker... Hindawi International Journal of Alzheimer’s Disease Volume 2022, Article ID 9960832, 6 pages https://doi.org/10.1155/2022/9960832 Research Article Multimer Detection System-Oligomerized Amyloid Beta (MDS-OAβ): A Plasma-Based Biomarker Differentiates Alzheimer’s Disease from Other Etiologies of Dementia 1,2,3 1 2,4 Jacqueline Cotoong Dominguez , Jeryl Ritzi Tan Yu, Ma Fe De Guzman, 1,2,5 2 1,2,5 Encarnita Ampil , Anne Cristine Guevarra, Ma. Lourdes Joson , 2,4,6,7,8 1,3 3,9 2 Macario Reandelar Jr., Ma. Socorro Martinez, Antonio Ligsay, Ferron Ocampo, and SangYun Kim St Luke’s Medical Center, Institute for Neurosciences, Philippines Institute for Dementia Care Asia, Philippines St. Luke’s College of Medicine William H. Quasha Memorial, Philippines Research and Biotechnology Division, St. Luke’s Medical Center, Philippines Department of Neuroscience and Behavioral Medicine, Faculty of Medicine and Surgery, University of Santo Tomas, Philippines Far Eastern University, Dr. Nicanor Reyes Medical Foundation, Philippines Our Lady of Fatima University, Philippines New Era University College of Medicine, Philippines College of Science and the Graduate School, University of Santo Tomas, Philippines Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea Correspondence should be addressed to Ma. Lourdes Joson; mcjoson@ust.edu.ph Received 23 December 2021; Accepted 12 April 2022; Published 2 May 2022 Academic Editor: Giulia Abate Copyright © 2022 Jacqueline Cotoong Dominguez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. With emerging amyloid therapies, documentation of the patient’s amyloid status to confirm the etiology of a clinical diagnosis is warranted prior to instituting amyloid-based therapy. The Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ)isa noninvasive blood-based biomarker utilized to measure Aβ oligomerization tendency. We determined the difference in MDS- OAβ ratio across the groups: (a) no cognitive impairment or subjective cognitive impairment (NCI/SCI), (b) Alzheimer’s disease (AD), (c) non-AD, and (d) mixed Alzheimer’s disease-Vascular dementia (AD-VaD). MDS-OAβ level was not significantly different between AD and mixed AD-VaD, but both groups were significantly different from the NCI/SCI and from the non-AD group. An MDS-OAβ level of >1 could potentially indicate clinical variants of AD or mixed pathology (AD-VaD). 1. Introduction cannot halt or reverse disease progression. Revisions in the diagnostic criteria of dementia due to AD based on the Alzheimer’s disease (AD) is a progressive neurodegenerative National Institute on Aging and the Alzheimer’s Association (NIA-AA) included documentation of brain amyloid via disorder that commonly affects the elderly [1], accounting for biomarkers [5]. Among these, the most well established and up to 80% of dementias, [2] with a heavy socio-economic validated are cerebrospinal fluid amyloid-β 42 (Aβ ) (CSF burden [3, 4]. The diagnosis of AD at preclinical stages is crit- Aβ ) and PET amyloid imaging [5, 6]. However, these ical, because treatment after the onset of clinical symptoms 42 2 International Journal of Alzheimer’s Disease MDS-OAβ result available. Diagnosis was made at the end biomarkers are rarely utilized in the clinical setting as they are invasive and expensive and have limited accessibility to of the clinical assessment without knowing the result of the patients [7], leading to the development of blood-based MDS-OAβ blood test. biomarkers [8–10] which can provide minimally invasive Each eligible participant was assigned a study code, and and inexpensive methods for early screening and diagnosis data on demographic characteristics, Clinical Dementia Rat- of AD. ing (CDR) score, and etiologic diagnosis based on the clini- Brain amyloidosis is a critical hallmark of AD, and its cian’s assessment were recorded. MDS-OAβ blood test for pathologic development starts 10-20 years prior to its clinical amyloid oligomerization tendency was done as per physi- manifestation and onset of cognitive symptoms [5, 11]. There cian’s request, and the MDS-OAβ levels were obtained. is accumulating evidence that oligomerized Aβ (OAβ) is the The data collection forms were documented by a nurse clini- most neurotoxic among different Aβ types and that aggrega- cian and reviewed by a neurologist. Data were encoded inde- tion of these oligomers is toxic in vivo [12]. Compared to pendently, and inconsistencies were double-checked with amyloid-β plaque loads, oligomerized amyloid-β (OAβ) the data source to ensure data accuracy. was found to have higher correlation with presence and Sample size was calculated using the test of hypothesis severity of cognitive symptoms [13, 14]. Hence, Aβ oligo- for the difference between mean and standard deviation mers played a key role in pathogenesis and prediction of (SD) of MDS-OAβ among patients with MCI versus those AD diagnosis [15]. Recently, an enzyme-linked immunosor- healthy normal control. Assuming that mean and SD of bent assay, the Multimer Detection System-Oligomeric MDS-OAß among MCI patients is 0:964 ± 0:098 and among healthy normal controls, 0:904 ± 0:130 [22], with an alpha Amyloid-β (MDS-OAβ), was utilized to detect Aβ oligomer- ization in plasma, correlating well with other clinical bio- error of 5%, power of 95%, and a one-tailed alternative markers such as CSF Aβ and amyloid PET [16]. It hypothesis, sample size required is 23 per group, for a total measures the dynamic change of plasma oligomeric Aβ con- of 92 for 4 groups. centration, which is higher in AD patients compared to older adults with normal cognition [15]. MDS-OAB had shown a 2.2. MDS-OAβ Assay Description and Procedure. The higher diagnostic accuracy in identifying AD from controls, inBlood™ oligomerized Aβ (OAβ)test (PeopleBio Inc., compared with other amyloid biomarkers that evaluates Republic of Korea) was used to quantify MDS-OAβ values plasma OAB concentrations [17–19]. However, limited stud- in the plasma from the subjects. This test is based on the ies have compared OAβ levels among individuals with AD Multimer Detection System (MDS), which is a modified enzyme-linked immunosorbent assay (ELISA) using epitope- and other dementia types [15, 17]. Given that underlying eti- ologies of cognitive decline impact emerging therapies that overlapping detection antibodies specific for the N-terminus are target-specific, clinicians need clinically valid and cost- of Aβ for the selective detection of OAβ over Aβ monomers. effective biomarkers that can be utilized to provide accurate Prior to the assay, aliquots of plasma samples were diagnosis of dementia etiology. The aim of this study is to thawed at 37 C for 15 min. As indicated in the assay protocol investigate whether MDS-OAβ could assist in determination of the inBlood™ OAβ test, PBR-1 (synthetic Aβ made by of AD from dementia of other etiologies. PeopleBio Inc.) was spiked into plasma, and the mixture was incubated at 37 C for 48 hours. The incubated plasma sample mixture and serially diluted standard samples were 2. Materials and Methods added to each well of the plates. The plates were incubated 2.1. Subjects. Participants were enrolled at the Memory Cen- at about 20-25 C for 1 hour. After washing three times with ter of St. Luke’s Medical Center Global City from January washing buffer, W02-HRP antibody (Absolute Antibody 2018 to March 2019. All participants underwent clinical Ltd., UK) was added to the wells, and the plates were incu- evaluation and detailed neuropsychological assessment, cra- bated for 1 hour at about 20 to 25 C. To increase the sensitiv- nial magnetic resonance imaging (MRI), and MDS-OAβ ity of detection, 100 μl/well of enhanced chemiluminescence blood test (first made available in the Philippines in Novem- substrate solution (Rockland Immunochemicals Inc., USA) ber 2017). The inclusion criteria were as follows: (1) adult was added, and the Relative Luminescence Unit (RLU) signal patients with subjective report of cognitive decline or mem- was detected using a multispectrophotometer. Dilutions pro- ory impairment; (2) diagnosed and categorized by a demen- viding signal in the linear range of the standard curves were tia specialist into one of the following: (a) no cognitive used for the conversion to RLU values to determine the con- impairment/subjective cognitive impairment (NCI/SCI): centration of oligomerized Aβ. presence of persistent cognitive symptoms without evidence of impairment in psychometric tests; (b) dementia, based on 2.3. Statistical Analysis. Data was analyzed using Statistical the DSM-IV TR criteria [20] and further classified into the Program for Social Sciences version 23 (SPSS Inc.: IBM). Dif- following clinical diagnosis: AD, NINCDS-ADRDA criteria ferences in patients’ clinical characteristics across different eti- [5]; mixed AD-VaD, coexistence of AD and vascular demen- ological diagnosis were analyzed using Pearson Chi-square tia (VaD) as defined in NINDS-AIREN criteria [21]; and test for categorical variables (i.e., sex, age groups, and CDR non-AD dementia, including frontotemporal dementia, severity stages), and one-way analysis of variance (ANOVA) Lewy body disease, and Parkinson dementia; (3) underwent was used for continuous variables. Two-way ANOVA was comprehensive neuropsychological assessment (clinical used to determine the difference in MDS-OAβ ratio of dementia protocol) at the Memory Service clinic; and (4) patients grouped by age and etiological diagnosis. LSD and International Journal of Alzheimer’s Disease 3 Patient recruitment 231 patients recruited Excluded: 84 incomplete evaluation or no MDS-OA𝛽 test available 147 were total sample included in the analysis Non-AD NCI/SCI AD Mixed AD/VAD dementia (N = 14) (N = 72) (N = 29) (N = 32) Figure 1: Study flow-chart. Bonferroni tests were used for post hoc analysis. Significance was only marginally significant difference when MDS-OAβ level was set at p ≤ 0:05 (95% confidence interval). patient/control (PT/C) ratio was compared across different The conduct of this study was guided by the principles of age groups (≤59, 60-69, 70-79, and ≥80 years old) among Good Clinical Practice and in accordance with local regula- four etiologic diagnosis (p =0:07, Table 1), indicating tions and was approved by the St. Luke’s Institutional Ethics MDS-OAβ level does not significantly vary based on age Review Committee (SL-20192). groups but more significantly on etiologic cause of cognitive impairment and dementia. 3. Results 4. Discussion A total of 231 patients were recruited. Of these participants, 84 were excluded due to incomplete evaluation, resulting in In this study, we found that MDS-OAβ could differentiate 147 patients included in the study (Figure 1). Among those between dementias due AD versus non-AD etiologies. included, majority were females (62.6%) with a mean age Majority of the patients in this study were in the mild stage of 75:0±10:0 years (age ranged from 38 to 94 years old; with Clinical Dementia Rating (CDR) 0.5 and 1, indicating Table 1). The most prevalent clinical diagnosis was AD that MDS-OAβ could detect AD. These findings have sev- (49.0%), followed by non-AD dementia (21.8%), mixed eral implications. Given the long preclinical stage of AD, AD-VaD (19.7%), and NCI/SCI (9.5%). Clinical characteris- patients would benefit from early diagnosis prior to the tics were compared across clinical diagnosis for cognitive onset of symptoms. This is consistent with results from a impairment and dementia. Results showed no significant study by Lee et al. in which MDS-OAβ was shown to be a difference in sex distribution among the four clinical diagno- useful screening tool for individuals in the MCI stage [23]. sis (p =0:66). On the other hand, age groups and CDR stage MDS-OAβ also had some correlation with brain volume distribution were significantly different across different etio- reduction consistent with AD [24] and showed correlation logic diagnosis (p <0:001; Table 1). The age group distribu- with decline in memory performance [25], further support- tion among the NCI/SCI group was younger compared ing its utility as a noninvasive biomarker for AD. In a study among patients with AD, non-AD, and mixed AD-VaD. In by Youn et al., MDS-OAβ was able to validate the clinical terms of severity, more than half of the patients were at diagnosis of AD when compared to normal controls (sensi- the earliest stage of cognitive impairment or dementia tivity of 100% and specificity of 92.31%) [15]. (CDR = 0:5; 57.1%), followed by mild (CDR = 1; 24.5%), The level of OAβ could provide valuable information moderate (CDR = 2; 8.2%), and severe (CDR = 3; 4.1%) with regard to the stage or AD progression. MDS-OAβ mea- dementia stages in decreasing order (Table 1). sures the oligomerization tendency of Aβ, and it was postu- The MDS-OAβ PT/C ratio was significantly different lated to correspond to the derivative of the sigmoid function among groups (p <0:001; Table 1). Consistently, the average of Aβ accumulation [15]. Studies have shown that oligomer oligomerized amyloid-β (OAβ) levels were highest among concentrations were higher in MCI or early stage AD [26]. patients with AD diagnosis, followed by mixed AD-VaD Therefore, an MDS-OAβ level of >1 in NCI/SCI subjects and lowest in the NCI/SCI group (Figure 2). Post hoc anal- can correspond to the preclinical stage of AD. As the disease ysis revealed that OAβ levels of patients with AD and mixed progresses, there is eventual attenuation in the expression of AD-VaD diagnosis were not significantly different from each this biomarker. Hence, low OAβ levels (<0.5) among AD other (p >0:05) but significantly different from patients with patients are highly suggestive of late-stage AD. A possible NCI/SCI (p <0:001) and non-AD (p <0.01) diagnosis. There explanation could be that the concentrations of biomarkers 4 International Journal of Alzheimer’s Disease Table 1: Clinical characteristics of participants. Etiologic diagnosis p value NCI/SCI (N =14)AD(N =72) Non-AD (N =32) Mixed AD-VaD (N =29) Total (N = 147) 66:07 ± 12:26 77:48 ± 7:88 71:47 ± 12:12 78:24 ± 6:94 75:08 ± 10:04 Age < 0.001 Age groups ≤59 years 6 (42.9) 1 (1.4) 6 (18.8) — 13 (8.9) 60-69 years 2 (14.3) 10 (14.1) 7 (21.9) 3 (10.3) 22 (15.1) < 0.001 70-79 years 4 (28.6) 28 (39.4) 12 (37.5) 11 (37.9) 55 (37.7) ≥80 years 2 (14.3) 32 (45.1) 7 (21.9) 15 (51.7) 56 (38.4) Sex Male 7 (50.0) 24 (33.3) 13 (40.6) 11 (37.9) 55 (37.4) 0.66 Female 7 (50.0) 48 (66.7) 19 (59.4) 18 (62.1) 92 (62.6) CDR stages Normal 9 (64.3) —— — 9 (6.1) Very mild 5 (35.7) 45 (62.5) 20 (62.5) 14 (48.3) 84 (57.1) Mild — 17 (23.6) 7 (21.9) 12 (41.4) 36 (24.5) < 0.001 Moderate — 6 (8.3) 4 (12.5) 2 (6.9) 12 (8.2) Severe — 4 (5.6) 1 (3.1) 1 (3.4) 6 (4.1) Total 14 (100.0) 72 (100.0) 32 (100.0) 29 (100.0) 147 (100.0) PT/C ratio 0:76 ± 0:32 1:22 ± 0:37 0:76 ± 0:37 1:09 ± 0:23 1:05 ± 0:40 < 0.001 PT/C ratio by age groups 0:76 ± 0:31 1:19 ± 0:00 0:65 ± 0:37 0:74 ± 0:34 ≤59 years — 0:75 ± 0:21 1:26 ± 0:57 0:89 ± 0:38 1:10 ± 0:14 1:07 ± 0:47 60-69 years 0.07 1:00 ± 0:20 1:16 ± 0:23 0:73 ± 0:40 1:19 ± 0:22 1:06 ± 0:32 70-79 years ≥80 years 0:29 ± 0:18 1:26 ± 0:41 0:79 ± 0:37 1:01 ± 0:24 1:10 ± 0:42 Data were presented as mean ± standard deviation or frequency (percentages). NCI: no cognitive impairment; SCI: subjective cognitive impairment; AD: Alzheimer’s disease; Non-AD: non-Alzheimer’s disease; Mixed AD-VaD: mixed etiology Alzheimer’s disease with either vascular cognitive impairment, subcortical ischemic vascular dementia, or cerebrovascular disease. (p > 0.05) 1.40 (p < 0.001) (p < 0.001) 1.20 1.00 (p <0.001) 0.80 0.60 (p <0.05) (p > 0.05) 0.40 NCI/SCI AD Non-AD Mixed AD/VAD Clinical diagnosis Figure 2: Comparison of the mean and 95% CI of MDS-OAβ per clinical diagnosis. Mean and 95% CI of MDS-OA International Journal of Alzheimer’s Disease 5 associated with AD pathogenesis, including OAβ, show 5. Conclusion decreasing trend after symptomatic disease progression, With the advent of emerging therapies that are targeted at denoting slowing of the neurodegenerative process [15]. the amyloid pathology, documentation of the patient’s amy- Moreover, low levels of amyloid in AD patients could also loid status to confirm etiology of clinical diagnosis is war- correspond to limbic-predominant age-related TDP-43 ranted prior to instituting amyloid-based therapy. Based on encephalopathy (LATE), which is seen in advanced elderly the current findings, MDS-OAβ is a simple, noninvasive test patients with features similar to AD. However, the underly- and could discriminate between AD and other types of neu- ing neuropathology for LATE is characterized by the pres- rodegenerative disorders. ence of TDP-43 protein inclusion bodies in the cytoplasm and accumulation of hyperphosphorylated TDP-43 in nuclei and cell processes of neurons [27]. Lastly, patients with non- Data Availability AD dementia are expected to have low levels of OAβ; there- fore, an MDS-OAβ level of >1 in these patients could poten- The technical appendix, statistical code, and dataset used to tially indicate clinical variants of AD or mixed pathology. support the findings of this study will be made available In clinical practice, patients with cognitive decline are from the corresponding author upon request. assessed using tools such as the Mini Mental Status Exam (MMSE) and Montreal Cognitive Assessment (MoCA). Conflicts of Interest When equivocal, additional neuropsychological evaluation is often warranted [1]. The incorporation of CSF Aβ and The authors declare no conflict of interest. PET amyloid biomarkers in the revised diagnostic criteria of Alzheimer’s disease (NIA-AA) [5] has resulted in diag- nostic and management shifts [28]. 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Multimer Detection System-Oligomerized Amyloid Beta (MDS-OAβ): A Plasma-Based Biomarker Differentiates Alzheimer’s Disease from Other Etiologies of Dementia

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Hindawi International Journal of Alzheimer’s Disease Volume 2022, Article ID 9960832, 6 pages https://doi.org/10.1155/2022/9960832 Research Article Multimer Detection System-Oligomerized Amyloid Beta (MDS-OAβ): A Plasma-Based Biomarker Differentiates Alzheimer’s Disease from Other Etiologies of Dementia 1,2,3 1 2,4 Jacqueline Cotoong Dominguez , Jeryl Ritzi Tan Yu, Ma Fe De Guzman, 1,2,5 2 1,2,5 Encarnita Ampil , Anne Cristine Guevarra, Ma. Lourdes Joson , 2,4,6,7,8 1,3 3,9 2 Macario Reandelar Jr., Ma. Socorro Martinez, Antonio Ligsay, Ferron Ocampo, and SangYun Kim St Luke’s Medical Center, Institute for Neurosciences, Philippines Institute for Dementia Care Asia, Philippines St. Luke’s College of Medicine William H. Quasha Memorial, Philippines Research and Biotechnology Division, St. Luke’s Medical Center, Philippines Department of Neuroscience and Behavioral Medicine, Faculty of Medicine and Surgery, University of Santo Tomas, Philippines Far Eastern University, Dr. Nicanor Reyes Medical Foundation, Philippines Our Lady of Fatima University, Philippines New Era University College of Medicine, Philippines College of Science and the Graduate School, University of Santo Tomas, Philippines Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea Correspondence should be addressed to Ma. Lourdes Joson; mcjoson@ust.edu.ph Received 23 December 2021; Accepted 12 April 2022; Published 2 May 2022 Academic Editor: Giulia Abate Copyright © 2022 Jacqueline Cotoong Dominguez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. With emerging amyloid therapies, documentation of the patient’s amyloid status to confirm the etiology of a clinical diagnosis is warranted prior to instituting amyloid-based therapy. The Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ)isa noninvasive blood-based biomarker utilized to measure Aβ oligomerization tendency. We determined the difference in MDS- OAβ ratio across the groups: (a) no cognitive impairment or subjective cognitive impairment (NCI/SCI), (b) Alzheimer’s disease (AD), (c) non-AD, and (d) mixed Alzheimer’s disease-Vascular dementia (AD-VaD). MDS-OAβ level was not significantly different between AD and mixed AD-VaD, but both groups were significantly different from the NCI/SCI and from the non-AD group. An MDS-OAβ level of >1 could potentially indicate clinical variants of AD or mixed pathology (AD-VaD). 1. Introduction cannot halt or reverse disease progression. Revisions in the diagnostic criteria of dementia due to AD based on the Alzheimer’s disease (AD) is a progressive neurodegenerative National Institute on Aging and the Alzheimer’s Association (NIA-AA) included documentation of brain amyloid via disorder that commonly affects the elderly [1], accounting for biomarkers [5]. Among these, the most well established and up to 80% of dementias, [2] with a heavy socio-economic validated are cerebrospinal fluid amyloid-β 42 (Aβ ) (CSF burden [3, 4]. The diagnosis of AD at preclinical stages is crit- Aβ ) and PET amyloid imaging [5, 6]. However, these ical, because treatment after the onset of clinical symptoms 42 2 International Journal of Alzheimer’s Disease MDS-OAβ result available. Diagnosis was made at the end biomarkers are rarely utilized in the clinical setting as they are invasive and expensive and have limited accessibility to of the clinical assessment without knowing the result of the patients [7], leading to the development of blood-based MDS-OAβ blood test. biomarkers [8–10] which can provide minimally invasive Each eligible participant was assigned a study code, and and inexpensive methods for early screening and diagnosis data on demographic characteristics, Clinical Dementia Rat- of AD. ing (CDR) score, and etiologic diagnosis based on the clini- Brain amyloidosis is a critical hallmark of AD, and its cian’s assessment were recorded. MDS-OAβ blood test for pathologic development starts 10-20 years prior to its clinical amyloid oligomerization tendency was done as per physi- manifestation and onset of cognitive symptoms [5, 11]. There cian’s request, and the MDS-OAβ levels were obtained. is accumulating evidence that oligomerized Aβ (OAβ) is the The data collection forms were documented by a nurse clini- most neurotoxic among different Aβ types and that aggrega- cian and reviewed by a neurologist. Data were encoded inde- tion of these oligomers is toxic in vivo [12]. Compared to pendently, and inconsistencies were double-checked with amyloid-β plaque loads, oligomerized amyloid-β (OAβ) the data source to ensure data accuracy. was found to have higher correlation with presence and Sample size was calculated using the test of hypothesis severity of cognitive symptoms [13, 14]. Hence, Aβ oligo- for the difference between mean and standard deviation mers played a key role in pathogenesis and prediction of (SD) of MDS-OAβ among patients with MCI versus those AD diagnosis [15]. Recently, an enzyme-linked immunosor- healthy normal control. Assuming that mean and SD of bent assay, the Multimer Detection System-Oligomeric MDS-OAß among MCI patients is 0:964 ± 0:098 and among healthy normal controls, 0:904 ± 0:130 [22], with an alpha Amyloid-β (MDS-OAβ), was utilized to detect Aβ oligomer- ization in plasma, correlating well with other clinical bio- error of 5%, power of 95%, and a one-tailed alternative markers such as CSF Aβ and amyloid PET [16]. It hypothesis, sample size required is 23 per group, for a total measures the dynamic change of plasma oligomeric Aβ con- of 92 for 4 groups. centration, which is higher in AD patients compared to older adults with normal cognition [15]. MDS-OAB had shown a 2.2. MDS-OAβ Assay Description and Procedure. The higher diagnostic accuracy in identifying AD from controls, inBlood™ oligomerized Aβ (OAβ)test (PeopleBio Inc., compared with other amyloid biomarkers that evaluates Republic of Korea) was used to quantify MDS-OAβ values plasma OAB concentrations [17–19]. However, limited stud- in the plasma from the subjects. This test is based on the ies have compared OAβ levels among individuals with AD Multimer Detection System (MDS), which is a modified enzyme-linked immunosorbent assay (ELISA) using epitope- and other dementia types [15, 17]. Given that underlying eti- ologies of cognitive decline impact emerging therapies that overlapping detection antibodies specific for the N-terminus are target-specific, clinicians need clinically valid and cost- of Aβ for the selective detection of OAβ over Aβ monomers. effective biomarkers that can be utilized to provide accurate Prior to the assay, aliquots of plasma samples were diagnosis of dementia etiology. The aim of this study is to thawed at 37 C for 15 min. As indicated in the assay protocol investigate whether MDS-OAβ could assist in determination of the inBlood™ OAβ test, PBR-1 (synthetic Aβ made by of AD from dementia of other etiologies. PeopleBio Inc.) was spiked into plasma, and the mixture was incubated at 37 C for 48 hours. The incubated plasma sample mixture and serially diluted standard samples were 2. Materials and Methods added to each well of the plates. The plates were incubated 2.1. Subjects. Participants were enrolled at the Memory Cen- at about 20-25 C for 1 hour. After washing three times with ter of St. Luke’s Medical Center Global City from January washing buffer, W02-HRP antibody (Absolute Antibody 2018 to March 2019. All participants underwent clinical Ltd., UK) was added to the wells, and the plates were incu- evaluation and detailed neuropsychological assessment, cra- bated for 1 hour at about 20 to 25 C. To increase the sensitiv- nial magnetic resonance imaging (MRI), and MDS-OAβ ity of detection, 100 μl/well of enhanced chemiluminescence blood test (first made available in the Philippines in Novem- substrate solution (Rockland Immunochemicals Inc., USA) ber 2017). The inclusion criteria were as follows: (1) adult was added, and the Relative Luminescence Unit (RLU) signal patients with subjective report of cognitive decline or mem- was detected using a multispectrophotometer. Dilutions pro- ory impairment; (2) diagnosed and categorized by a demen- viding signal in the linear range of the standard curves were tia specialist into one of the following: (a) no cognitive used for the conversion to RLU values to determine the con- impairment/subjective cognitive impairment (NCI/SCI): centration of oligomerized Aβ. presence of persistent cognitive symptoms without evidence of impairment in psychometric tests; (b) dementia, based on 2.3. Statistical Analysis. Data was analyzed using Statistical the DSM-IV TR criteria [20] and further classified into the Program for Social Sciences version 23 (SPSS Inc.: IBM). Dif- following clinical diagnosis: AD, NINCDS-ADRDA criteria ferences in patients’ clinical characteristics across different eti- [5]; mixed AD-VaD, coexistence of AD and vascular demen- ological diagnosis were analyzed using Pearson Chi-square tia (VaD) as defined in NINDS-AIREN criteria [21]; and test for categorical variables (i.e., sex, age groups, and CDR non-AD dementia, including frontotemporal dementia, severity stages), and one-way analysis of variance (ANOVA) Lewy body disease, and Parkinson dementia; (3) underwent was used for continuous variables. Two-way ANOVA was comprehensive neuropsychological assessment (clinical used to determine the difference in MDS-OAβ ratio of dementia protocol) at the Memory Service clinic; and (4) patients grouped by age and etiological diagnosis. LSD and International Journal of Alzheimer’s Disease 3 Patient recruitment 231 patients recruited Excluded: 84 incomplete evaluation or no MDS-OA𝛽 test available 147 were total sample included in the analysis Non-AD NCI/SCI AD Mixed AD/VAD dementia (N = 14) (N = 72) (N = 29) (N = 32) Figure 1: Study flow-chart. Bonferroni tests were used for post hoc analysis. Significance was only marginally significant difference when MDS-OAβ level was set at p ≤ 0:05 (95% confidence interval). patient/control (PT/C) ratio was compared across different The conduct of this study was guided by the principles of age groups (≤59, 60-69, 70-79, and ≥80 years old) among Good Clinical Practice and in accordance with local regula- four etiologic diagnosis (p =0:07, Table 1), indicating tions and was approved by the St. Luke’s Institutional Ethics MDS-OAβ level does not significantly vary based on age Review Committee (SL-20192). groups but more significantly on etiologic cause of cognitive impairment and dementia. 3. Results 4. Discussion A total of 231 patients were recruited. Of these participants, 84 were excluded due to incomplete evaluation, resulting in In this study, we found that MDS-OAβ could differentiate 147 patients included in the study (Figure 1). Among those between dementias due AD versus non-AD etiologies. included, majority were females (62.6%) with a mean age Majority of the patients in this study were in the mild stage of 75:0±10:0 years (age ranged from 38 to 94 years old; with Clinical Dementia Rating (CDR) 0.5 and 1, indicating Table 1). The most prevalent clinical diagnosis was AD that MDS-OAβ could detect AD. These findings have sev- (49.0%), followed by non-AD dementia (21.8%), mixed eral implications. Given the long preclinical stage of AD, AD-VaD (19.7%), and NCI/SCI (9.5%). Clinical characteris- patients would benefit from early diagnosis prior to the tics were compared across clinical diagnosis for cognitive onset of symptoms. This is consistent with results from a impairment and dementia. Results showed no significant study by Lee et al. in which MDS-OAβ was shown to be a difference in sex distribution among the four clinical diagno- useful screening tool for individuals in the MCI stage [23]. sis (p =0:66). On the other hand, age groups and CDR stage MDS-OAβ also had some correlation with brain volume distribution were significantly different across different etio- reduction consistent with AD [24] and showed correlation logic diagnosis (p <0:001; Table 1). The age group distribu- with decline in memory performance [25], further support- tion among the NCI/SCI group was younger compared ing its utility as a noninvasive biomarker for AD. In a study among patients with AD, non-AD, and mixed AD-VaD. In by Youn et al., MDS-OAβ was able to validate the clinical terms of severity, more than half of the patients were at diagnosis of AD when compared to normal controls (sensi- the earliest stage of cognitive impairment or dementia tivity of 100% and specificity of 92.31%) [15]. (CDR = 0:5; 57.1%), followed by mild (CDR = 1; 24.5%), The level of OAβ could provide valuable information moderate (CDR = 2; 8.2%), and severe (CDR = 3; 4.1%) with regard to the stage or AD progression. MDS-OAβ mea- dementia stages in decreasing order (Table 1). sures the oligomerization tendency of Aβ, and it was postu- The MDS-OAβ PT/C ratio was significantly different lated to correspond to the derivative of the sigmoid function among groups (p <0:001; Table 1). Consistently, the average of Aβ accumulation [15]. Studies have shown that oligomer oligomerized amyloid-β (OAβ) levels were highest among concentrations were higher in MCI or early stage AD [26]. patients with AD diagnosis, followed by mixed AD-VaD Therefore, an MDS-OAβ level of >1 in NCI/SCI subjects and lowest in the NCI/SCI group (Figure 2). Post hoc anal- can correspond to the preclinical stage of AD. As the disease ysis revealed that OAβ levels of patients with AD and mixed progresses, there is eventual attenuation in the expression of AD-VaD diagnosis were not significantly different from each this biomarker. Hence, low OAβ levels (<0.5) among AD other (p >0:05) but significantly different from patients with patients are highly suggestive of late-stage AD. A possible NCI/SCI (p <0:001) and non-AD (p <0.01) diagnosis. There explanation could be that the concentrations of biomarkers 4 International Journal of Alzheimer’s Disease Table 1: Clinical characteristics of participants. Etiologic diagnosis p value NCI/SCI (N =14)AD(N =72) Non-AD (N =32) Mixed AD-VaD (N =29) Total (N = 147) 66:07 ± 12:26 77:48 ± 7:88 71:47 ± 12:12 78:24 ± 6:94 75:08 ± 10:04 Age < 0.001 Age groups ≤59 years 6 (42.9) 1 (1.4) 6 (18.8) — 13 (8.9) 60-69 years 2 (14.3) 10 (14.1) 7 (21.9) 3 (10.3) 22 (15.1) < 0.001 70-79 years 4 (28.6) 28 (39.4) 12 (37.5) 11 (37.9) 55 (37.7) ≥80 years 2 (14.3) 32 (45.1) 7 (21.9) 15 (51.7) 56 (38.4) Sex Male 7 (50.0) 24 (33.3) 13 (40.6) 11 (37.9) 55 (37.4) 0.66 Female 7 (50.0) 48 (66.7) 19 (59.4) 18 (62.1) 92 (62.6) CDR stages Normal 9 (64.3) —— — 9 (6.1) Very mild 5 (35.7) 45 (62.5) 20 (62.5) 14 (48.3) 84 (57.1) Mild — 17 (23.6) 7 (21.9) 12 (41.4) 36 (24.5) < 0.001 Moderate — 6 (8.3) 4 (12.5) 2 (6.9) 12 (8.2) Severe — 4 (5.6) 1 (3.1) 1 (3.4) 6 (4.1) Total 14 (100.0) 72 (100.0) 32 (100.0) 29 (100.0) 147 (100.0) PT/C ratio 0:76 ± 0:32 1:22 ± 0:37 0:76 ± 0:37 1:09 ± 0:23 1:05 ± 0:40 < 0.001 PT/C ratio by age groups 0:76 ± 0:31 1:19 ± 0:00 0:65 ± 0:37 0:74 ± 0:34 ≤59 years — 0:75 ± 0:21 1:26 ± 0:57 0:89 ± 0:38 1:10 ± 0:14 1:07 ± 0:47 60-69 years 0.07 1:00 ± 0:20 1:16 ± 0:23 0:73 ± 0:40 1:19 ± 0:22 1:06 ± 0:32 70-79 years ≥80 years 0:29 ± 0:18 1:26 ± 0:41 0:79 ± 0:37 1:01 ± 0:24 1:10 ± 0:42 Data were presented as mean ± standard deviation or frequency (percentages). NCI: no cognitive impairment; SCI: subjective cognitive impairment; AD: Alzheimer’s disease; Non-AD: non-Alzheimer’s disease; Mixed AD-VaD: mixed etiology Alzheimer’s disease with either vascular cognitive impairment, subcortical ischemic vascular dementia, or cerebrovascular disease. (p > 0.05) 1.40 (p < 0.001) (p < 0.001) 1.20 1.00 (p <0.001) 0.80 0.60 (p <0.05) (p > 0.05) 0.40 NCI/SCI AD Non-AD Mixed AD/VAD Clinical diagnosis Figure 2: Comparison of the mean and 95% CI of MDS-OAβ per clinical diagnosis. Mean and 95% CI of MDS-OA International Journal of Alzheimer’s Disease 5 associated with AD pathogenesis, including OAβ, show 5. Conclusion decreasing trend after symptomatic disease progression, With the advent of emerging therapies that are targeted at denoting slowing of the neurodegenerative process [15]. the amyloid pathology, documentation of the patient’s amy- Moreover, low levels of amyloid in AD patients could also loid status to confirm etiology of clinical diagnosis is war- correspond to limbic-predominant age-related TDP-43 ranted prior to instituting amyloid-based therapy. Based on encephalopathy (LATE), which is seen in advanced elderly the current findings, MDS-OAβ is a simple, noninvasive test patients with features similar to AD. However, the underly- and could discriminate between AD and other types of neu- ing neuropathology for LATE is characterized by the pres- rodegenerative disorders. ence of TDP-43 protein inclusion bodies in the cytoplasm and accumulation of hyperphosphorylated TDP-43 in nuclei and cell processes of neurons [27]. Lastly, patients with non- Data Availability AD dementia are expected to have low levels of OAβ; there- fore, an MDS-OAβ level of >1 in these patients could poten- The technical appendix, statistical code, and dataset used to tially indicate clinical variants of AD or mixed pathology. support the findings of this study will be made available In clinical practice, patients with cognitive decline are from the corresponding author upon request. assessed using tools such as the Mini Mental Status Exam (MMSE) and Montreal Cognitive Assessment (MoCA). Conflicts of Interest When equivocal, additional neuropsychological evaluation is often warranted [1]. The incorporation of CSF Aβ and The authors declare no conflict of interest. PET amyloid biomarkers in the revised diagnostic criteria of Alzheimer’s disease (NIA-AA) [5] has resulted in diag- nostic and management shifts [28]. 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International Journal of Alzheimer's DiseaseHindawi Publishing Corporation

Published: May 2, 2022

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