1. Introduction
The prevalence of mild cognitive impairment (MCI) without dementia among people over 71 is 22%. While 11.7% of the patients with all-cause MCI convert to dementia annually, prodromal Alzheimer’s disease (AD) progresses to dementia at a higher rate of 20.1% [
1]. All in all, more than half of MCI cases progress to dementia within 5 years [
1,
2]. Some MCI patients, however, remain stationary or even improve in cognitive function over time. Clinically, to identify which MCIs will progress along the AD continuum is important, as cholinesterase inhibitor (ChEI) may have benefits to early AD patients [
3]. Moreover, with new disease-modifying therapies (DMTs) having been recently approved [
4,
5], the discrimination of MCI due to AD from MCI due to non-AD is even more salient than before. Without using amyloid positron emission tomography (PET) scan, cerebrospinal fluid (CSF), or plasma biomarkers, it is difficult to differentiate one neurodegenerative disease from another at the MCI stage, see
Table 1.
Single-photon emission computerized tomography (SPECT) is commonly used to diagnose AD since it is more acceptable than amyloid PET in availability and affordability. The easy Z-score imaging system (eZIS) is a quantitative method for detecting brain hypoperfusion, and it is more objective and reliable than visual interpretation by physicians. eZIS-assisted SPECT accurately detects hypoperfusion in the posterior cingulate cortex, precuneus, and inferior parietal cortex, which are cerebral regions commonly involved in early AD [
6]. The three indicators of the eZIS (severity, extent, and ratio) can adequately discriminate very early AD from healthy controls [
7,
8,
9]. Three indicators for characterizing perfusion decreases in patients with very early AD were determined [
9,
10]: First, the severity of hypoperfusion in specific areas showing hypoperfusion in very early AD from the mean positive Z-score in a specific volume of interest (VOI) consisting of the posterior cingulate gyrus, precuneus, and parietal lobes. Second, the extent of areas showing significant hypoperfusion in a specific VOI, i.e., the percentage of coordinates where the Z-score exceeds a threshold value of 2. Third, the ratio of the extent of areas showing significant hypoperfusion at a specific VOI to the extent of areas showing significant hypoperfusion in the whole brain. This ratio indicates the specificity of the hypoperfusion at a specific VOI relative to the hypoperfusion in the whole brain. When combined with Mini-mental State Examination (MMSE) scores, the Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD), and eZIS, the discrimination between MCI and early AD is more powerful than using MMSE alone [
11]. Meanwhile, higher values of eZIS indicators of the posterior cingulate gyrus, precuneus, and parietal lobe have been reported to be associated with AD pathology [
12,
13].
In terms of the association between eZIS indicators and cerebral amyloid pathology, one study compared two groups of amnestic MCI patients. The results showed that a higher eZIS ratio was significantly related to positive 11C-Pittsburgh Compound B positron emission tomography (PiB-PET) in MCI [
12]. Another study also revealed that among 37 probable AD dementia patients with an amnestic presentation according to the National Institute on Aging–Alzheimer’s Association criteria, higher eZIS severity, extent, and ratio were associated with the PiB-PET-positive group (24 patients) compared to the PiB-PET-negative group (13 patients) [
13].
In differentiating between AD and non-AD patients, the eZIS also plays a significant role. eZIS severity was greater in AD than in vascular dementia (VD) and frontotemporal dementia (FTD) patients; eZIS extent was higher in AD than in FTD; and the eZIS ratio was greater in VD and FTD [
14]. Additionally, higher eZIS severity, extent, and ratio were all associated with early-onset AD compared to late-onset AD [
15].
Based on the aforementioned studies, the three eZIS indicators show a powerful capacity to discriminate dementia of AD from non-AD type [
14], support the presence of cerebral amyloid pathology (CAP) in amnestic MCI (aMCI) individuals [
12,
13], and are correlated with the scores of mental examination [
15]. When in the clinical stage of MCI, many patients and their families are eager to know whether the condition will advance with age. In this study, we used the eZIS to answer this question.
4. Discussion
In this 3-year follow-up study, MCI patients with an index of eZIS severity greater than 1.22 were more likely to convert to dementia. Although no amyloid PET scan or CSF/plasma biomarkers were examined, based on many previous reports, we can speculate that a large proportion of the progressive MCI patients in this study have CAP. First, MCI due to AD progresses to dementia at a higher annual rate compared to MCI due to non-AD [
1]. In the same way, studies also showed that MCI with CAP were more likely to progress to dementia compared with those without [
25,
26]. In the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project, according to the ATN classification system, subjective cognitive decline (SCD) individuals with CAP were at higher risk of progression to dementia or MCI compared with those without [
27]. Secondly, the eZIS indicators have been shown to be positively associated with CAP [
12,
13]. Thirdly, a recent study that enrolled 67 MCI with CAP and 54 MCI without CAP and 64 controls also reported that during 5-year follow-up, MMSE and CASI deteriorated over time in MCI with CAP, while MCI without CAP and control subject did not exhibit an obvious trajectory of cognitive decline [
28]. In sum, the three eZIS indicators could aid clinicians to make a diagnosis of MCI due to AD. Since early AD may experience benefits from ChEI, with the application of the eZIS to MCI patients, prescription of ChEI could be more accurate. Moreover, under certain conditions, the eZIS may be of help to pre-select candidates for new DMT for AD [
4,
5].
The deterioration rate in cognition and daily function over time may reflect the stage of MCI. MCI has been further categorized as early and late stage in several studies. In the Alzheimer ’s Disease Neuroimaging Initiative (ANDI), for example, MCI was classified into early and late based on WMS-R Logical Memory II story A score [
29]. The ADNI reported that annual conversion rate from MCI to dementia was 2.3% for early MCI and 17.5% for late MCI [
30]. A German study divided MCI into early and late based on delayed recall task of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery [
31]. Risk of conversion to AD was highest for late MCI compared with early MCI and controls. In our study, MCI was not further classified into early or late MCI. However, baseline CDR-SB was positively associated with conversion from MCI to dementia, which implied similar results to the mentioned studies. CDR-SB reflects functional ability and higher CDR-SB scores indicate more dysfunction or advancement in MCI stage and hence a higher likelihood to convert to dementia in three years. Nevertheless, more studies are needed to evaluate the application of the eZIS to predict the conversion to dementia in early and late MCI.
The MTA scale has been identified as a predictor of progression from MCI to dementia. One study reported that for every one-point increase in MTA score, the hazard ratio for MCI progressing to dementia increased by 1.5 during an average follow-up of 34 months [
32]. Another study found that individuals with a mean MTA score greater than 2 were more than twice as likely to transition from MCI to dementia over a 3-year follow-up period [
33]. As shown in
Figure 2, the AUC for MTA closely approximated that for severity. However, it is important to note that a limitation of MTA is its subjectivity, whereas the eZIS provides a relatively objective assessment.
Limitations of this study are addressed here. First, drug prescription and compliance may affect the results. Even though more patients with progressive MCI used ChEI, which has been shown to be a DMT in AD, the overall rate of progression was even higher than the rate in the stable MCI group. We thus speculated that progressive MCI might include more individuals with CAP. Second, from clinical observation and longitudinal studies, some individuals with CAP, as confirmed by amyloid PET or CSF levels, may remain cognitively stable in the MCI AD stage for 10 years or longer. Differences in an individual’s genetic background, lifestyle, or environmental factors may affect the rate of progression in AD. In this study, however, we did not test ApoE genotypes and did not inquire into lifestyle or environmental factors, which should be added in future research. Furthermore, the results of this study cannot be applied to populations which are excluded from the research criteria. Hence, caution is advised when applying the results to real-world scenarios. Finally, the development of the eZIS used parameters based on Japanese norms, and the accuracy of the eZIS application to Taiwanese patients must be carefully interpreted.