3.1 Eligible and included studies
Our parallel searches yielded a total of 365 (PubMed) and 463 (WoS) articles. After removing duplicates, a total of 425 articles were screened by title/abstract reading. After further reading and applying inclusion/exclusion criteria, 51 studies were selected for review (Figure 1).
3.2 Study characteristics
Most of the studies were published between 2010 and 2020 (n=46). Only 5 studies were published during the first decade of the 2000s, being 2015 the year in which most studies were published (n=8). The different ways of sample recruitment were: patients or referrals from memory clinics (n=31), population-based cohort (n=12), or a combination of both (n=8). 3 studies were based on pre-existing data banks. Regarding the design of the study, most of the articles included were retrospective (n=42).
The studies used different techniques to study the volume of grey matter in the brain. 26 studies exclusively performed a ROI analysis, being the most common analysis; 10 studies exclusively performed a VBM analysis and 6 exclusively analysed the cortical thickness. The remaining 9 studies performed a combination of two types of analysis (ROI & VBM analysis n=5 or ROI & Cortical thickness n=4; results compared in Supplementary Table 1). Hence, 35 studies performed ROI analysis, 15 VBM analysis, and 10 studies cortical thickness analysis.
3.2.1 Voxel-based morphometry analysis
15 studies performed a VBM analysis (Table 1), and 8 found statistical differences between SCD and HC participants (16–23). Five of them found grey matter volume reduction in the hippocampus in SCD compared with HC (18,20–23). Saykin et al. (22) found bilateral volume reduction in the whole hippocampus, Liang et al (20) found bilateral volume reduction in the hippocampal tail, and Perrotin et al (21) found bilateral volume reduction in the CA1. Lastly, 2 studies only found unilateral volume reduction in the right hippocampal in the SCD group (18,23). Additional temporal areas were also involved in 3 studies. Volume reductions were found in the SCD group compared with HC in the right insula (17), right amygdala (18), and in the inferior temporal gyrus (19).
In the frontal lobe, Saykin et al., (22) found volume reductions in the whole lobe in the SCD group compared with HC. Other studies found differences in some specific frontal areas like the bilateral (16) and left (25) superior frontal, bilateral (26) or left (25) medial frontal, left inferior frontal (19), the bilateral anterior cingulate (18,19) and in the left orbitofrontal cortices (19). In the parietal cortex, Choi et al., 2015 found SCD volume reductions in the left superior and inferior cortex, and in the right precuneus. Hafkemeijer et al., (18) also found bilateral precuneus atrophy in the SCD group compared with HC. In the occipital lobe, volume reductions were found in the bilateral cuneus (18), right calcarine and in the lingual gyrus (19). Finally, only one study found higher volume in SCD compared with HC, located in the paracentral lobe (20).
On the contrary, 7 studies did not find any significant difference in SCD compared with HC (11,12,27–31).
3.2.2 ROI analysis
A total of 35 studies performed a ROI analysis (Table 2), and 13 of them found a volume reduction in the hippocampus in SCD compared with HC (37.1%). Particularly, 6 of them found a volume reduction of the whole bilateral hippocampus (18,21,32–35). Focusing on the whole left hippocampus, 3 studies found it smaller in SCD compared with HC (36–38). Heeding to some different left hippocampus subfields, CA1 (21,36,39), CA3 (39) CA4 (36,38,39), dentate gyrus (36), molecular layer (36,38,39), subiculum (21,38), presubiculum (38) and hippocampal tail (38,39) were smaller in SCD compared with HC. The whole right hippocampus was smaller in SCD compared with HC in 2 studies (23,40). Some right hippocampal subfields were also smaller in SCD, like perirhinal area (41), dentate gyrus (41), presubiculum (38) (Zhao et al., 2019) and fimbria (38).
On the other hand, 20 studies did not find any significant difference in the hippocampal volume between SCD and HC (57.1%) (13,19,49–58,22,42–48).
3 studies found a reduced volume in the entorhinal cortex (EC) bilaterally in SCD compared with HC (34,47,54). On the contrary, one study also analysed this ROI, but did not find any significant difference (51).
5 studies found less grey matter volume in the amygdala in SCD compared with HC, 3 of them bilaterally (32,35,55) and 2 in the right hemisphere (34,59). Three studies did not find differences between groups (18,33,60).
One study found grey matter atrophy in the posterior cingulate in SCD compared with HC (35). Two studies did not find statistical differences between groups (19,23).
Scheef et al., (61) found the cholinergic basal forebrain (Ch1/2 and Ch 4p) smaller in SCD compared with HC. Zhao et al., (35) found the temporal lobe, the occipital lobe and the insular cortex smaller in SCD than in HC. Other studies analysed different brain areas like the thalamus, the putamen, the accumbens nucleus, the caudate nucleus, the globus pallidus (18), the corpus callosum (19), the precuneus, the parahippocampus (13), the inferior parietal, the middle temporal lobe or the retrosplenial cortex (13), but did not find any significant difference between SCD and HC.
3.2.3 Cortical thickness
Cortical thickness was analysed in 10 studies (Table 3). 6 of them found increased thinning in SCD compared to HC in several regions such us the bilateral entorhinal cortex (55,62), left entorhinal cortex (45,63), the right entorhinal cortex, bilateral parahippocampus, left perirhinal cortex (60), left medial orbitofrontal cortex (64) and whole frontal, temporal and parietal lobes (65). Also, focal cortical thinning was found in fusiform, posterior cingulate, and inferior parietal cortex (55). On the other hand, 4 studies did not find differences in cortical thickness between groups (13,51,66,67).
3.3 Factors determining the statistical significance of findings
We observed that the studies with a recruitment sample in a memory clinic tend to identify more frequently statistically significant findings compared with those with a population-based or mixed recruitment (70% vs 50%, p=0.09). Moreover, articles that identify statistically significant findings were published earlier than those without statistically significant findings (median 2015 vs 2017, p=0.03). However, we did not find any other variable related to the statistical significance of findings (type of the study, sample size, age, nor MRI strength, p>0.05) (Supplementary Table 2).
3.4 Quality assessment
All 51 studies included in this review received quality assessment (Table 4) following the Newcastle-Ottawa Quality Assessment Scale (15). Out of a maximum of 9 points, average was 6.84, indicating good overall quality in the articles selected for review. However, only two studies correctly reported non-response rate (27,68), being Ivanoiu et al., (68) the only study obtaining the maximum score. Lowest score was 5 out of 9 points (n=4).