Dear Editor,
Carranza-Lira et al. published in a recent issue of Menopause Review an article titled The relationship between carotid intima-media thickness and cognitive function and depression in postmenopausal women [1].
The authors wrote: Atherosclerosis, cognitive impairment, and depression are common entities in postmenopausal patients. Our aim was to ascertain the relationship between the carotid intima-media thickness (IMT) and cognitive function and depression in postmenopausal women [1].
Seventy-five patients (with a median age of 52 years) were included in their observational, cross-sectional, comparative study among postmenopausal women. To assess for mental function the mini-mental state examination and for depression the Hamilton depression rating scale were used [1].
Intima-media thickness ultrasound was performed in all subjects.
Intima-media thickness was greater in the group with depression (n = 45) than in the group without depression (n = 30) (IMT 1.2 mm [0.7–2.0 mm] vs. IMT 0.9 mm [0.6–1.9 mm] p-value 0.001); IMT was greater in the group with cognitive impairment (n = 19) than in the group without cognitive impairment (n = 56) (IMT 1.5 mm [0.7–2.0 mm] vs. 1.0 mm [0.6–1.9 mm] p-value 0.001) [1].
The authors concluded that increased IMT is associated with a higher risk of depression and cognitive impairment [1].
Some comments are needed to evaluate the results and conclusions of this study in a more balanced way.
Carotid intima-media thickness measurement protocol
The authors wrote, Carotid artery ultrasound was performed in all subjects, and the IMT was evaluated as follows: in the soft tissue category, locating the carotid artery 1 cm from its bifurcation, the image was maximized by visualizing on the screen the diameter of the lumen of the vessel and then measuring the distance between the first and second echogenic lines. The highest value obtained was used for the analysis [1].
The carotid IMT (cIMT) measurement protocol is still a controversial matter [2, 3]. Some authors recommend cIMT data acquisition at a single location, preferably at the distal (far) wall of the common carotid artery (CCA) for the higher spatial resolution with respect the proximal (near) wall, in a plaque-free area in proximity of the bifurcation [2]; or cIMT can be measured at multiple sites (CCA, bifurcation and the internal CA) [4]. Measurements can be performed manually or with an automated-assisted method [5]. Carranza-Lira et al. did not specify at which wall the cIMT measurement occurred and how many measurements were performed, from which the highest value was used for analysis [1]. It is also not clear if the mea-surements were performed in a plaque-free segment and if one or 2 operators was/were involved, to assess for inter-user/reader-variability [6].
Cut-off values
Carranza-Lira et al. wrote, The intima-media thickness was considered normal when it was < 1 mm and abnormal when ≥ 1 mm [1]. As there is no agreement within the vascular-neurology community to define increased cIMT [7], it becomes still more stringent to explain the rational of the used cut-off value; Carranza- Lira et al. did not explain why they selected 1 mm as their cut-off [1]. It is important to bear in mind that cIMT values above 1.5 mm are considered plaques; The Mannheim carotid intima-media thickness plaque consensus paper (henceforth called the Mannheim Consensus paper) defines plaques as focal structures encroaching into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value, or demonstrates a thickness > 1.5 mm as measured from the intima-lumen interface to the media-adventitia interface [2]. Carranza-Lira et al. indicated cIMT values as high as 2.0 mm [1]. Therefore, it remains unclear if they included plaques in their cIMT measurement. There is an important difference between cIMT and plaques. The Mannheim Consensus paper states that Carotid IMT and plaques are different phenotypes indicating increased vascular risk. Plaque presence demonstrates a higher risk and therefore overrides IMT predictive values. However, IMT without plaque remains a significant marker of an increased risk of vascular events and significantly predicts plaque occurrence [2]. The authors missed to specify this critical aspect in their measurement [1].
Carotid intima-media thickness measurement protocol and the cardiac cycle
Carotid IMT measurement should be synchronised with the cardiac cycle and occur at the end-diastolic phase because cIMT varies during the cardiac cycle, due to vessel diameter changes [2, 8]. It appears that the authors [1] did not synchronise with the cardiac cycle, and the measurements might have occurred randomly in both phases, rendering the cIMT values between the subjects incomparable.
Carotid intima-media thickness measurement protocol and depression
Carranza-Lira et al. wrote, The intima-media thickness was significantly higher in the group with depression, which is consistent with a study in which anxiety was increased in those with carotid stenosis but not with another in which it was not associated with depression [1].
The authors [1] cite for the anxiety study a paper by Everts et al., 2014 [9], which is perplexing because this study investigated primarily the relationship between cognitive impairment/anxiety (not depression) and carotid stenosis; importantly, cIMT measurements were not performed by Everts et al. [9].
Carranza-Lira et al. [1] cite a further study, from Pucite et al. [10], which, according to Carranza-Lira et al., investigated the relationship between cIMT and depression. However, Pucite et al. [10] also did not perform any cIMT measurements.
The authors of this letter have recently published a meta-analysis on the potential relationship between depression and cIMT and found a significantly increased cIMT in patients with depression, compared with controls and importantly underlined a possible bidirectional link between atherosclerosis and depression [11].
Carotid intima-media thickness measurement protocol and cognitive impairment
As to the relationship between cIMT and cognitive impairment, the authors wrote, It was observed that a high IMT increases the risk of cognitive impairment and depression, probably in relation to the lower cerebral blood flow, as shown by the lower MSS in the groups with depression and with cognitive impairment, but this requires further studies [1].
Carranza-Lira et al. [1] based their conclusion on a potential relationship between increased cIMT and cognitive impairment on a single study by Komulainen et al. [12]. In 2011 one of the authors of this letter (CS) published a review paper on this topic on 20 studies [13]. A definitive statement could not be made given the contrasting results, concluding, There was a huge variability in methods of IMT measurement, with regard to location, referenced IMT values and measurement techniques. This heterogeneity made it difficult to directly compare IMT results in these twenty studies. …here is also an imperative need for a consensus regarding the precise definition of cognitive impairment and the use of standardized methods in the assessment of early cognitive impairment, alongside a uniform way to perform IMT measurements for future epidemiological studies on the relationship between IMT and cognitive impairment [13].
Association vs. causation
Carranza-Lira et al. stated that increased IMT is associated with a higher risk of depression and cognitive impairment. However, association does not imply causation, and the directionality between atherosclerosis and depression/cognitive impairment is not established. In the current research, a bidirectional link between atherosclerosis and depression/cognitive impairment, within the context of a potential immune-system dysregulation, is being hypothesized [11, 14–17].
Conclusions
In light of the multiple methodological issues, the cIMT data of this study and the conclusions drawn by Carranza- Lira et al. [1] that, in postmenopausal women, increased IMT is associated with a higher risk of depression and cognitive impairment, should be considered within the above mentioned limitations.
