Neurodegenerative processess are a major cause of the long-term disability accumulation in MS [3–5]. The thalamus is among the first brain regions to become atrophic [22]. The thalamus has connections with widespread areas of neocortex and subcortical structures mediating many brain functions, thus damage to the thalamic nuclei might result in wide range of neurologic symptoms, including cognitive imapirment. Moreover, extensive connections of the thalamus make this structure vulnarable to atrophy caused by the focal and diffused brain pathology, as a retrograde consequention of axonal damage in the white matter [23, 24].
The third ventricle is a cavity located in the midline, separating the right and left thalamus. Widening of the third ventricle might result from atrophy of adjacent structures, especially thalami. Actually, it was shown that 3VW is associated with thalamic volume, and is enlarged in patients with MS [10, 24]. There are several approaches to monitor brain atrophy in patients with MS. However, these techniques are still not implemented in the clinical routine. As it is an easily calculated measure, 3VW could be widely used in the daily clinical setting as a marker of neurodegenerative processes reflected by atrophy of diencephalon. However, the predictive value of this parameter for neurological status of patients with MS must be confirmed at first.
Cognitive impairment occurs in 40-70% of patients with MS and the pathological basis of cognitive signs is complex [25]. Many MRI findings were shown to be associated with cognitive deterioration in patients with MS [1–6]. Cognitive disturbances, including information processing speed, as well as verbal and visual memory deficites, were associated with 3VW in this study. The strongest correlation was found for SDMT which evaluates information processing speed and attention. Relations of 3VW to SDMT, CVLT and BVMT-R were shown previously [3, 26]. Moreover, 3VW was a better predictor of psychomotor speed and verbal memory disturbances than brain, neocortical, gray and white matter volumes [26]. 3VW explained also more variance in cognitive status than FLAIR, as well as T1 hypointense lesion volumes [3]. Thalamic atrophy, which is directly associated with 3VW, was also shown to be related to cognitive impairment [23, 27].
After adjustment for demographic and clinical confounders, including depression, anxiety, and fatigue we found that 3VW, after age, accounted for most of the variance in predicting cognitive dysfunction. Education, EDSS and fatigue were also associated with cognitive status and such observations were made previously [28–30]. Multiple regression model including age, 3VW, education, EDSS and fatigue explained 63% of the variance of neuropsychological performance in this study. Depressive and anxiety symptoms did not correlate with cognitive impairment in this study. Data regarding association between depression or anxiety and cognitive disturbances is not uniform. However, the lack of such relations together with the presence of correlation between fatigue and cognitive functioning was noticed previously [31].
We found a weak association between 3VW and physical disability assessed with EDSS. A weak to moderate association between 3VW and EDSS was observed previously [10]. Physical disability of MS patients correlates with MRI metrics, for example T1 hypointense lesion volume and gray matter volume [5]. Particularly, thalamic atrophy and damage to the thalamus assessed with diffusion tensor imaging were found to be associated with EDSS [32, 33]. However, correlation of thalamic volume to physical disability was weaker than to cognitive function [23], and this corresponds with the current results, as association between 3VW and neuropsychological performance was stronger than between 3VW and EDSS. Age and duration of the disease were also associated with EDSS, what is in line with the previous observations [5].
Although depressive symptoms in patients with MS are associated with atrophy of cortical and subcortical grey matter, including left thalamus [34], 3VW was not associated with depression [35], and the same was observed in this study. We did not observed correlation between anxiety and 3VW as well. Fatigue can affect up to 80% of patients with MS and is considered to be related to thalamus pathology. Severity of fatigue in patients with MS is associated with thalamus atrophy [36]. However, this study did not reveal the association between 3VW and fatigue.
Significant thalamic atrophy was found in SPMS compared to PPMS and RRMS [22]. 3VW was greater in SPMS than RRMS as well [26], which was confirmed in our study and this association was independent of age and duration of the disease. We noticed that males had greater 3VW than females. It is in accordance with the finding that atrophy, including thalamic atrophy, is more pronounced in MS males than females [37].
Important limitation of 3VW measurement is the low test-retest reliability [3, 38]. Intra- and interrater reproducibility was not evaluated in this study. Image acquisition quality and slice positioning might affect reproducibility. Thus the importance of slice alignment to anatomical landmarks (lower borders of corpus callosum) is highlighted [10]. A limitation of this study is a lack of other MRI measurements, such as grey and white matter volumes, and advanced MRI techniques including diffusion tensor imaging, magnetization transfer imaging or proton magnetic resonance spectroscopy evaluating diffused brain pathology to compare predictive value of 3 VW with other MRI metrics. Due to retrospective character of the study there is lack of 3VW measurement in healthy controls. Furthermore, longitudinal assessment of 3VW, cognitive and disability status changes over time is not available.