Cerebral small vessel disease (SVD) is a major health problem for its contribution to ≈45% of dementias, and about a fifth of all strokes worldwide, representing one of the most important causes of disabilities.1 The term SVD refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. The most common forms are age- and hypertension-related SVD and cerebral amyloid angiopathy (CAA).2 Vessel wall changes may lead to both ischemic and hemorrhagic consequences: (1) a state of chronic hypoperfusion or vascular dysfunction responsible for incomplete infarction,3,4 (2) acute focal necrosis (lacunar infarct), or (3) vessel rupture manifesting as hemorrhagic SVD. The clinical consequences of SVD are various and mainly consist of cognitive, mood, and motor dysfunctions leading to functional disability in the late stages of the disease. Magnetic resonance imaging (MRI) has become crucial in the diagnosis of SVD enabling the evaluation of the disease progression both in the clinical and research settings. However, correlations between clinical features of SVD and conventional MRI measures have been partially discordant. Some authors suggested that the cumulative effect of SVD lesions, rather than the individual lesions themselves determines the clinical impact,5 whereas others suggested that the presence and severity of alterations nonvisible on conventional MRI might also be an explanation.6 In the past decade, diffusion tensor imaging (DTI) has been increasingly used for the evaluation of SVD patients because it is sensitive to tissue damage and can show abnormalities in both areas of white matter hyperintensities (WMH) and in normal appearing WM (NAWM). Despite the high sensitivity in detecting cerebral damage, DTI has a low specificity in detecting the underlying cause. In fact, we can only infer that DTI changes reflect a loss of WM …