Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS): Revisiting the Meaning and Significance of the Method

Abstract

More than 5 years have passed since the Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS) method was proposed with the intention of evaluating the glymphatic system. This method is handy due to its noninvasiveness, provision of a simple index in a straightforward formula, and the possibility of retrospective analysis. Therefore, the ALPS method was adopted to evaluate the glymphatic system for many disorders in many studies. The purpose of this review is to look back and discuss the ALPS method at this moment.The ALPS-index was found to be an indicator of a number of conditions related to the glymphatic system. Thus, although this was expected in the original report, the results of the ALPS method are often interpreted as uniquely corresponding to the function of the glymphatic system. However, a number of subsequent studies have pointed out the problems on the data interpretation. As they rightly point out, a higher ALPS-index indicates predominant Brownian motion of water molecules in the radial direction at the lateral ventricular body level, no more and no less. Fortunately, the term "ALPS-index" has become common and is now known as a common term by many researchers. Therefore, the ALPS-index should simply be expressed as high or low, and whether it reflects a glymphatic system is better to be discussed carefully. In other words, when a decreased ALPS-index is observed, it should be expressed as "decreased ALPS-index" and not directly as "glymphatic dysfunction". Recently, various methods have been proposed to evaluate the glymphatic system. It has become clear that these methods also do not seem to reflect the entirety of the extremely complex glymphatic system. This means that it would be desirable to use various methods in combination to evaluate the glymphatic system in a comprehensive manner.

Keywords: Diffusion Tensor Image Analysis aLong the Perivascular Space; brain; glymphatic system; magnetic resonance imaging; waste clearance.

Fig. 1

Concept of DTI-ALPS method. The assumed direction of mass transport within the brain parenchyma is shown in a. For waste material to reach the superficial cerebral veins or the subependymal veins, it must travel in the x-direction, indicated by the red arrow. In actual brain tissue, the medullary vessels also run in this x-direction. The positional relationship between the running direction of major fibers in the white matter outside the lateral ventricles and the location of the medullary vessels and perivascular space is shown in b and c. At this location, projection fibers and medullary vessels and association fibers and medullary vessels are in an orthogonal position to each other. This makes it possible to evaluate the diffusion component in the direction of the medullary vessels by eliminating the influence of the strong diffusion component of the projection and association fibers. The formula for the ALPS-index is shown in d. The ratio of the diffusion component perpendicular to both the projection fiber and the medullary vessels and the diffusion component perpendicular to both the association fiber and the medullary vessels is employed as an internal reference to evaluate the diffusion component in the direction of the medullary vessels. The image of the diffusion tensor ellipsoid is shown in e. The major axes of the ellipsoid correspond to projection fibers (blue) and association fibers (green), respectively. The small oval in e is the image of the ALPS-index. The oval that is large in the x-direction corresponds to a large ALPS-index, as shown in f. DTI-ALPS, Diffusion Tensor Image Analysis aLong the Perivascular Space.

Fig. 2

Application of ALPS method in AD. Violin and box plots of the mean ALPS-index, PVSVF-ALL, PVSVF-WM, PVSVF-BG, PVSVF-Hipp, and FW-WM among the HC participants, patients with MCI, and patients with AD are shown. Compared to HC, AD patients had significantly higher total PVSVF, WM, BG PVSVF (Cohen d = 1.15−1.48, P < 0.001) and FW-WM (Cohen d = 0.73, P < 0.05) and lower ALPS-index (Cohen d = 0.63, P < 0.05). The MCI group had significantly higher total PVSVF (Cohen d = 0.99, P < 0.05) and WM (Cohen d = 0.91, P < 0.05). Figure quoted from Ref. . AD, Alzheimer’s disease; PVSVF, perivascular space volume fraction; WM, white matter; BG, basal ganglia; FW, free water; HC, healthy control; MCI, mild cognitive impairment.

Fig. 3

Application of ALPS method in PD. Differences in ALPS-index between the PD group and NCs and between two PD subgroups and NCs were compared. Relationships between ALPS-index and MMSE score in early PD group (A), relationships between ALPS-index and EPVS score in early PD group (B) and relationships between ALPS-index and age in late PD group (C) are shown. There was a significant positive correlation between ALPS-index and MMSE score (β = 0.021, P = 0.029) (A), and a negative correlation between ALPS-index and EPVS score (β = − 0.050, P = 0.034). ALPS-index negatively related with age (β = − 0.012, P = 0.004). Figure quoted from Ref. . PD, Parkinson’s disease; NC, normal control; MMSE, Mini-Mental State Examination; EPVS, enlarged perivascular space.

Fig. 4

Application of ALPS method in iNPH. A study of changes in ALPS-index after LPS surgery in iNPH is presented, comparing patients who responded to LPS with those who did not. The mean ALPS-index of the postoperative group was significantly higher than that of the preoperative group (A). Furthermore, for responding subjects, the mean ALPS-index in the postoperative group was significantly higher than in the preoperative group (B). On the other hand, in the non-responder group, the mean ALPS-index of the postoperative group was not significantly higher than that of the preoperative group (C). The mean ALPS indices of the responder group were not significantly different compared to those of the non-responder group in both the pre-operation and post-operation groups (D). Figure quoted from Ref. . iNPH, idiopathic normal pressure hydrocephalus; LPS, lumboperitoneal shunt.

Fig. 5

Time-of-day dependency of ALPS-index. Circadian rhythm dependence of ALPS-index was assessed by repeated MRI measurements at five time points from 8:00 to 23:00. Very long echo-time low-b diffusion tensor imaging (DTIlow-b), which measures SAS flow along the middle cerebral artery, and conventional DTI-ALPS were performed. A, B show the time course of the glymphatic system influx and efflux measured by DTIlow-b and DTI-ALPS, respectively. Neither ADlow-b of the MCA SAS fluid nor the ALPS-index differed significantly in the data acquired at the five time points. Figure quoted from Ref. 159. MRI, magnetic resonance imaging; DTI, Diffusion Tensor Image; SAS, subarachnoid space; DTI-ALPS, Diffusion Tensor Image Analysis aLong the Perivascular Space; AD, Alzheimer’s disease; MCA, middle cerebral artery.

Fig. 6

Placement of ROI for ALPS method. The most important point in the placement of the ROI is to ensure that all of the subject groups of cases are measured in a uniform manner. It is also important to make sure that the projection and association fibers are perpendicular to the x-axis. In particular, when setting the ROI in the area of association fibers, care should be taken to avoid mixing of subcortical fibers whose main axis is in the x-direction. If subcortical fibers are included, the ALPS-index will be higher than it should be. After that, there are various ways to place ROIs: only on the left side of the dominant hemisphere (a), bilateral placement (b), Atlas-based placement (c), and placement with conversion to the standard brain (d).