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Altered glymphatic system in idiopathic normal pressure hydrocephalus

  • Author Footnotes
    1 These authors contributed equally to the manuscript.
    Yun Jung Bae
    Footnotes
    1 These authors contributed equally to the manuscript.
    Affiliations
    Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally to the manuscript.
    Byung Se Choi
    Footnotes
    1 These authors contributed equally to the manuscript.
    Affiliations
    Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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  • Jong-Min Kim
    Correspondence
    Corresponding author. Departments of Neurology, Seoul National University Bundang Hospital 173-82, Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea.
    Affiliations
    Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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  • Ji-Hyun Choi
    Affiliations
    Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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  • Se Jin Cho
    Affiliations
    Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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  • Jae Hyoung Kim
    Affiliations
    Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally to the manuscript.

      Highlights

      • The DTI-ALPS method can effectively demonstrate the glymphatic function in NPH.
      • The ALPS-index, reflecting perivascular glymphatic flow, were reduced in NPH.
      • The ALPS-index was further reduced in non-responders to CSF diversion.
      • The ALPS-index was correlated with the callosal angle reflecting disease severity.

      Abstract

      Objective

      To assess the glymphatic activity in patients with idiopathic normal pressure hydrocephalus (NPH) using the “Diffusion Tensor Image-Analysis aLong the Perivascular Space (DTI-ALPS)” method, and determine the feasibility of non-invasive MRI for the evaluation of the glymphatic function.

      Methods

      Between April 2017 and March 2019, 16 patients diagnosed with NPH and 16 age- and sex-matched controls were included. On 3T DTI-MRI, the diffusivities along x-, y-, and z-axes were measured, and the ALPS-index – a ratio that accentuated water diffusion along the perivascular space – was calculated by two independent readers. The inter-observer agreement was tested using the interclass correlation coefficient. The differences in the diffusivities and the ALPS-index between the NPH and control groups were compared using the Mann-Whitney test. The values were also compared according to the treatment response to the cerebrospinal fluid drainage and correlated with the callosal angle using a correlation coefficient.

      Results

      The inter-observer agreements were excellent for the diffusivities and the ALPS-index. The diffusivity along the x-axis in the projection fibers area and the ALPS-index were significantly lower in patients with NPH (median, 0.556/1.181) than in the controls (0.610/1.540), respectively (P = 0.032/< 0.0001). The ALPS-index was significantly lower in the NPH group who did not show treatment response than those who showed symptomatic relief (0.987/1.329; P < 0.0001). The ALPS-index showed a significant positive correlation with the callosal angle (r = 0.82, P = 0.0001).

      Conclusions

      The DTI-ALPS method can be a useful imaging tool for identifying glymphatic dysfunction and for individually quantifying glymphatic activity in patients with NPH.

      Graphical abstract

      Keywords

      1. Introduction

      Idiopathic normal pressure hydrocephalus (NPH) is a syndrome with non-obstructive ventriculomegaly and clinical symptoms of gait disorder, cognitive deficits, and urinary dysfunction [
      • Espay A.J.
      • Da Prat G.A.
      • Dwivedi A.K.
      • Rodriguez-Porcel F.
      • Vaughan J.E.
      • Rosso M.
      • Devoto J.L.
      • Duker A.P.
      • Masellis M.
      • Smith C.D.
      • Mandybur G.T.
      • Merola A.
      • Lang A.E.
      Deconstructing normal pressure hydrocephalus: ventriculomegaly as early sign of neurodegeneration.
      ]. Lately, an attempt to reassess NPH as an entity of neurodegenerative disorders has been made, considering NPH is a diagnosis without disease-specific pathophysiology, but rather shares many clinico-radiological features with neurodegenerative disorders such as Alzheimer's disease [
      • Espay A.J.
      • Da Prat G.A.
      • Dwivedi A.K.
      • Rodriguez-Porcel F.
      • Vaughan J.E.
      • Rosso M.
      • Devoto J.L.
      • Duker A.P.
      • Masellis M.
      • Smith C.D.
      • Mandybur G.T.
      • Merola A.
      • Lang A.E.
      Deconstructing normal pressure hydrocephalus: ventriculomegaly as early sign of neurodegeneration.
      ].
      Meanwhile, the impairment of the glymphatic system – waste clearance system in the brain – has been suggested to cause neurodegenerative diseases [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ,
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. Several studies have revealed that decreased glymphatic function is linked to NPH [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ,
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. However, evaluating glymphatic activity in humans remains challenging, since the complex imaging requirements, including invasive intra-thecal or intra-venous contrast, limits its widespread clinical application [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ,
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ].
      Recently, a non-invasive method called “Diffusion Tensor Image-Analysis aLong the Perivascular Space (DTI-ALPS)” has been introduced for glymphatic assessment without need for contrast injection [
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. However, this has not been widely utilized in neurodegenerative disorders. Here, we aimed to adopt the DTI-ALPS method to evaluate the glymphatic alteration in NPH, correlating with clinical disease severity. Our purpose was to assess the glymphatic activity in individuals with NPH and to determine the feasibility of non-invasive magnetic resonance imaging (MRI) for demonstrating glymphatic system.

      2. Methods

      The institutional review board of our institution approved this study. Written informed consent was obtained from all participants.

      2.1 Participants

      Between April 2017 and March 2019, study participants were included from those referred to the Department of Neurology of our institution with a clinical suspicion of NPH. Clinical assessment was performed by a neurologist (J.M.K.) with 17 years' experience in movement disorders. NPH was diagnosed according to the International Guidelines (Supplementary Table 1) [
      • Relkin N.
      • Marmarou A.
      • Klinge P.
      • Bergsneider M.
      • Black P.M.
      Diagnosing idiopathic normal-pressure hydrocephalus.
      ,
      • Fasano A.
      • Espay A.J.
      • Tang-Wai D.F.
      • Wikklelso C.
      • Krauss J.K.
      Gaps, controversies, and proposed roadmap for research in normal pressure hydrocephalus.
      ]. Patients who did not undergo 3T brain MRI including DTI and susceptibility-weighted imaging (SWI) necessary for DTI-ALPS analysis, who had history of vascular ischemia, and who were confirmed to have recent infarction on MRI, were excluded. Clinical status was assessed using the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MOCA), and the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). All patients underwent diagnostic CSF drainage (lumbar puncture of 50 cc) process within a month from the MRI acquisition [
      • Fasano A.
      • Espay A.J.
      • Tang-Wai D.F.
      • Wikklelso C.
      • Krauss J.K.
      Gaps, controversies, and proposed roadmap for research in normal pressure hydrocephalus.
      ,
      • Isaacs A.M.
      • Williams M.A.
      • Hamilton M.G.
      Current update on treatment strategies for idiopathic normal pressure hydrocephalus.
      ]. Response to CSF drainage was assessed after 24 h using the 10-m timed walk test [
      • Rossier P.
      • Wade D.T.
      Validity and reliability comparison of 4 mobility measures in patients presenting with neurologic impairment.
      ,
      • Stolze H.
      • Kuhtz-Buschbeck J.P.
      • Drucke H.
      • Johnk K.
      • Illert M.
      • Deuschl G.
      Comparative analysis of the gait disorder of normal pressure hydrocephalus and Parkinson's disease.
      ], wherein a gait speed improvement more than 20% was considered as a responder. During the same period, age- and sex-matched control group who underwent neurological examination and 3T brain MRI and who did not present cognitive deficits or hydrocephalus were included.

      2.2 MRI acquisition

      The details are elaborated in Supplementary Materials.

      2.3 DTI-ALPS processing and image analysis

      We adopted the method for DTI-ALPS processing and measurement from the previous publication [
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. The details are explained in Fig. 1 and Supplementary Materials.
      Fig. 1
      Fig. 1Schematic drawing of the diffusivity measurement using the DTI-ALPS methods
      [Top-Left] On axial susceptibility-weighted image, the parenchymal vessels run laterally at the level of the lateral ventricle body, along the x-axis (arrows). [Top-Middle] Color fractional anisotropy (FA) map of diffusion tensor image (DTI) can demonstrate the distribution of the projection neural fibers running along the z-axis (blue color), that of the association neural fibers along the y-axis (green color), and that of the subcortical neural fibers along the x-axis (red color) areas. [Top-Right] The direction of the perivascular space (along blue spaces around the red and blue cylinders representing vessels) is perpendicular to both projection and association neural fibers (blue and green arrows). Therefore, the measured diffusivity along the x-axis at the projection and association neural fiber areas can reflect the glymphatic functioning via perivascular interstitial flows. [Bottom] Three regions-of-interest (ROIs) (yellow circles) along the horizontal course of the parenchymal vessels are allocated in the areas of projection neural fibers (projection area), association neural fibers (association area), and subcortical neural fibers (subcortical area) on color-coded FA map, then copied and pasted onto the three diffusivity maps to measure diffusivities along the x-, y-, and z-axes (Left, diffusivity map along the x-axis; Middle, diffusivity map along y-axis; Right, diffusivity map along z-axis). As a result, the measurement in ROI 1 matches to Dxproj, ROI 2 to Dxassoc, ROI 3 to Dxsubc, ROI 4 to Dyproj, ROI 5 to Dyassoc, ROI 6 to Dysubc, ROI 7 to Dzproj, ROI 8 to Dzassoc, and ROI 9 to Dzsubc. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      On the diffusivity maps, two neuro-radiologists (Y.J.B. and B·S.C. with 10- and 20-years’ experience, respectively), blinded to the clinical findings, independently measured a> the diffusivities along the x-axis (Dx) in the projection (Dxproj), the association (Dxassoc), and the subcortical (Dxsubc) neural fiber areas, b> the diffusivities along the y-axis (Dy) in three neural fiber areas (Dyproj, Dyassoc, Dysubc), and c> the diffusivities along the z-axis (Dz) in three neural fiber areas (Dzproj, Dzassoc, Dzsubc). According to the previous study [
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ], Dxproj and/or Dxassoc would express the water diffusion along the perivascular space without interference from neural fibers, thus reflecting the glymphatic activity. On the contrary, Dxsubc would not reflect pure perivascular water diffusion, since the subcortical neural fibers pass parallel to the perivascular flow obscuring glymphatic diffusion. In addition, Dy and Dz which lay perpendicular to the perivascular flow would not reflect glymphatic diffusion, either.
      Since the periventricular white matter hyperintensities (PVH) can increase water diffusivity [
      • Yokota H.
      • Vijayasarathi A.
      • Cekic M.
      • Hirata Y.
      • Linetsky M.
      • Ho M.
      • Kim W.
      • Salamon N.
      Diagnostic performance of glymphatic system evaluation using diffusion tensor imaging in idiopathic normal pressure hydrocephalus and mimickers.
      ], ALPS-index was calculated using the following equation to remove the PVH effect by the division calculation:
      ALPS-index = mean (Dxproj, Dxassoc) / mean (Dyproj, Dzassoc)


      ALPS-index is close to 1, when the perivascular water diffusion is minimal, but gets larger with larger perivascular diffusivity. All diffusivities and the ALPS-index from two readers were then averaged and used for further analysis.
      Further, routine MRIs were evaluated by a neuroradiologist (Y.J.B.), also blinded to the clinical data. The detailed radiologic measurements in NPH [
      • Relkin N.
      • Marmarou A.
      • Klinge P.
      • Bergsneider M.
      • Black P.M.
      Diagnosing idiopathic normal-pressure hydrocephalus.
      ,
      • Fasano A.
      • Espay A.J.
      • Tang-Wai D.F.
      • Wikklelso C.
      • Krauss J.K.
      Gaps, controversies, and proposed roadmap for research in normal pressure hydrocephalus.
      ,
      • Virhammar J.
      • Laurell K.
      • Cesarini K.G.
      • Larsson E.M.
      Preoperative prognostic value of MRI findings in 108 patients with idiopathic normal pressure hydrocephalus.
      ] are elaborated in Supplementary Materials.

      2.4 Statistical analysis

      The details are explained in Supplemental Materials.

      3. Results

      3.1 Study patients

      As a result, 16 patients with NPH and 16 control subjects were included (Supplementary Tables 2 and 3). The clinical and radiologic findings are explained in Supplementary Materials.

      3.2 Inter-observer agreement of the diffusivities and ALPS-index

      The results are elaborated in Supplemental Materials.

      3.3 Diffusivities and ALPS-index between the NPH and the control groups

      Dxproj and ALPS-index were significantly lower in NPH patients than in control subjects (median values, Dxproj, 0.556 vs. 0.610, P = 0.032; ALPS-index, 1.181 vs. 1.540, P < 0.0001) (Table 1, Supplementary Figure 1). Dyproj, Dyassoc, and Dzassoc were significantly higher in NPH patients than in control subjects (all, P < 0.05).
      Table 1Comparison of the diffusivities and ALPS-index.
      DiffusivityPatients with NPHControl subjectsP-value
      Dxproj0.556 (0.42–0.689)0.610 (0.504–0.764)0.032*
      Dxassoc0.576 (0.335–0.815)0.613 (0.4–0.73)0.696
      Dxsubc1.044 (0.835–1.378)1.027 (0.655–1.505)0.926
      Dyproj0.511 (0.357–0.691)0.390 (0.311–0.621)0.007*
      Dyassoc1.107 (0.904–1.28)0.937 (0.739–1.213)0.004*
      Dysubc0.705 (0.455–1.127)0.558 (0.455–1.702)0.080
      Dzproj1.348 (0.804–1.809)1.175 (0.755–1.468)0.051
      Dzassoc0.437 (0.315–0.767)0.334 (0.208–0.582)0.003*
      Dzsubc0.766 (0.585–1.166)0.544 (0.299–0.935)0.001*
      ALPS-index1.181 (0.802–1.432)1.540 (1.316–1.955)<0.0001*
      Values are shown as median (range).
      Diffusivity was measured with apparent diffusion coefficient values ( × 10−3 mm2/s).
      NPH, idiopathic normal pressure hydrocephalus; Dxproj, diffusivity along the x-axis in projection fiber area; Dxassoc, diffusivity along the x-axis in association fiber area; Dxsubc, diffusivity along the x-axis in subcortical fiber area; Dyproj, diffusivity along the y-axis in projection fiber area; Dyassoc, diffusivity along the y-axis in association fiber area; Dysubc, diffusivity along the y-axis in subcortical fiber area; Dzproj, diffusivity along the z-axis in projection fiber area; Dzassoc, diffusivity along the z-axis in association fiber area; Dzsubc, diffusivity along the z-axis in subcortical fiber area.
      *P-values less than 0.05 indicate statistical significance.

      3.4 Correlation of diffusivities and ALPS-index with clinical and radiological measures in NPH

      In NPH group, non-responders showed significantly lower ALPS-index and Dxassoc (0.987 and 0.486) than responders (1.329 and 0.659, P < 0.0001 and = 0.005, respectively). However, Dxproj, Dxassoc, and ALPS-index did not show significant correlation with MMSE, MOCA, and UPDRS-III.
      Regarding MRI findings in NPH patients, ALPS-index showed a significant positive correlation with callosal angle (r = 0.820, 95% confidence interval 0.547–0.935, P = 0.0001) (Supplementary Figure 2). However, there was no significant correlation between Dxproj and callosal angle, and between Dxassoc and callosal angle. ALPS-index did not show significant correlation with white matter hyperintensities in NPH patients, nor did other diffusivities.

      4. Discussion

      We demonstrated the reduced glymphatic activity in NPH using non-invasive MRI. Dxproj and ALPS-index were significantly lower in NPH patients than in control subjects, suggesting the impaired perivascular water flow, i.e., the impaired glymphatic drainage. ALPS-index was significantly lower in non-responders of NPH patients than responders, and was significantly correlated with callosal angle, reflecting disease severity. Therefore, the DTI-ALPS measurement could provide non-invasive indices for identifying altered glymphatic function and quantifying the glymphatic activity in NPH.
      Glymphatic system, a clearance pathway of brain metabolites, depends upon the convective fluid transport via interstitial spaces, mediated by aquaporin-4 channels at the astrocytic perivascular end-feet [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ]. The impaired glymphatic transport results in the accumulation of the wastes such as amyloid-β and tau proteins, which are implicated in the development of neurodegenerative disorders [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ,
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. Particularly, in NPH, the arterial pulsation – the driving force of the perivascular glymphatic transport – is restricted, and the intracranial compliance is reduced [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ,
      • Eide P.K.
      • Saehle T.
      Is ventriculomegaly in idiopathic normal pressure hydrocephalus associated with a transmantle gradient in pulsatile intracranial pressure?.
      ]. Moreover, a recent study has suggested that NPH can be an initial manifestation with ventriculomegaly from the altered CSF dynamics in neurodegenerative disorders such as Alzheimer's disease [
      • Espay A.J.
      • Da Prat G.A.
      • Dwivedi A.K.
      • Rodriguez-Porcel F.
      • Vaughan J.E.
      • Rosso M.
      • Devoto J.L.
      • Duker A.P.
      • Masellis M.
      • Smith C.D.
      • Mandybur G.T.
      • Merola A.
      • Lang A.E.
      Deconstructing normal pressure hydrocephalus: ventriculomegaly as early sign of neurodegeneration.
      ], which can support the hypothesis of the glymphatic dysfunction being the underlying pathophysiology of NPH.
      The decreased glymphatic drainage in NPH has been visualized in a few human studies using dynamic MRI scanning during 24 h, followed by intra-thecal injection of gadolinium-based contrast agent delivered by lumbar puncture [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ,
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. These studies have shown the delayed clearance, the ventricular reflux and the trans-ependymal migration of the contrast [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ,
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. However, intra-thecal contrast injection is an invasive procedure and even administratively disapproved in some countries; therefore, this approach has been done sparingly only in a few selected patients with a clear clinical indication. Moreover, the gadolinium-based contrast administration into CSF space – or, even with the repeated intra-venous injection – can lead to the gadolinium deposition in the brain [
      • Oner A.Y.
      • Barutcu B.
      • Aykol S.
      • Tali E.T.
      Intrathecal contrast-enhanced magnetic resonance imaging-related brain signal changes: residual gadolinium deposition?.
      ]. This entails the need for a non-invasive imaging modality to assess glymphatic function to enable the routine clinical application.
      To address this unmet need, the DTI-ALPS method has been developed utilizing non-invasive DTI-MRI without necessitating contrast agent [
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ,
      • Yokota H.
      • Vijayasarathi A.
      • Cekic M.
      • Hirata Y.
      • Linetsky M.
      • Ho M.
      • Kim W.
      • Salamon N.
      Diagnostic performance of glymphatic system evaluation using diffusion tensor imaging in idiopathic normal pressure hydrocephalus and mimickers.
      ]. DTI acquisition is rapid, and allows multiple image acquisition in a single subject, thereby enabling the monitoring of the status of the glymphatic activity over time [
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ]. Previous application of this method in patients with Alzheimer's disease revealed the reduced Dxproj and the positive correlation of ALPS-index with MMSE scores, suggesting that the reduced glymphatic activity could be quantified and correlated with the disease severity. This method not only is effective and easy-to-approach, but also focuses on the perivascular flow in the “periventricular” area, where the NPH-related glymphatic change should be most evident [
      • Ringstad G.
      • Vatnehol S.A.S.
      • Eide P.K.
      Glymphatic MRI in idiopathic normal pressure hydrocephalus.
      ]. Therefore, we believed that the DTI-ALPS method is optimal for assessing patients with NPH.
      In our study, we could effectively demonstrate the reduced glymphatic activity in NPH by identifying the reduced Dxproj and ALPS-index. Particularly, ALPS-index showed more distinct differences between the NPH and the control groups. Since ALPS-index can minimize the influence of the white matter changes and the neural tract degeneration, it may be more suitable for the individual assessment of the glymphatic function than Dxproj [
      • Taoka T.
      • Masutani Y.
      • Kawai H.
      • Nakane T.
      • Matsuoka K.
      • Yasuno F.
      • Kishimoto T.
      • Naganawa S.
      Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases.
      ,
      • Yokota H.
      • Vijayasarathi A.
      • Cekic M.
      • Hirata Y.
      • Linetsky M.
      • Ho M.
      • Kim W.
      • Salamon N.
      Diagnostic performance of glymphatic system evaluation using diffusion tensor imaging in idiopathic normal pressure hydrocephalus and mimickers.
      ]. Whereas, Dyproj, Dyassoc, and Dzassoc were significantly higher in NPH patients than control subjects. This could be due to the increased water diffusivity around PVH [
      • Yokota H.
      • Vijayasarathi A.
      • Cekic M.
      • Hirata Y.
      • Linetsky M.
      • Ho M.
      • Kim W.
      • Salamon N.
      Diagnostic performance of glymphatic system evaluation using diffusion tensor imaging in idiopathic normal pressure hydrocephalus and mimickers.
      ]. Indeed, the degree of PVH tended to be higher in NPH patients than in control subjects in our study, although it did not reach the statistical significance.
      Noteworthy was that the ALPS-index was significantly lower in non-responders of NPH patients than responders. This result may verify that the unfavorable outcome following CSF shunting could be the result of severely impaired glymphatic activity. There have been many attempts to identify the suitable candidates for CSF shunt operation for the treatment of NPH [
      • Virhammar J.
      • Laurell K.
      • Cesarini K.G.
      • Larsson E.M.
      Preoperative prognostic value of MRI findings in 108 patients with idiopathic normal pressure hydrocephalus.
      ]. Virhammar et al. [
      • Virhammar J.
      • Laurell K.
      • Cesarini K.G.
      • Larsson E.M.
      Preoperative prognostic value of MRI findings in 108 patients with idiopathic normal pressure hydrocephalus.
      ] reported that callosal angle, the diameter of temporal horns, and the occurrence of disproportionally enlarged subarachnoid spaces were significant predictors of a positive shunt outcome. Considering this, our results that demonstrated a strong positive correlation between ALPS-index and callosal angle can add a clinical significance on ALPS-index as a predictor for the shunt outcome in patients with NPH, thereby aiding in the selection of the appropriate candidate for the shunt surgery.
      Our study has some limitations. First, we did not analyze the diagnostic performance of the DTI-ALPS method for NPH. However, the diagnosis of NPH requires pre-requisite clinical and radiological findings as well as the consideration of the response to the CSF diversion. Therefore, we believe that the diagnostic performance solely based on the DTI-ALPS measurements for NPH would be of little clinical significance. Rather, the genuine significance of the DTI-ALPS measurement in NPH would be that the ALPS-index and/or Dxproj could effectively demonstrate and quantify the reduced glymphatic activity, with the ability to predict and prognosticate the utility of CSF shunt diversion. Second, since the follow-up period for our study population was not long enough, we could not perform the follow-up MRI study to reassess DTI-ALPS values after therapeutic CSF diversion. Future follow-up study after CSF diversion to possibly confirm the interval improvement of the glymphatic function is warranted. Third, the number of study subjects was small. Moreover, we might have achieved considerable clinical improvement in the non-responders by repeated, higher volume CSF drainage with longer duration such as external lumbar drainage. Therefore, future studies with a larger number of patients including those who underwent shunt surgery and with an application of the repeated, higher volume CSF drainage with longer duration will be needed. Furthermore, future studies that compare the glymphatic measurement before and after CSF drainage may add significance to our result. Fourth, according to the DTI-ALPS measurement, the diffusivities were only available at the area outside the lateral ventricle along the plane of the lateral ventricular body. Accordingly, the evaluation of perivascular diffusivity in other regions where the perivascular space does not run in the direction of x-, y-, or z-axes is impossible. However, as we discussed, the periventricular area would be the optimal place for assessing the glymphatic dysfunction in NPH. Therefore, this could rather be an advantage to our study.
      In conclusion, non-invasive MRI-based DTI-ALPS method can effectively demonstrate the altered glymphatic activity in patients with NPH. Lower ALPS-index in non-responders was correlated with the reduced glymphatic activity and worse symptom severity. Therefore, the DTI-ALPS method can be a useful imaging tool for identifying glymphatic dysfunction and quantifying its activity in individuals with NPH.

      Author contributions

      Yun Jung Bae, Byung Se Choi, Jong-Min Kim, Ji-Hyun Choi, Se Jin Cho, and Jae Hyoung Kim participated in conception and organization of the study design, data acquisition and analysis.
      Yun Jung Bae and Byung Se Choi execution of the research project, execution of statistical analysis, and wrote the first draft. Byung Se Choi and Jong-Min Kim participated in the review and the revision of the manuscript. Ji-Hyun Choi and Se Jin Cho participated in the MRI processing, and reviewed the results and the manuscript. Jae Hyoung Kim reviewed and revised the results and the manuscript.

      Funding source

      This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1F1A1063771 ) and grant No. 09-2019-003 from the SNUBH Research Fund .

      Funding source role

      Yun Jung Bae received the NRF grant from the Korea government and the grant from the SNUBH Research Fund.

      Data availability

      The research data including the post-processed DTI is confidential.

      Declaration of competing interest

      The authors declare no conflict of interest related to funding sources, or financial holdings that might raise questions about possible sources of bias.

      Acknowledgements

      The authors thank the Medical Research Collaborating Center at Seoul National University Bundang Hospital for consultation on the statistical analyses.
      We would like to thank Editage (www.editage.co.kr) for English language editing.
      We wish to acknowledge and thank Pf. Dong Su Jang and the studioMID (Medical Illustration & Design) for creating illustrations.

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