RPS 1411 - Charting the brain's next frontier: glymphatic system imaging

Author Block: H. Wu; Chongqing/CN
Purpose: Poor sleep quality is prevalent among medical interns and residents, often characterized by insufficient sleep .Our objective is to examine the associations between glymphatic function, sleep quality, and neuropsychological performance within this population.
Methods or Background: 30 medical Interns and 15 residents on 2-week Internal Medicine and Radiology rotations were included . Sleep profile was accessed using questionnaires and polysomnography. Wechsler Memory Scale (WMS) was used for evaluation of the memory performance. The MRI for each subject was scheduled at least 72 hours after the completion of the night shift. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index was used to evaluate glymphatic function.
Results or Findings: Multivariate linear regression model for interns group determined that intern year (unstandardized β=-0.0045 [SE 0.0001]; p < 0.001), and the N3 sleep duration, index (unstandardized β=0.0071 [SE=0.0004]; p = 0.0013) were independently associated with DTI-ALPS. Increased DTI-ALPS was linked to enhanced memory scores (unstandardized β = −0.77 [SE = 0.23]; p = 0.014).
Interns group had higher percentages of N1 and N2 sleep and a modestly higher amount of REM sleep than residents group. The higher percentages of N1, N2, and REM sleep were offset by a lower percentage of N3 sleep in interns. There was no significant difference of memory scales between these two groups.
Conclusion: Interns tend to have poorer sleep structure compared to residents, likely due to their more frequent extended overnight shifts, whereas residents rarely or never work such extended shifts. This study identified associations between DTI-ALPS and memory performance, suggesting the potential of DTI-ALPS as a biomarker for evaluating the neuropsychological status of young doctors.
Limitations: Our study does not include longitudinal data on temporal changes in DTI-ALPS between night shifts for individual participants.
Funding for this study: None
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The authors report no disclosures relevant to the Abstract.

Author Block: B. Genç, A. Özçağlayan, M. S. Buruk, L. Incesu, K. Aslan; Samsun/TR
Purpose: COVID-19 has also been associated with the development
of dementia, cortical atrophy, and cognitive impairments such as
brain fog, which are challenging or often impossible to detect
using conventional MRI. Peak width of skeletonized mean diffusivity
(PSMD), a recently developed quantitative marker, has been proposed as
a sensitive biomarker for small vessel disease. The aim of
this study is to investigate changes in PSMD, associated with small
vessel disease, and DTI-ALPS parameters, related to the glymphatic
system, in COVID-19 patients.
Methods or Background: Clinical, demographic data, and MRI images were obtained from
the "neuroCOVID MRI dWIand fMRI with reversal learning" dataset
available on OpenNeuro (https://openneuro.org/datasets/ds005364/versions/1.0.0 . After
denoising and eddy current corrections, DTI-ALPS and PSMD index
measurements were performed similarly to the previous literature. The
values of the hospitalized and non-hospitalized COVID groups were
compared separately with the control group.
Results or Findings: The PSMD index was significantly higher in the hospitalized
COVID-positive group (326 x10⁻⁶ mm²/s) compared to the control group
(298 x10⁻⁶ mm²/s, p=0.028), while there was no significant difference
between the non-hospitalized COVID-positive group (301 x10⁻⁶ mm²/s)
and the control group (p=0.953). no significant differences were
observed in left or right DTI-ALPS values between the hospitalized,
non-hospitalized COVID-positive groups, and the control group.
Conclusion: Our study shows that hospitalized COVID-19
patients exhibit an increase in PSMD index, indicative of small vessel
disease, while no such risk exists in non-hospitalized COVID-19
patients. Additionally, contrary to initial concerns, COVID-19 does
not appear to cause glymphatic dysfunction.
Limitations: The use of the DTI-ALPS method to measure glymphatic function remains controversial. Perivascular spaces account for only 1% of cerebral tissue, making it difficult for this method to differentiate diffusion within perivascular spaces from diffusion along other axes.
Funding for this study: No funding was received for this study.
Has your study been approved by an ethics committee? Not applicable
Ethics committee - additional information: We did not apply for ethics approval as the data utilized in this study were obtained from the OpenNeuro database.

Author Block: V. Khasminsky, J. Naftali, G. Danieli, E. Uriel; Tel Aviv/IL
Purpose: The aim of our study was to measure the changes in density of the ventricular CSF and vitreous fluid of the eyes in AIS patients who underwent emergent diagnostic CT work-up and endovascular thrombectomy. Our assumption was that iodine contrast medium leaked into infarcted brain parenchyma would be cleared by the glymphatic system into CSF and would be detected there by CT.
Methods or Background: A cohort of 119 subjects with the diagnosis of AIS who underwent head NCCT, CT-angiography, CT-perfusion, endovascular thrombectomy, and another follow-up head NCCT in up to 36 hours was selected. The density of CSF in Hounsfield units (HU) was measured in the frontal horns of lateral ventricles, in the third ventricle and in the vitreous body of both eyes on the admission head NCCT and compared to the same measurements on the follow-up head NCCT.
Results or Findings: Small but statistically significant increases in HU were observed across various locations on the follow-up CT. The average HU in the frontal and third ventricles combined rose from 3.89±1.49 to 5.01±2.24, a difference of 1.12±2.14 (P < 0.001). The average HU in both eyeballs rose from 5.93±2.75 to 7.14±4.18, a difference of 1.2±4.57 (P = 0.003). In the subgroup with ASPECT score below 8 we found a difference of 1.68±2.14 (P < 0.001) in the ventricles and 3.16±5.29 (P < 0.011) in the vitreous.
Conclusion: Our findings can be explained in the framework of glymphatic system theory by the clearence of leaked iodine via the bulk flow of CSF in the perivenular space to the lateral ventricles.
The density increase in the vitreous fluid may be due to secondarily increased permeability of blood-retinal barrier or connections between intra-cranial and intra-ocular glymphatic systems.
Limitations: Not applicable.
Funding for this study: No funding was provided for this study.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Uid: Rmc-0825-23

Author Block: L. De Carolis, R. Pascuzzo, D. Aquino, S. A. Della Seta, R. Eleopra, F. Doniselli, R. Cilia; Milan/IT
Purpose: Glymphatic system dysfunction has been associated with neurodegeneration in Parkinson's disease (PD). However, its role in PD patients carrying GBA mutations (GBA-PD), a key genetic risk factor for PD, remains unclear. This study aimed to compare glymphatic function in idiopathic PD (iPD) and GBA-PD using Diffusion Tensor Imaging Along the Perivascular Spaces (DTI-ALPS) and investigate correlations with motor and non-motor symptoms.
Methods or Background: Brain DTI sequences (32 directions, b=1000 s/mm2) acquired with a 3T MRI scanner were retrospectively collected from 40 PD (20 iPD, 20 GBA-PD) and 40 age- and sex-matched patients with essential tremor (ET, serving as controls). DTI-ALPS indeces were computed for both hemispheres using Taoka’s method. Severity of motor and non-motor symptoms of PD patients were assessed by Hoehn and Yahr (H&Y) and Unified Parkinson’s Disease Rating scales (UPDRS). DTI-ALPS values were compared between groups of patients using Mann-Whitney test and were correlated with clinical variables using Spearman’s (rho) correlation coefficient.
Results or Findings: DTI-ALPS values were similar between iPD and GBA-PD patients. However, DTI-ALPS values in the hemisphere contralateral to the less affected side (DTI-ALPS-ctrl) were significantly higher (p<0.001) in PD patients with H&Y stage <2 (1.42±0.07) compared to others (PD with H&Y stage ≥2: 1.26±0.18; ET: 1.27±0.19). In GBA-PD patients, DTI-ALPS-ctrl values were positively correlated with visual memory (rho=0.726, p<0.001) but negatively correlated with sleep disturbances (rho=-0.576, p=0.008), while in iPD they were negatively correlated with age at onset (rho=-0.591, p=0.006), worse response to dopaminergic medication (rho=-0.588, p=0.007), and total UPDRS score (rho=-0.591, p=0.006).
Conclusion: Glymphatic dysfunction is linked to disease severity in PD and may play distinct roles in the pathology of iPD and GBA-PD.
Limitations: The study limitations are the relatively small sample size and the absence of healthy controls.
Funding for this study: Funding was provided by the Italian Ministry of Health
Has your study been approved by an ethics committee? Not applicable
Ethics committee - additional information: The study is retrospective

Author Block: Z. Li; Nanjing/CN
Purpose: Parkinson's disease (PD) is commonly characterized by asymmetric motor symptoms. Previous studies have implicated abnormal α-synuclein aggregation as a key factor in PD pathogenesis and suggested that glymphatic system dysfunction may be responsible for the disease progression. However, the relationship between glymphatic system asymmetry and the side of motor symptom onset in PD remains unclear.
Methods or Background: 27 left-onset PD (LPD) patients, 36 right-onset PD (RPD) patients, and 49 age- and sex-matched healthy controls (HCs) were included in this study. The bilateral hemispheric ALPS indices were used to evaluate glymphatic function. Asymmetry of the glymphatic system was assessed by the asymmetry index (AI). Partial correlation analysis was conducted to examine the relationship between impaired glymphatic system function and motor deficits.
Results or Findings: Compared to HCs, RPD patients exhibited a significant reduction in the left ALPS index, while both left and right ALPS indices were significantly reduced in LPD patients. In both LPD patients and HCs, the right ALPS index was lower than the left, suggesting a natural leftward asymmetry. However, this asymmetry was diminished in RPD patients, as indicated by a reduced AI. Moreover, in RPD patients, the Unified Parkinson's Disease Rating Scale Part III score showed a negative correlation with the left ALPS index, and with AI.
Conclusion: This study demonstrated PD patients with different onset sides have different patterns of glymphatic system function. The glymphatic system asymmetry may provide new insights into the mechanism underlying the lateralized onset of PD.
Limitations: Firstly, being a retrospective cohort study conducted at a single center, it involved a relatively small sample size. Secondly, further research is needed to investigate the potential therapeutic implications of targeting the glymphatic system in PD
Funding for this study: National Natural Science Foundation of China( 81671258)
Nanjing Medical University-Qilu Clinical Research Fund Project (2024KF0254)
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University, and the requirement for written informed consent was achieved. IRB number: No. 2014-SRFA-097.

Author Block: A. Innocenzi, M. Cella, G. Saltarelli, P. Badini, F. Pistoia, A. Catalucci, F. Bruno, E. Di Cesare, A. Splendiani; L'Aquila/IT
Purpose: This study aims to assess the presence of glymphatic system alterations in patients with Essential tremor (ET) and Parkinson’s disease (PD) through the analysis of diffusion tensors along perivascular spaces (DTI-ALPS index).
Methods or Background: We retrospectively evaluated 35 patients (19 PD, 16 TE, 28 males, mean age 67 years) who were eligible for Vim thalamotomy using MRgFUS (2018-2022) and 17 healthy controls (13 female, mean age 39 years). All MR images were obtained using a 3.0 Tesla MRI and a 32-channel head coil. DTI images were analyzed using open-source software. The ALPS indices were compared between the ET and PD patient populations, respectively. Both these populations were compared to healthy controls.
Results or Findings: PD and ET groups were matched for disease duration, age, gender and cognitive score. The ALPS index in PD patients showed a mean of 1.33, with no statistically significant differences compared to ET patients (1.31, p-value = 0.31), both reduced compared to healthy controls (1.62; p-value < 0.001). We observed a more intense tremor in ET patients rather than in PD patients (FTM 34,14 VS 28,64; p-value = 0.041). There was a significant correlation between the ALPS index and tremor intensity in ET patients (R = -0.76; p-value < 0.001). We did not find statistically significant correlations between ALPS –index and MoCA score in PD and TE groups.
Conclusion: There were no differences observed in the MRI indices of the glymphatic system between ET and PD patients, and both are reduced with respect to healthy subjects. Our results suggest the need for further studies to better define the role of the ALPS index as a marker of disease progression and to evaluate the possibility of neuro-degenerative pathophysiology in ET.
Limitations: Small sample size.
Funding for this study: This research received no external funding.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Our study received approval from the Internal Review Board of the University of L'Aquila (protocol code 21 January 2020 n. 01/2020), and all participating patients provided signed informed consent to take part in the study.

Author Block: R. Dahiya, S. Rohilla; Rohtak/IN
Purpose: idiopathic intracranial hypertension (IIH) is a common headache disorder in young and middle age females. A few theories postulate impaired cerebral glymphatic clearance in IIH, however there is a paucity of methods to quantify glymphatic activity in human brains. The purpose of this study was to use diffusion-tensor imaging to evaluate the glymphatic clearance of IIH patients and how it may relate to various clinical parameters.
Methods or Background: This observational cross-sectional study was conducted on 25 patients clinically diagnosed with IIH. DTI was used to separately evaluate the diffusivity in lateral association and projection fibers, with the degree of diffusivity used as a surrogate for glymphatic function (diffusion tensor image analysis along the perivascular space). Glymphatic clearance was correlated with several clinical metrics, including lumbar puncture opening pressure and Frisen papilledema grade and combined conduit score for transverse sinus stenosis.
Results or Findings: At an ALPS Index cut off of 1.64, ROC curve analysis showed sensitivity of 100%, specificity of 84.6%, PPV of 83.3%, NPV of 100%, DA of 91.3% and PLR of 6.5 with AUC of 0.973 demonstrating excellent diagnostic performance in differentiating severe from mild IIH. Also ALPS index showed significant negative correlation with BMI(P=0.012), CSF pressure(p=0.032), papilledema(p=0.001) indicating increasing ALPS index(i.e.worsened glymphatic clearance) with increasing severity of disease. CSF pressure and papilledema showed positive correlation(p=0.008).
Conclusion: Our results show that patients with IIH possess impaired glymphatic clearance, which is directly related to the extent of clinical severity and ALPS Index can be used for clinical diagnosis as a non invasive investigation.
Limitations: Since we did not record response to treatment on most recent follow up and its correlation with ALPS, we could assess whether ALPS can be used to guide treatment for IIH
Funding for this study: Not provided
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The ethics committee notification can be found under the
number BREC/22/231.

Author Block: L-P. Schmill, S. Seehafer, S. Aludin, S. Peters, O. Jansen, N. Larsen; Kiel/DE
Purpose: After decades of doubt, it has finally been proven that the human brain has its own glial-lymphatic system. Its role in various diseases has been studied and discussed. Although its exact function is still unclear, perivascular spaces and fluid transport by glial cells are thought to be the main components, and drainage appears to occur via the perivenous spaces and meningeal lymphatic vessels. These have been delineated by MRI for the first time in recent years, but there is still a lack of established methods to assess their functionality. The aim of this study was to investigate whether intracranial tumours have increased drainage via adjacent meningeal lymphatic vessels.
Methods or Background: MRI scans were performed on patients with glioblastomas and cerebral metastases of different primary tumours. The protocol included a fluid-attenuated inversion recovery sequence and a contrast-enhanced T1-weighted black blood sequence, which can be used to delineate meningeal lymphatic vessels. This study looked specifically at the contrast enhancement of these vessels and compared the signal intensities of lymphatics near the intracranial mass with those contralateral to it.
Results or Findings: Results from the first 5 out of 30 patients show increased visual contrast enhancement in the meningeal lymphatics adjacent to the tumour compared to the contralateral side. These results indicate an increased lymphatic drainage of intracranial masses in addition to their venous drainage.
Conclusion: The current aim is to gain new insights into the glymphatic system and its relationship with the pathogenesis of brain diseases. This study has already provided evidence for increased glymphatic drainage in intracranial tumours. However, the exact drainage areas and which sequences that can be used for optimal detection of lymphatic vessels are still unclear.
Limitations: Not applicable
Funding for this study: No funding was provided for this study.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Ethic approval was obtained from the IRB of the Medical Faculty of the Christian-Albrechts-University Kiel.