Diffusion Tensor Imaging as an Indicator Glymphatic Dysfunction Over Time in Patients with ALS
Poster No:
253
Submission Type:
Abstract Submission
Authors:
Rachel Sharkey1, Filomeno Cortese1, Bradley Goodyear1, Lawrence Korngut1, Keith Sharkey1, Sanjay Kalra2, Minh Dang Nguyen1, Richard Frayne1, Gerald Pfeffer1
Institutions:
1University of Calgary, Calgary, Alberta, 2University of Alberta, Edmonton, Alberta
First Author:
Co-Author(s):
Introduction:
Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of upper and lower motoneurons (Yedavalli, Patil, and Shah 2018). ALS is associated with the accumulation of misfolded proteins in brain tissue. The brain's glymphatic drainage system, which consists of perivascular channels that drain fluid from the brain parenchyma through aquaporin-4 channels expressed on astrocyte endfeet, is capable of draining these proteins from the brain, thereby reducing proteinopathy. It is a relatively recent discovery and remains poorly understood in the context of neurodegeneration (Liu et al. 2023; Jessen et al. 2015).
One of the major challenges in studying the human glymphatic system is the difficulty in visualizing the glymphatic flow in living tissue (Naganawa and Taoka 2022). The perivascular spaces that make up the glymphatic system are too small to be easily viewed using conventional neuroimaging methods. The new diffusion tensor image analysis along perivascular space (DTI-ALPS) technique takes advantage of conventional diffusion analysis methods applied to the major white matter tracts, to calculate an indirect measure of glymphatic flow. DTI-ALPS can be applied to many commonly collected diffusion images sets (Taoka et al. 2017; Naganawa and Taoka 2022; Steward et al. 2021).
Prior work using the DTI-ALPS index by Liu et al. has identified a reduced value in patients with early-stage ALS relative to controls at a single time point. Using DTI-ALPS, our study presents the advantage of a longitudinal analysis (three timepoints over 8 months) in a mixed cohort of patients with ALS and primary lateral sclerosis (PLS) that affects only upper motoneurons (Yedavalli, Patil, and Shah 2018).
One of the major challenges in studying the human glymphatic system is the difficulty in visualizing the glymphatic flow in living tissue (Naganawa and Taoka 2022). The perivascular spaces that make up the glymphatic system are too small to be easily viewed using conventional neuroimaging methods. The new diffusion tensor image analysis along perivascular space (DTI-ALPS) technique takes advantage of conventional diffusion analysis methods applied to the major white matter tracts, to calculate an indirect measure of glymphatic flow. DTI-ALPS can be applied to many commonly collected diffusion images sets (Taoka et al. 2017; Naganawa and Taoka 2022; Steward et al. 2021).
Prior work using the DTI-ALPS index by Liu et al. has identified a reduced value in patients with early-stage ALS relative to controls at a single time point. Using DTI-ALPS, our study presents the advantage of a longitudinal analysis (three timepoints over 8 months) in a mixed cohort of patients with ALS and primary lateral sclerosis (PLS) that affects only upper motoneurons (Yedavalli, Patil, and Shah 2018).
Methods:
Diffusion magnetic resonance images from the Calgary cohort of the Canadian ALS Neuroimaging Consortium (CALSNIC) (patients, n = 23; controls, n=22) were processed using custom scripts based image processing and analysis tools from FSL, SPM and MRtrix to calculate the DTI-ALPS index from voxel-wise tensor values (Taoka et al. 2017; Kalra et al. 2020). A linear mixed effects model was used to compare patients to controls across three imaging sessions over eight months, controlling for age and sex, and including an interaction with diagnosis and time. This evaluation was repeated with a second exploratory model with patients grouped by diagnosis (ALS: n = 18, PLS: n = 5). Both models were followed up with models examining diagnosis, age, sex, ALSFRS score and estimated disease progression rate, as well as their interactions with time.
Results:
ALS and PLS participants had reduced DTI-ALPS index values compared to controls (p < 0.05). This effect was driven by ALS participants (p < 0.01). PLS participants do not show the same relative reduction. Data from ALS and PLS participants showed a different pattern of change over time than controls (p < 0.05). ALS and PLS patients have a more similar trajectory over time compared to controls, despite the difference in mean DTI-ALPS index. We did not find a significant relationship between the DTI-ALPS index with specific symptom scores or symptom progression.
Conclusions:
We observed a reduced DTI-ALPS index in ALS patients consistent with the findings of Liu et al. but did not replicate the association they identified with ALSFRS score (Liu et al. 2023). This last finding may relate to the longer disease duration in our cohort. We also found a differing trajectory between ALS/PLS participants and controls in DTI-ALPS change over time. Patients with PLS did not show the same reduction in DTI-ALPS but did show a similar trajectory over time, suggesting that the glymphatic system plays a different role in these two motor neuron disorders given that ALS and PLS have very different clinical trajectories (Yedavalli, Patil, and Shah 2018). Future comparative studies with a larger cohort of PLS patients are warranted.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Lifespan Development:
Aging
Modeling and Analysis Methods:
Diffusion MRI Modeling and Analysis 2
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems
Keywords:
Aging
MRI
Other - Diffusion Imaging
1|2Indicates the priority used for review
Provide references using author date format
Kalra, Sanjay (2020) “A Prospective Harmonized Multicenter DTI Study of Cerebral White Matter Degeneration in ALS.” Neurology 95 (8): e943–52.
Liu, Shuangwu (2023) “Glymphatic Dysfunction in Patients with Early-Stage Amyotrophic Lateral Sclerosis.” Brain, August 16
Naganawa, Shinji (2022) “The Glymphatic System: A Review of the Challenges in Visualizing Its Structure and Function with MR Imaging.” Magnetic Resonance in Medical Sciences 21 (1): 182–94.
Steward, Christopher E. (2021) “Assessment of the DTI‐ALPS Parameter Along the Perivascular Space in Older Adults at Risk of Dementia.” Journal of Neuroimaging 31 (3): 569–78.
Taoka, Toshiaki (2017) “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.” Japanese Journal of Radiology 35 (4): 172–78.
Yedavalli, Vivek S, Abhijit Patil, and Parinda Shah. 2018. “Amyotrophic Lateral Sclerosis and Its Mimics/Variants: A Comprehensive Review.” Journal of Clinical Imaging Science Dec 6: 8:53.