Sudarshan Ragunathan1, Laura C Bell1, Ashley M Stokes1, Natenael Semmineh1, Jessie Duncan2, Nicole Turcotte2, Shafeeq Ladha2, and Chad C Quarles1
1Neuroimaging Research, Barrow Neurological Institute, Phoenix, AZ, United States, 2Gregory W. Fulton ALS and Neuromuscular Center, Barrow Neurological Institute, Phoenix, AZ, United States
Synopsis
Amyotrophic lateral
sclerosis (ALS) is a neurodegenerative disease characterized by loss of upper
and lower motor neurons (UMN and LMN), resulting in muscle atrophy and eventual
death. Clinical indicators such as ALSFRS-R scores can be confounded by
inter-rater variability and low sensitivity. MR Cytography based TRATE has been shown to identify changes to myofiber microstructure. This work aims to demonstrate that TRATE is a more sensitive and consistent metric to evaluate longitudinal muscle degeneration in ALS patients than existing clinical indicators such as ALSFRS-R scores.
INTRODUCTION
The recent growth of the ALS therapeutic
pipeline has galvanized efforts to develop new biomarkers of disease
progression. While there are imaging biomarkers for upper motor neuron (UMN) characterization, there
are few that assess lower motor neuron (LMN) function. Since the hallmark of LMN degeneration is muscle denervation and atrophy, a muscle-based imaging technique
could be a useful biomarker. Through pilot data, we have demonstrated the potential
of MR Cytography (MRC)1 in identifying muscle cytoarchitecture changes
among ALS patient population2. In this work, we highlight the
performance of TRATE when compared to existing muscle imaging metrics, and also
demonstrate that MRC based approach is more sensitive to monitoring muscle
changes when compared to ALS Functional Rating Scale – Revised (ALSFRS-R) and Hand
Held Dynamometry (HHD) over two visits separated by a period of 6 months. METHODS
In this IRB-approved study, 23 subjects
(12 ALS patients and 11 healthy controls) were scanned at 3T (Philips,
Netherlands). Data for MRC analysis was obtained using a dynamic dual echo
DCE-MRI pulse sequence (TE1/TE2 : 1.1/20 ms; TR : 21 ms;
temporal res : 5.1 s). In addition to MRC data, fat fraction (FF) information
was obtained using a 3 point m-Dixon protocol. Multi-echo GRE with ETL = 5 was
used to estimate pre and post T2* changes. T1 mapping was performed using a
multiple flip angle approach (10 values of flip angles with increments of 2o
were used). Four of the 12 ALS patients underwent a second scan after a period
of 6 months to record longitudinal changes. ALSFRS-R scores and muscle strength
test measures were used as clinical indicators in this study.
Muscle groups from anterior
(Tibialis Anterior, and Peroneus Longus), and posterior (Tibialis Posterior,
Lateral Gatrocnemius, and Medial Gastrocnemius) regions of the calf were identified for postprocessing
and analysis. Muscle ROIs were drawn manually on a slice by slice basis by the
same operator. Transverse relaxivity at tracer equilibrium (TRATE)1 was
computed as the ratio of at contrast agent (CA)
equilibrium where, Ct is the CA (Gadavist) concentration. T2* maps from pre and post Gd data were obtained by fitting the
multi-echo data to a decaying exponential. TRATE estimates in the 5 muscle ROIs
were compared to Fat Fraction, T2 values and T2* changes between ALS patients
and healthy controls; longitudinal TRATE estimates were also compared to
ALSFRS-R (total), and ALSFRS-R (lower
limb) scores among the ALS population.RESULTS
Single slice (axial)
computed TRATE maps are shown in Fig. 1(B). The heterogeneity among TRATE
values is evident from these maps in the ALS patient as well as the healthy
control. TRATE
was consistently lower in ALS affected muscle than in healthy muscle in the 5
ROIs (Δmean
~31%). Among the different muscle ROIs, TRATE
values in the anterior tibial muscle and lateral gastrocnemius muscle of an ALS
patient were markedly lower between visit 1 and visit 2 (63% drop in TA; 32%
drop in LG between visit 1 and 2), as shown in Fig.2. Fat
Fraction was utilized as a measure of fatty infiltration (Fig. 1C). The average
increase in fat fraction across the ALS patient population was estimated at 8%.
TRATE estimates were compared to the ALSFRS-R overall (max score: 48) and lower
limb scores (max score: 12), as depicted in Fig.3. Two of the 4 patients did not
register a change in both ALSFRS-R scores between visits, but their corresponding TRATE
estimates reduced by 13.2% and 17.3% respectively.
DISCUSSION
With increased enthusiasm in biomarker development to study ALS
disease progression, it is well established that in ALS patients, myofiber
diameter and density both decrease with disease progression, thereby reducing TRATE
as shown previously in select ALS muscle groups2. While T2 signal
values and fat fraction maps have been utilized in neuromuscular disease
studies3,4, changes in TRATE were observed to be more consistent
than changes in fat fraction and voxel based T2 values. MR Cytography’s role as
a successful imaging biomarker is contingent on its sensitivity to muscle
degeneration over time. The presentation and progression of ALS is heterogeneous
across muscle groups, patients and over time, consistent with the varied TRATE
estimates observed here. Going forward, it will be important to characterize
TRATE in diverse groups of healthy controls as it could be influenced by
multiple factors, including age, state of exercise, and prior injuries to the
area of interest. A key finding of this study is that TRATE measures were
observed to decrease between visits even when there appeared to be no change to
the overall and lower limb ALSFRS-R scores. This supports the premise that while
ALSFRS-R scores can be subjective and be affected by inter-operator variability
between visits, TRATE could provide a more quantitative and consistent assessment
of ALS affected muscle health. CONCLUSION
Having shown the
potential of MR Cytography as a means to identify diseased muscle
cytoarchitecture changes, TRATE was shown to characterize longitudinal changes
in anterior and posterior regions of ALS affected calf muscles. Future work
includes incorporating MRC based bulbar imaging and neuroimaging to provide a
wholistic understanding of ALS disease progression and establishing the
repeatability of these biomarkers.Acknowledgements
This work was supported by the FLINN Foundation award #2094, and in part by Philips Healthcare.References
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