Rationale and Objectives
T2-weighted magnetic resonance imaging (MRI) hyperintensity assessed visually in the corticospinal tract (CST) lacks sensitivity for a diagnosis of amyotrophic lateral sclerosis (ALS). We sought to explore a quantitative approach to fluid-attenuated inversion recovery (FLAIR) MRI intensity across a range of ALS phenotypes.
Materials and Methods
Thirty-three classical ALS patients, 10 with a flail arm presentation, and six with primary lateral sclerosis underwent MRI at 3 Tesla. Comparisons of quantitative FLAIR intensity in the CST and corpus callosum were made between 21 healthy controls and within patient phenotypic subgroups, some of whom were studied longitudinally.
Results
Mean FLAIR intensity was greater in patient groups. The cerebral peduncle intensity provided the strongest subgroup classification. FLAIR intensity increased longitudinally. The rate of change of FLAIR within CST correlated with rate of decline in executive function and ALS functional rating score.
Conclusions
FLAIR MRI encodes quantifiable information of potential diagnostic, stratification, and monitoring value.
Introduction
The neurodegenerative disorder amyotrophic lateral sclerosis (ALS) remains predominantly a clinical diagnosis with significant heterogeneity in rate of disability accumulation. Therapeutic trials rely on survival or change in disability accumulation rate as the primary endpoints. Biomarkers are therefore a research priority . Research-based magnetic resonance imaging (MRI) techniques, in particular diffusion tensor imaging (DTI), have demonstrated a consistent involvement of the corticospinal tracts (CSTs) and corpus callosum (CC) in ALS across a range of phenotypes (reviewed in Reference ).
Classical ALS is characterized by the presence of both upper motor neuron (UMN) and lower motor neuron (LMN) clinical signs . Current diagnostic criteria rely heavily on the presence of UMN signs , but these may be difficult to elicit and are minimal or absent in a substantial proportion of ALS cases . Those with clinically LMN predominant forms of ALS have a similar clinical progression and postmortem evidence of CST involvement , yet may be excluded from therapeutic trials.
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Methods
Participants
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Image Acquisition
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Image Analysis and Statistics
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Creation of CST ROI
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Quantitative FLAIR Analysis
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Clinical Measures
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Classification Analysis
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Longitudinal Study
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Results
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Table 1
(a) Participant Characteristics (Cross-Sectional Group). (b) Participant Characteristics (Longitudinal Group)
(a) Participant Characteristics (Cross-Sectional Group) Controls ( n = 21) Cross-Sectional Patients ( n = 49) Mean ± SD Range Mean ± SD Range_P_ † Age (years) \* 51.1 ± 12.7 28–72 60.9 ± 11.1 31–83 0.002 Classical ALS — — 59.3 ± 11.0 31–77 0.021 “Flail arm” ALS — — 61.7 ± 12.5 41–83 0.042 PLS — — 68.8 ± 6.2 62–76 0.003 Disease duration (months) \* — — 59 ± 66.4 5–366 — UMN score \* — — 9.5 ± 4.7 0–25 — ALSFRS-R \* — — 33.3 ± 5.8 18–44 — TMT B − A \* — — 36.8 ± 22 0–86 —
n %n %P Male 11 52.4% 31 63.3% 0.433 ‡ Classical ALS — — 33 67.4% — “Flail arm” ALS — — 10 20.4% — PLS — — 6 12.2% —
Disease Duration (Months ± SD) Classical ALS 35.1 ±29.2 “Flail arm” ALS 64.7 ±34.6 PLS 180.5 ±114.9
(b) Participant Characteristics (Longitudinal Group) Controls ( n = 21) Single-Scan Patients ( n = 28) Longitudinal Patients ( n = 21) Mean ± SD Range Mean ± SD Range_P_ † Mean ± SD Range_P_ § Age (years) \* 51.1 ± 12.7 28–72 60.9 ± 10.6 31–77 0.143 61.6 ± 12.2 39–83 0.954 Disease duration (months) \* — — 37.3 ± 39.1 5–190 — 91.5 ± 84 21–366 0.007 UMN score \* — — 10.0 ± 5.0 2–25 — 8.7 ± 4.7 0–15 0.494 ALSFRS-R \* — — 33.2 ± 7.2 18–44 — 33.3 ± 3.4 26–37 0.906 TMT B − A \* — — 39.5 ± 22.5 8–81 — 36.4 ± 19.9 10–86 0.472 Number of scans — — — — — 3.6 ± 1.1 2–5 —
n %n %P ‡ n %P ¶ Male 11 52.4% 19 67.7% 0.376 11 52.4% 0.553 Classical ALS — — 24 85.7% — 9 42.9% 0.002 “Flail arm” ALS — — 3 10.7% — 7 33.3% 0.076 PLS — — 1 3.6% — 5 23.8% 0.072
Disease Duration (Months ± SD) Disease Duration_P_ ‖ Classical ALS 29.8 ± 25.0 49.4 ±36.0 0.222 “Flail arm” ALS 46.8 ± 30.5 72.3 ±35.4 0.665 PLS 189.9 — 178.6 128.4 0.980
Longitudinal Patient Clinical Progression_n_ Mean ± SD Range Rate of change of ALSFRS \\ 20 −0.379 ±9 0.25 −1.07 to −0.11 Rate of change of TMT B − A \\ 14 0.31 ± 1.7 −4.09 to 1.95 Rate of change of CST FLAIR †† 21 1.47 ± 2.78 — Rate of change of CC FLAIR †† 21 0.58 ± 3.08 —
ALS, amyotrophic lateral sclerosis; ALSFRS-R, revised Amyotrophic Lateral Sclerosis Functional Rating Scale; CC, corpus callosum; CST, corticospinal tract; FLAIR, fluid-attenuated inversion recovery; PLS, primary lateral sclerosis; SD, standard deviation; TMT, Trail Making Test; UMN, upper motor neuron.
ALS vs PLS: P = 0.049.
ALS vs Flail arm: P = 0.589.
Flail arm vs PLS: P = 0.149.
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Quantitative FLAIR Analysis
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Table 2
Quantitative FLAIR in Subregions of the CST and CC
Control All ALS Patients Classical ALS Flail Arm PLS Intensity Intensity_P_ \* Intensity_P_ \* Intensity_P_ \* Intensity_P_ \* Whole CST 1.121 1.167 0.001 1.167 0.003 1.144 0.114 1.207 <0.001 Corona radiata 1.154 1.210 <0.001 1.208 0.001 1.188 0.038 1.258 <0.001 Internal capsule 1.066 1.091 0.081 1.094 0.084 1.069 0.625 1.114 0.022 Cerebral peduncle 0.984 1.010 0.099 1.017 0.046 0.972 0.462 1.034 0.032 Whole CC 1.085 1.132 0.003 1.127 0.007 1.122 0.070 1.176 0.001 Genu of CC 1.114 1.168 0.009 1.157 0.050 1.176 0.019 1.217 0.001 Body of CC 1.149 1.202 0.001 1.199 0.002 1.191 0.060 1.237 0.001 Splenium of CC 0.996 1.032 0.025 1.029 0.033 1.011 0.386 1.081 0.004
Control All ALS Patients Classical ALS Flail Arm PLS Intensity Intensity_P_ † Intensity_P_ † Intensity_P_ † Intensity_P_ † Whole CST 1.12 0–30 months — 1.16 0.013 1.16 0.009 1.11 0.579 — — 30–100 months — 1.17 0.001 1.16 0.011 1.14 0.277 1.25 <0.001 >100 months — 1.18 <0.001 1.14 0.460 1.19 0.002 1.20 <0.001 Whole CC 1.08 0–30 months — 1.12 0.020 1.12 0.009 1.06 0.041 — — 30–100 months — 1.12 0.020 1.11 0.133 1.11 0.283 1.18 <0.001 >100 months – 1.15 <0.001 1.10 0.672 1.16 0.001 1.18 <0.001
ALS, amyotrophic lateral sclerosis; CC, corpus callosum; CST, corticospinal tract; PLS, primary lateral sclerosis.
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Clinical Measures
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Classification Analysis
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Longitudinal Analysis
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Discussion
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Conclusions
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Appendix
Supplementary Data
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Figure S1
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