MRI Tool Shows Promise as ALS Biomarker

Diffusion tensor imaging (DTI) fractional anisotropy may measure disease progression in amyotrophic lateral sclerosis (ALS) and may be a prognostic biomarker, a longitudinal, multi-center study suggested.

Abnormal white matter findings in ALS patients correlated with clinical variables including upper motor neuron function and a clinical rating score, reported Sanjay Kalra MD, of the University of Alberta, Canada, and co-authors, in Neurology.

The study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS, Kalra and colleagues noted.

“The largest reduction in fractional anisotropy in our prospective cohort was observed in tracts associated with stage 1 of the disease (corticospinal tract), which theoretically would be present in all ALS patients, and progressively less reductions were observed in tracts associated with later pathological stages of the disease,” they wrote.

DTI showed mean progressive decline in fractional anisotropy of the corticospinal tract and frontal lobes, and corticospinal tract fractional anisotropy correlated with upper motor neuron scores, including finger-tapping.

Frontal lobe fractional anisotropy correlated with disability as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), which includes dyspnea, orthopnea, and the need for ventilatory support.

Moreover, longitudinal scans, available in a subset of ALS patients and controls, showed that progressive decline in corticospinal tract fractional anisotropy correlated with decline in the ALSFRS-R and worsening upper motor neuron signs.

“The principal strength of this study is demonstrating the validity of using DTI fractional anisotropy as a measure of disease progression and as a prognostic biomarker in ALS, based on multi-center data,” noted Hitoshi Shinotoh, MD, PhD, of the Neurology Clinic Chiba, Japan, and Carmel Armon, MD, MHS, of the Tel Aviv University School of Medicine, in an accompanying editorial.

“Corticospinal tract loss and frontal lobe loss, measured with fractional anisotropy, were associated with dysfunction, as measured by the ALSFRS-R, and predicted its progression,” they continued. “These observations provide additional support for the role of loss of upper motor neurons in driving disease progression in ALS, enhancing the understanding of disease pathophysiology.”

Biomarkers in ALS are under active exploration

DTI, an MRI tool, provides a quantitative measure of tract pathology and identifies paths of directional flow based on the diffusivity of water measured at different points. Disruptions in tracts from injuries of various kinds decrease the integrity of tract-oriented flow, measured as decreased fractional anisotropy.

In ALS, DTI has demonstrated progression of disease in the corticospinal tract in single-center studies. The present study was an effort to demonstrate applicability in a larger population through the Canadian ALS Neuroimaging Consortium.

Kalra and colleagues conducted a longitudinal, prospective multicenter study of 66 ALS patients and 43 healthy controls with clinical assessments at 0, 4, and 8 months. A baseline scan was done, and a follow-up scan was done for longitudinal data in 46 ALS patients and 34 controls.

Mean age varied across the four sites from 56 to 61 in the ALS group, and 53 to 59 in controls.

Tracts of interest, known to be progressively involved at different ALS stages, were defined as the corticospinal tract (stage 1), the corticorubral and corticopontine tracts (stage 2), the corticostriatal pathway (stage 3), and the proximal portion of the perforant path (connecting entorhinal cortex to the hippocampus; stage 4). These were compared to a usually uninvolved reference, the optic tract.

In prior research, “DTI-based in vivo staging system has been shown to correlate with functional severity and cognitive decline in ALS,” the authors noted. “It is important to note that these studies were conducted in retrospective, heterogeneous cohorts.”

In their analysis, Kalra and co-authors also compared fast progressors (ALSFRS-R loss of >5 points per year) to slow progressors. “Fast progressors (n=28) showed a greater reduction in fractional anisotropy of the corticospinal tract and upper frontal lobe compared with slow progressors (n=38), suggesting that DTI fractional anisotropy at the time of an initial evaluation may be a prognostic biomarker,” the editorialists observed.

Limitations include a small sample size, preventing clinical subtype analysis. Behavioral or cognitive abnormalities, which are frequent in ALS, were not assessed, and pathological correlates of fractional anisotropy alterations in ALS remain unknown.

“Additional data are needed to determine if DTI fractional anisotropy measures would do well as primary outcome measures in clinical trials of therapeutic interventions in ALS,” the editorialists wrote. They suggested:

• Data need to be acquired from an ALS population comparable to that which is enrolled into clinical trials, where patients progress at a faster rate (average ALSFRS-R decline of 9-12 points per year), and some have only mild or minimal upper motor neuron findings.
• The treatment duration needed to see a meaningful change should be determined and the loss of patients to follow up, which would likely increase with longer treatment duration, factored into study design.
• DTI fractional anisotropy measures should be compared to other potential ALS biomarkers and choices made based on available options.

1. Diffusion tensor imaging (DTI) fractional anisotropy may measure disease progression in amyotrophic lateral sclerosis (ALS) and may be a prognostic biomarker, a longitudinal, multi-center study suggested.

2. Additional data are needed to determine whether DTI fractional anisotropy measures would do well as primary outcome measures in ALS clinical trials, the editorialists noted.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Cat ID: 130

Topic ID: 82,130,730,130,192,925