Findings also suggested that the lower motor neuron system — nerve cells of the spinal cord that connect to skeletal muscles — was relatively spared in those with longer disease duration. The study, “Neuropathological profile of long duration amyotrophic lateral sclerosis in military Veterans,” was published in the journal Brain Pathology.
Military veterans have a higher prevalence of ALS that the general public. In response, the Department of Veterans Affairs Biorepository Brain Bank (VABBB) was established in 2006 as a central nervous system tissue biobank with samples collected at autopsy from veterans with ALS.
About 10% of ALS patients overall are reported to survive beyond 10 years after diagnosis.
Interestingly, the median survival time of those veterans with samples in the VABBB is seen to be much longer, and “nearly double the 4.7 years from symptom onset observed in the VA National Registry,” the researchers wrote.
As such, the VABBB cohort opens to study genetic, clinical, and neurological factors related to unusually long disease duration. Researchers at Boston University School of Medicine, in collaboration with scientists from the Veteran Affairs (VA) Boston Healthcare System, collected medical records of 179 veterans in the VABBB, with additional information from the VA National ALS Registry. The group was mostly male (98%) and Caucasian (97%).
Demographic information collected included sex, ethnicity, and race, along with military information that included service branch, years of service, and deployment history.
Information on a family history of ALS or other neurological diseases was gathered in addition to clinical details, genetic assessments, and tissue sample analysis.
Data were divided into two groups based on disease duration. Those from a total of 103 patients were considered to have a standard disease duration with survival time of fewer than 10 years, while data from 76 patients were part of the long duration group with a survival time of 10 or more years.
“The proportion of participants with long-duration ALS in this cohort of Veterans was therefore 42%, which is substantially higher than the approximately 10% reported in other ALS cohorts,” the researchers wrote. Of the 76, 44 lived 10 to 15 years post-diagnosis, 15 lived 15 to 20 years, 12 lived 20 to 30 years, and five more than 30 years after years diagnosis.
“Each of the 30 years or greater duration cases were limb onset; none had a familial history of ALS, and no known mutations were found during genetic analysis,” the study noted. A comparison of the two groups found those who survived beyond 10 years had a significantly younger age of disease onset, slower initial disease progression, and older age at death.
The time between symptom onset and diagnosis was higher in the long duration group (2.7 years vs. 1.2 years), with a trend toward a different site of onset between groups. Onset was more often in the brain stem area (bulbar) in those in the standard duration group, while a trend toward more traumatic brain injury was seen in the longer duration group. (Bulbar-onset ALS is marked by first symptoms involving the head and neck, including trouble speaking or swallowing.)
Although upper motor neuron degeneration was similar between long and standard duration ALS, patients with long-duration had less severe degeneration of lower motor neurons, those that connect the central nervous system with muscles to be innervated. In the long duration group, a reduction was found in TDP-43 pathology, a protein that accumulates in cells causing inflammation and making neurons more vulnerable.
An increase and activation of microglia — immune cells in the brain — are a hallmark of ALS pathology. A significantly lower microglia density was found in the long duration cases, even after adjusting for age.
Researchers also noted differences in microglia shape, with those in the standard group having shapes associated with reactive (more prone to inflammatory responses) cells. Those in the long duration group had a more resting shape.
No significant differences between the two groups were found for race, ethnicity, sex, or familial history of neurological disease as well as military-related factors nor the frequency of common ALS-associated mutations.
“In the largest reported collection of ALS cases with disease durations lasting longer than ten years, we demonstrated pathological differences related to disease duration,” the researchers wrote.
“These findings suggest that the lower motor neuron system is relatively spared in long-duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers,” they added.