The onset and early progression of motor and cognitive symptoms, specific by disease type to each amyotrophic lateral sclerosis (ALS) patient, are determined by age and sex, and to some extend by mutations in ALS genes, a large data study has found.
The study, “ALS phenotype is influenced by age, sex, and genetics,” was published in the journal Neurology.
ALS is a neurodegenerative disease that predominantly affects motor neurons, specialized nerve cells that are essential for the brain to control the body’s muscles. In its classic form, ALS starts as weakness in one part of the body and spreads gradually within that part and then elsewhere.
But the disease manifests differently among patients, depending on the type of motor neurons affected. Those with predominantly upper motor neuron (PUMN) disease, show excess reflexes, continuous muscle contraction, and a much longer disease course.
Disease onset in other patients is marked by speech and swallowing problems (bulbar disease), or by difficulty breathing (respiratory ALS). Still others experience weakness in their legs (flail leg ALS) or arms (flail arm ALS) as their first symptom.
Likewise, some ALS patients never experience dementia, while about half have some degree of cognitive impairment.
A group of researchers in Italy had previously shown that the prevalence of each disease subtype is different in men and women. Now, they set out to investigate whether factors like age, sex, and gene mutations could affect the motor and cognitive manifestations seen in patients.
They examined data covering 2,839 ALS patients, diagnosed from 1995 through 2015, and classified them according to their disease symptoms as classic, bulbar, flail arm, flail leg, PUMN, and respiratory ALS. Their median age at diagnosis was 67 years.
Patients were also assessed for their cognitive abilities, and classified as having no difficulties (normal cognition), executive cognitive impairment (ALSci), behavioral impairment (ALSbi), or frontotemporal dementia (FTD).
All 2,839 patients had data regarding their age and sex. But only 1,410 were tested for mutations (tests began in 2005), and 763 had data on cognitive health (testing began in 2007).
Looking first at whether age and sex had any influence on motor symptoms, the researchers found that bulbar ALS correlated with older age, being four times more likely in people ages 80 to 89 (the oldest group) compared to those between 20 and 49 (the youngest group). Bulbar ALS also affected women more than men at increasing ages.
Classic and PUMN ALS were both associated with younger age — the oldest patients were 44% and 89% less likely to have these forms of disease than younger patients, respectively. A similar association was found for flail arm ALS.
Men were more likely to have flail arm or respiratory ALS, and their likelihood of developing flail leg disease rose with age. Respiratory ALS also showed a trend toward a higher frequency in older age, but this did not reach statistical significance.
Among patients with genetic data, investigators found that C9orf72 expansions increased the likelihood (by two-fold) of bulbar disease, but lowered the likelihood of PUMN disease (by 67%) and of flail leg disease. SOD1 mutations decreased the frequency of bulbar disease by 3.5-fold, but increased the frequency of flail leg disease by the same amount.
Except for behavioral problems only, all types of cognitive deficits had some association with sex, age, genetic mutations, or disease subtype. For example, frontotemporal dementia was mostly determined by the presence of C9orf72 expansions, though it was also more likely in older women with bulbar disease.
Cognitive problems were more frequently seen in older patients, and a combination of cognitive and behavioral problems were more often observed in PUMN patients.
These data suggests that motor and cognitive symptoms of ALS do not develop randomly, and are instead associated with demographic factors — age and sex — as well as genetic factors.
“We found that the onset and early progression of motor and cognitive manifestations of ALS is strongly determined by at least [two] demographic factors, age and sex, and, to some extent, also by genetic variations,” the researchers concluded. ” A strong interrelation between motor and cognitive phenotypes” was also observed, they added.
Identifying factors that regulate ALS manifestations may help in reclassifying patients into subgroups based on similarities, suggesting within a “meaningful subgroup” they may also respond similarly to tailored treatments.
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