ALS, Frontotemporal Dementia Have Distinct Patterns of Brain Inflammation, Study Shows

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by Alice Melão |

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are caused by different patterns of inflammation in the brain, which may help explain why these two illnesses are so distinct.

The German study, “Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase,” appeared in the Journal of Neurology, Neurosurgery & Psychiatry.

Doctors don’t know what causes most ALS and FTD cases. However, 5 to 10 percent of cases stem from genetic mutations affecting the C9orf72 gene, as well as other genes such as SOD1, FUS, TARDBP, TBK1, NEK1, MAPT and GRN.

Despite the two diseases’ common genetic landscape, they present quite different symptoms.

In the study, led by Germany’s Ulm University Hospital, researchers enrolled 26 asymptomatic subjects who carried genetic mutations linked to ALS and FTD, 66 and 33 patients with genetically confirmed ALS and FTD, and 36 healthy volunteers. In addition, the study also recruited 70 and 25 patients with sporadic ALS and FTD.

The team evaluated levels of chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) – all markers of neuroinflammation – in cerebrospinal fluid (CSF) and blood samples of the participants.

ALS patients were found to have four to nine times as much CHIT1 measured in CSF as did controls, asymptomatic mutation carriers and FTD patients. In addition, the amount of CHIT1 in CSF samples was found to be strongly correlated with the levels of nerve cell degeneration markers such as NfL and pNfH.

Researchers also found that ALS and FTD patients had two to five times higher CSF values of the YKL-40 marker than did controls and asymptomatic mutation carriers, while blood levels of the marker remained similar among groups.

As little information on YKL-40’s role in these diseases exists, the team also evaluated its levels in age- and sex-matched patients with sporadic ALS and FTD. The analysis revealed that YKL-40 CSF levels were slightly higher in sporadic FTD cases than in sporadic ALS patients. Still, both patient groups had higher YKL-40 CSF levels than did controls.

Likewise, YKL-40 levels in CSF samples were found to be strongly associated with NfL and pNfH neuron degeneration markers. In addition, the researchers found a link between YKL-40 levels and disability scores, as determined by the ALSFRS-R scale.

Finally, the GFAP marker levels in CSF samples were significantly higher in FTD patients than in controls and ALS patients. By contrast, values were similar among ALS patients, genetic mutation carriers, and controls.

Researchers found a similar pattern in patients with sporadic disease, with sporadic FTD cases having higher CFS values of GFAP than sporadic ALS cases and healthy volunteers.

The levels of this marker, however, were not linked with NfL and pNfH biomarkers,k or with disability scores.

Based on the patients’ disease onset and duration, and the pattern of CHIT1, YKL-40, and GFAP levels, researchers estimated the time course of asymptomatic mutation carriers and ALS patients. They concluded that the sudden increase in these markers levels could indicate the onset of symptoms, “similar to the previously reported neurofilaments,” they stated.

Collectively, these results showed that neuroinflammation is linked to the symptomatic phase of ALS and FTD, rather than the asymptomatic phase in mutation carriers.

“We show that neuroinflammation is a shared mechanism in sporadic and genetic forms of both diseases,” researchers said. Still, “ALS and FTD are characterized by a different neuroinflammatory pattern.” These difference may help explain the “manifestation of the ALS/FTD syndrome as FTD or ALS.”