Signs of frontotemporal dementia seen in about 35% of ALS patients

Clumps of TDP-43 protein seen in 90+% of tissue examined in study

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by Steve Bryson, PhD |

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More than a third of people diagnosed with amyotrophic lateral sclerosis (ALS) also showed signs of frontotemporal dementia (FTD), according to a new study of brain tissue.

In more than 90% of tissues examined, patients had clumps of the TDP-43 protein, a hallmark of ALS that contributes to nerve damage, but ALS patients with FTD signs showed more extensive involvement. Moreover, when the tissue analysis was compared with clinical examination, ALS was more accurately diagnosed than ALS-FTD due to a wide variability in clinical presentation in FTD, the researchers noted.

“Neuropathological [tissue-examination] studies and correlation with clinical characteristics help us expand our knowledge of the basis of diseases such as ALS and frontotemporal dementia, opening doors to future studies on biomarkers and specific therapies,” Álvaro Carbayo, MD, co-lead author and a researcher at the Sant Pau Research Institute, in Spain, said in a press release.

The tissue examination study, “Clinicopathological correlates in frontotemporal lobar degeneration: motor neuron disease spectrum,” was published in Brain.

ALS, also called motor neuron disease, is marked by progressive muscle weakness and wasting (atrophy). It’s caused by the degeneration of motor neurons, the specialized nerve cells that control voluntary muscle movements, in the brain, brainstem, and spinal cord. FTD is a group of dementias marked by changes in behavior and language. Like ALS, it’s also caused by motor neuron degeneration, but it mainly affects neurons in two different brain regions, the frontal and temporal lobes.

In most ALS patients, and up to half of those with FTD, motor neuron function is disrupted by the toxic accumulation of a misfolded version of the TDP-43 protein. The two diseases are also associated with mutations in the C9orf72, TBK1, and TARDBP genes. Moreover, about half of ALS patients will develop behavior and cognition changes, with an estimated 10-15% meeting the criteria for an FTD diagnosis.

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 Frequency of FTD in ALS explored

Because brain tissue analysis remains the reference for a definite diagnosis of FTD, and not many studies have performed those analyses in ALS, the exact frequency of FTD in ALS patients is difficult to estimate.

To find out, a team of researchers led by Carbayo and Ricard Rojas, MD, PhD, examined clinical data and brain tissue from ALS patients with and without FTD to analyze the frequency of FTD and also to define specific subgroups based on their clinical, genetic, and tissue-related characteristics.

“It is crucial that we work together to better understand this spectrum of neurodegenerative diseases and to better care for our patients,” Carbayo said.

The researchers examined brain samples from 124 patients, whose mean age at death and brain donation was 66.4. Among them, 44 (35.5%) showed features associated with FTD (ALS-FTD), which exceeded previous clinical estimates, the researchers noted.

Nearly all brain samples (93.6%), with or without FTD, had TDP-43 protein aggregates. Among those with signs of FTD, 90.9% had TDP-43 aggregates, which were more widely distributed across brain tissue than in people with ALS alone.

Cognitive or behavioral changes during clinical follow-up were seen in 38.7% of patients, but significantly more patients in the FTD group had these changes than those with ALS alone (88.6% vs. 13.3%).

A clinical diagnosis of FTD was more common in ALS patients with FTD signs than in those with ALS alone (67.4% vs. 6.3%). Five patients received an FTD diagnosis without tissue signs of FTD, but they had other disease-related changes in brain tissue that could explain cognitive-behavioral impairment.

When the team compared diagnosis between clinical data and tissue analysis, ALS disease was more accurately diagnosed than ALS-FTD (93.8% vs. 61.4%).

No statistically significant differences were found in the survival rate between ALS and ALS-FTD, with both groups showing a similar disease duration. Similar survival rates were also found regardless of area of onset, the presence of symptoms affecting the face and throat, or disease-causing mutations.

Genetic mutations related to ALS occurred more frequently in ALS-FTD than in ALS (31.8% vs. 5%) and C9orf72 mutations were independently associated with signs of FTD in brain tissue.

“We have observed astonishing heterogeneity [variability] in the clinical presentation and pathological and genetic characteristics of patients, with a higher frequency of frontotemporal dementia than described in other series,” Carbayo said.

Said the researchers: “We describe a frequency of [FTD] of 35.5% in our series of neuropathologically confirmed cases of MND. The [ALS-FTD] spectrum is highly heterogeneous in all aspects, especially in patients with [FTD], in whom it is particularly difficult to define specific subgroups.”