Distinct Clinical Features and Outcomes in Motor Neuron Disease Associated with Behavioural Variant Frontotemporal Dementia

Abstract

Aim: To determine the motor phenotype and outcome in a clinically ascertained group of patients with motor neuron disease (MND) and frontotemporal dementia (FTD). Methods: This is an observational retrospective clinical study of patients fulfilling the clinical criteria for MND-FTD. A contemporary series of patients with amyotrophic lateral sclerosis (ALS) without dementia were included for comparison. Demographic, clinical, genetic, and neuropathological data were collected. A descriptive and comparative data analysis was performed. Results: We identified 22 patients with MND-FTD. Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients – in 15 of them associated with severe dysphagia. Aspiration pneumonia was the most common cause of death (12/19; 63%) despite gastrostomy. One-third of the patients did not develop upper motor neuron dysfunction. When compared to classic ALS without dementia (n = 162), these features were significantly different. A neuro­pathological examination was performed on 7 patients, and it confirmed the presence of MND with TDP43 protein aggregates in all patients. Conclusions: The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research.

Cortical microstructure in the amyotrophic lateral sclerosis–frontotemporal dementia continuum

“…20 The observed differences in the topography of neurodegeneration between the ALSno-cbi and ALScbi groups support earlier observations of a distinct phenotype in ALS with FTD that is characterized by severe and predominantly affected bulbar and distal upper limb muscles. 35 This motor phenotype corresponds well with the observed neurodegeneration in the ALScbi, affecting cortical motor areas of the motor homunculus related to bulbar weakness and extramotor features. 35 Conversely, the ALSnocbi group showed a pattern of neurodegeneration involving dorsal motor areas and minimal extramotor involvement, in agreement with the lower frequency of bulbar presentation in this group.…”

“…35 This motor phenotype corresponds well with the observed neurodegeneration in the ALScbi, affecting cortical motor areas of the motor homunculus related to bulbar weakness and extramotor features. 35 Conversely, the ALSnocbi group showed a pattern of neurodegeneration involving dorsal motor areas and minimal extramotor involvement, in agreement with the lower frequency of bulbar presentation in this group. 12 Of note, when we compared the cortical thickness of all ALS groups with controls, we found cortical thinning in the primary motor cortex and inferior frontal, in agreement with previous meta-analyses of neuroimaging studies.…”

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants

“…Also in accordance with previous studies, the presence of a mutation was the strongest determinant for comorbid ALS and FTLD (14), even in the absence of family history within the ALS/FTD spectrum (36). Bulbar onset was more frequent in subjects with ALS-FTD, a finding that also has been found in other studies (37,41).…”

“…Mutations in genes reported as causative of or at risk for ALS were found in 21 subjects: 14 C9orf72 , 2 TARDBP (p.A90V and p.I383V), 2 SQSTM1 (both c.1157C > T), 1 TBK1 (p.T79del), 1 VCP (p.I27V), and 1 TAF15 (p.G462S). Most of these mutation carriers have been previously reported (34,36,37). More than half of ALS‐FTD subjects presented an ALS/FTD related mutation (61.3%), this percentage was higher than in ALSci (0%) and ALSni (3.1%) subjects ( p < 0.001).…”

Differences in Sex Distribution Between Genetic and Sporadic Frontotemporal Dementia

“…For instance, head trauma has been associated in one study with a three-fold increased risk of sporadic bvFTD [ 40 ]; in general, males have a higher incidence rate of traumatic brain injury (TBI) [ 41 ]. Likewise, men seem to have an overall higher risk of developing amyotrophic lateral sclerosis (ALS) [ 28 ], with the exception of bulbar ALS, that seems to be more frequent in post-menopausal women [ 24 ]. Head trauma, which is more frequent in men, is also pointed out as possible risk factor.…”