By Erin Manning, MD
Frontotemporal lobar degeneration commonly occurs with motor neuron disease and has similar cytoplasmic neuronal aggregates of TAR deoxyribonucleic acid-binding protein 43 (TDP-43) in the brain as well as the spinal cord.
Carbayo A, Borrego-Ecija S, Turon-Sans J, et al. Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum. Brain 2024;147:2357-2367.
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder that causes progressive muscle weakness and muscle atrophy as a result of the degeneration of motor neurons in the brain and spinal cord. Most patients die within two and five years from respiratory failure. Cognitive disorders have been recognized in this disease and may present in about 50% of patients. A smaller number of patients fulfill the clinical criteria for frontotemporal degeneration. In addition, about 12% of patients who initially present with frontotemporal lobar degeneration (FTLD) may develop motor neuron impairment that progresses. A larger number have some degree of peripheral motor signs and symptoms that are mild.
This report is an observational, retrospective, multicenter cohort study of 124 patients with motor neuron disease (MND) with or without FTLD. The cases were selected from the Neurologic Tissue Bank in Barcelona, Spain, and included all donated brains meeting criteria for MND. Exclusion criteria were motor neuron loss as the result of other neurogenerative diseases, lack of adequate clinical information, and incomplete or equivocal clinical data. The patients then were divided by the presence or lack of FTLD pathology in the brain. Medical records were reviewed by the patient’s treating neurologist during life. Genetic testing for C9orf72 was performed on cerebellar tissue. Other genetic mutations were only identified via prior screening in life.
Of the 124 patients included in the study, 56% were male. Mean age at death was 66 years. The pathologic diagnosis was isolated MND in 64% and FTLD-MND in 36%. Ten patients in the FTLD-MND group had no motor neuron symptoms during life and three patients were diagnosed with frontotemporal dementia (FTD). The other patients were diagnosed with other neurodegenerative diseases. All the isolated MND patients had motor neuron symptoms in life. Bulbar onset motor symptoms and distal upper limb impairment were more common in the FTLD-MND group. Thirty-one percent of patients met clinical criteria for FTD, and this was significantly more common in the FTLD-MND group. In the FTLD-MND group, 67% of patients received a clinical diagnosis of FTD compared to 6% in the isolated MND group. The patients in the isolated MND group with a clinical diagnosis of FTD but no FTLD pathology had pathologic findings of other neurodegenerative diseases that could explain the cognitive changes. There was no significant difference between the groups in survival when patients with no motor symptoms during life were excluded. Genetic mutations were more common in the FTLD-MND group, with C9orf72 being the most common.
Commentary
This study may give a better indication of the true frequency of FTLD co-occurring with MND, since cognitive evaluation can become more difficult as MND advances. Also, other neurodegenerative diseases can co-occur with MND, and early changes associated with MND may be missed with advanced neurodegenerative disease. As has been shown in other studies, the presence of C9orf72 does not predict specific clinical characteristics but is associated with a higher risk of FTLD-MND.
This study was limited by a smaller sample than the general MND or FTLD-MND population, since it only included patients who donated to the brain bank. This also was a retrospective study that included patients before the formal FTD-ALS criteria were established and relied on the evaluation of the treating neurologist without formal neuropsychological testing. Also, more extensive genetic testing was not performed, such as for SOD1 mutations that may have limited some of the genetic correlations. Prospective studies through a registry that include pathologic evaluation would be the next step to better evaluate the clinicopathologic correlation of FTLD-MND patients.
Erin Manning, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medicine and the Hospital for Special Surgery.
