Molecular Pathology of ALS: What We Currently Know and What Important Information Is Still Missing

Abstract

Despite an early understanding of amyotrophic lateral sclerosis (ALS) as a disease affecting the motor system, including motoneurons in the motor cortex, brainstem, and spinal cord, today, many cases involving dementia and behavioral disorders are reported. Therefore, we currently divide ALS not only based on genetic predisposition into the most common sporadic variant (90% of cases) and the familial variant (10%), but also based on cognitive and/or behavioral symptoms, with five specific subgroups of clinical manifestation—ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, the fully developed behavioral variant of frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer’s disease (AD). Generally, these cases are referred to as amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD). Clinical behaviors and the presence of the same pathognomonic deposits suggest that FTLD and ALS could be a continuum of one entity. This review was designed primarily to compare neuropathological findings in different types of ALS relative to their characteristic locations as well as the immunoreactivity of the inclusions, and thus, foster a better understanding of the immunoreactivity, distribution, and morphology of the pathological deposits in relation to genetic mutations, which can be useful in specifying the final diagnosis.

RETRACTED: CSF p-tau as a potential cognition impairment biomarker in ALS

“…The correlation between p-tau and ALSFRS-r had also been reported, but, it was not confirmed by our results. Some scholars have also found that CSF tau protein increases in the early stage of ALS, with a gradual decline in later stages of the disease ( 25 ). The delay in enrollment and diagnosis of patients with ALS may be an additional reason for the decreased level of p-tau ( 25 , 26 ).…”

“…Some scholars have also found that CSF tau protein increases in the early stage of ALS, with a gradual decline in later stages of the disease ( 25 ). The delay in enrollment and diagnosis of patients with ALS may be an additional reason for the decreased level of p-tau ( 25 , 26 ). There was no correlation between serum and CSF p-tau in patients with ALS in this study, which suggests that the CSF p-tau test may not be explained by serologic detection.…”

Cerebral Iron Deposition in Neurodegeneration

“…Diagnostic criteria include progressive motor impairment and presence of upper and lower motor dysfunction [335]. The cardinal neuropathological findings in ALS are nerve cell atrophy in the anterior spinal cord, reactive gliosis in the anterior horns, phosphorylated neurofilament aggregates in anterior horn axons and presence of protein aggregates with various types of cytoplasmatic inclusions [336]. Brain MRI shows bilateral hypointensities on SWI at the precentral gyrus [132] corresponding to the motor cortex, and in some cases frontotemporal atrophy.…”

Common Fatal Neurodegenerative Diseases Revisited: Beyond Age, Comorbidities, and Devastating Terminal Neuropathology There Is Hope With Prevention

“…Transactivation response DNA binding protein 43 kDa (TDP-43)-normally a nuclear protein-, becomes a key pathologic protein in ALS and FTD. Neurons and glial cells in ALS, FTD, and the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) exhibit nuclear TDP-43 mislocalization, and cytoplasmic inclusions ( 22 – 25 ). ALS is associated with a spectrum of clinical phenotypes, with cognitive and/or behavioral symptoms and shows progressive degeneration of upper and/or lower motor neurons ( 26 ).…”