Boylan, Kevin

AbstractThis study aimed to assess and compare the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate‐to‐severe Alzheimer's disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death: 75 years or older (old‐ALS, n = 8), 64–74 years (middle‐ALS, n = 23), and 63 years or younger (young‐ALS, n = 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS‐CBS), were summarized. Sections of paraffin‐embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho‐TDP‐43 immunohistochemistry. The burden of TDP‐43 pathology was analyzed using digital image analysis. The TDP‐43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old‐ALS than in young‐ALS and middle‐ALS. TDP‐43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS‐CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP‐43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic‐predominant, age‐related TDP‐43 encephalopathy neuropathologic change.

ABSTRACT Introduction: The Amyotrophic Lateral Sclerosis (ALS)‐Specific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOL‐R) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOL‐SF) suitable for limited clinic time and patient stamina. Methods: The ALSSQOL‐SF was created using Item Response Theory and confirmatory factor analysis on 389 patients. A cross‐validation sample of 162 patients assessed convergent, divergent, and construct validity of the ALSSQOL‐SF compared with psychosocial and physical functioning measures. Results: The ALSSQOL‐SF consisted of 20 items. Compared with the ALSSQOL‐R, optimal precision was retained, and completion time was reduced from 15–25 minutes to 2–4 minutes. Psychometric properties for the ALSSQOL‐SF and its subscales were strong. Discussion: The ALSSQOL‐SF is a disease‐specific global QOL instrument that has a short administration time suitable for clinical use, and can provide clinically useful, valid information about persons with ALS. Muscle Nerve 58: 646–654, 2018

Targeting three defects with one strategy The neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia are most commonly caused by a mutation in the C9orf72 gene. The mutation is an expanded hexanucleotide repeat in a noncoding region. The expanded repeat produces sense and antisense RNA transcripts, which accumulate in patient cells and appear to sequester RNA-binding proteins. The sense and antisense transcripts are also translated into dipeptide repeat proteins, which are aggregation-prone and accumulate in the brain and spinal cord. Last, loss of function from reduced expression of C9orf72 in neurons and glia could contribute to the disease. Kramer et al. targeted both sense and antisense repeats by blocking a single gene called SPT4 , which mitigated degeneration in human cells by reducing all three types of pathologies. Science , this issue p. 708