To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = - 0.813, p < 0.001), Serum-NFL (r = - 0.493, p = 0.001), CSF-pNFH (r = - 0.637, p < 0.001), and Serum-pNFH (r = - 0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = - 0.562, p < 0.001), CSF-pNFH (r = - 0.506, p = 0.001), and Serum-pNFH (r = - 0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.
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Sci Rep
January 2025
NeMO Lab, ASST GOM Niguarda Cà Granda Hospital, Milan, Italy.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that can result in a progressive loss of speech due to bulbar dysfunction, which can have significant negative impact on the patient's mental well-being. Alternative Augmentative Communication (AAC) strategies based on synthetic voices have been shown to assist patients in maintaining communication and improving their Quality of Life (QoL). However, such synthetic voices are often perceived as impersonal and fail to capture the unique voice and identity of the patient.
View Article and Find Full Text PDFThe most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic GC repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy.
View Article and Find Full Text PDFNat Commun
January 2025
Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA.
An abnormal expansion of a GGGGCC (GC) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the GC repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits.
View Article and Find Full Text PDFJ Med Genet
January 2025
Department of Neurology, Sichuan University, Chengdu, Sichuan, China
Background: Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene () mutations, as reported in prior studies. The study aimed to elucidate the correlation between genotypes and phenotypes.
Methods: gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants.
J Med Chem
January 2025
Centro de Investigaciones Biológicas "Margarita Salas"-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control.
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