Introduction/Aims In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1‐ALS), the antisense oligonucleotide tofersen had been investigated in a phase III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess neurofilament light chain (NfL) before and during tofersen treatment. Methods In six SOD1‐ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF‐NfL) and/or serum (sNfL) were investigated using the ALS Functional Rating Scale Revised (ALSFRS‐R) and ALS progression rate (ALS‐PR), defined by monthly decline of ALSFRS‐R. Results Three of the six SOD1‐ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS‐PR <0.9), whereas one patient demonstrated rapidly progressing ALS (ALS‐PR = 2.66). Mean treatment duration was 6.5 (range 5 to 8) months. In all patients, NfL decreased (mean CSF‐NfL: −66%, range −52% to −86%; mean sNfL: −62%, range −36% to −84%). sNfL after 5 months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P = .017). ALS‐PR decreased in two patients, whereas no changes in ALSFRS‐R were observed in four participants who had very low ALS‐PR or ALSFRS‐R values before treatment. Discussion In this case series, the significant NfL decline after tofersen treatment confirmed its value as response biomarker in an expanded clinical spectrum of SOD1‐ALS. Given the previously reported strong correlation between sNfL and ALS progression, the NfL treatment response supports the notion of tofersen having disease‐modifying activity.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.
Background Spinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by mutations of the SMN1 gene. Deficient SMN protein causes irreversible degeneration of alpha motor neurons characterized by progressive muscle weakness and atrophy. Considering that SMA is a multi-systemic disorder and SMN protein was found to be expressed in cortical structures, the cognitive profile of adult patients with SMA has recently been of particular interest. With nusinersen, a novel, disease-modifying drug has been established, but its effects on neuropsychological functions have not been validated yet. Aim of this study was to investigate the cognitive profile of adult patients with SMA during treatment initiation with nusinersen and to reveal improvement or deterioration in cognitive performance. Methods This monocentric longitudinal study included 23 patients with SMA type 2 and 3. All patients were assessed with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) before and after 14 months of treatment initiation with nusinersen. Additionally, motor function was evaluated by Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Results Of the treatment-naive patients, only three were below the age- and education-matched cut-off for cognitive impairment in the ECAS total score. Significant differences between SMA type 2 and 3 were only detected in the domain of Language. After 14 months of treatment, patients showed significant improvement of absolute scores in all three ALS-specific domains, in the non-ALS-specific domain of Memory, in both subscores and in the ECAS total score. No associations were detected between cognitive and functional outcome measures. Conclusions In some adult patients with SMA abnormal cognitive performance in ALS-specific functions of the ECAS was evident. However, the presented results suggest no clinically significant cognitive changes during the observed treatment period with nusinersen.
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