Publications by authors named "Susanne Petri"

182 Publications

A Multi-Center Cohort Study on Characteristics of Pain, Its Impact and Pharmacotherapeutic Management in Patients with ALS.

J Clin Med 2021 Sep 30;10(19). Epub 2021 Sep 30.

Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany.

Background: Although pain is common in amyotrophic lateral sclerosis (ALS) and an effectively treatable symptom, it is widely under-recognized and undertreated. This study investigates epidemiological and clinical characteristics of pain, its impact and pharmacological treatment in ALS patients. In addition, opportunities for further optimization of pain therapy need to be identified.

Methods: Patients from three German ALS outpatient clinics were asked to complete the Brief Pain Inventory and the ALS Functional Rating Scale-Extension and to participate in semi-structured telephone interviews.

Results: Of the 150 study participants, 84 patients reported pain. Pain occurred across all disease stages, predominantly in the neck, back and lower extremities. It was described with a broad spectrum of pain descriptors and mostly interfered with activity-related functions. Of the 84 pain patients, 53.8% reported an average pain intensity ≥4 on the numerical rating scale (NRS), indicating pain of at least moderate intensity, and 64.3% used pain medication. Irrespective of the medication type, 20.4% of them had no sufficient pain relief. Thirteen out of 30 patients without pain medication reported an average NRS value ≥4. Eleven of them-mainly in the context of high pain interference with daily functions-were supposed to benefit from adequate pain therapy. However, many patients had relevant concerns and misconceptions about pain therapy.

Conclusion: Given the frequency, extent and multi-faceted impact of pain, it is necessary to systematically assess pain throughout the disease course. Potentials to optimize pain therapy were seen in the subset of patients with insufficient pain relief despite medication and in those patients without pain medication but high pain interference. However, there is a need to respond to patients' barriers to pain therapy.
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http://dx.doi.org/10.3390/jcm10194552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509485PMC
September 2021

Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial.

Lancet Neurol 2021 10;20(10):821-831

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, and Department of Neurology, King's College Hospital, King's College London, London, UK.

Background: There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function.

Methods: The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately.

Findings: Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5-51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4-48·1) weeks. Change from baseline in supine SVC at 12 weeks was -6·73% with levosimendan and -6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI -2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI -15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis.

Interpretation: Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.

Funding: Orion Corporation.
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http://dx.doi.org/10.1016/S1474-4422(21)00242-8DOI Listing
October 2021

Characteristics of pain and the burden it causes in patients with amyotrophic lateral sclerosis - a longitudinal study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Aug 14:1-8. Epub 2021 Aug 14.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

Objective: Pain currently plays a subordinate role in the clinical care of patients with ALS. We aim to examine epidemiological and clinical characteristics of pain as well as its impact throughout the disease course.

Methods: During a longitudinal follow-up at three time points, 151 ALS patients from three German outpatient clinics completed the Brief Pain Inventory, ALS-Functional Rating Scale-Extension and ALS Depression Inventory. Analysis of variance and covariance with repeated measures were performed.

Results: Pain was prevalent in 56% of the 151 patients at baseline and in 70% of the remaining 40 patients at the third survey. Of the 28 patients with pain who participated in all three surveys, about two thirds suffered from an average pain intensity corresponding to at least moderate pain on the numerical rating scale (NRS ≥ 4). Patients reported different pain qualities and localized the pain most frequently in the extremities, back and neck. Pain moderately impaired the functions of daily living. Pain intensity, pain quality and pain-related impairment did not significantly change over time. One third of the patients suffered from clinically relevant depressive symptoms. However, there was no conclusive evidence of a link between pain intensity and depressive symptoms.

Conclusion: Pain is frequent and constitutes an additional strain on ALS patients who have to endure a rapidly progressive and severely debilitating disease. This study contributes to better understanding of the characteristics of pain and its impact on ALS patients throughout the disease course and may thus help to more effectively address this symptom.
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http://dx.doi.org/10.1080/21678421.2021.1962354DOI Listing
August 2021

Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy.

Orphanet J Rare Dis 2021 07 28;16(1):330. Epub 2021 Jul 28.

Department of Neurology, Technische Universität Dresden, Dresden, Germany.

Background: Studies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen.

Methods: In this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed.

Results: CHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy.

Conclusions: CHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.
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http://dx.doi.org/10.1186/s13023-021-01961-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320162PMC
July 2021

Motor neuron disease beginning with frontotemporal dementia: clinical features and progression.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jul 7:1-9. Epub 2021 Jul 7.

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

: To study disease characteristics, progression and outcome in a group of motor neuron disease (MND) patients beginning with frontotemporal dementia (FTD) by comparing them with patients with the typical motor-onset. 849 patients recruited from tertiary centers were studied according to FTD-onset and motor-onset. We studied clinical data, functional decline and survival. Twenty six patients (3.1%) had FTD-onset of whom seven (26.9%) had coincident motor dysfunction. In those with isolated FTD-onset, motor symptoms developed after a median of 12 months (IQR: 4-18). FTD-onset patients were older at presentation; the bulbar-region was more frequently first affected than in the motor-onset group; there was a predominant upper motor neuron (UMN) phenotype; fasciculations were less common than in motor onset disease but facial and upper limb apraxia was more frequent; as well as ALS and FTD familial history. No differences were observed for gender, frequency of hexanucleotide repeat expansion, family history of Alzheimer's and Parkinson's diseases, median delay from motor symptoms to diagnosis, median ALSFRS-R rate of change, handedness, emotional lability, depression, weight loss, resting tremor, bradykinesia, sensory changes or neuropathy. Clinical and demographic features were similar between FTD-onset patients developing bulbar MND and bulbar-onset ALS patients. Once bulbar symptoms manifested functional progression and survival were similar to those of bulbar-onset ALS patients. MND patients with FTD-onset have a distinctive phenotype characterized by predominant UMN presentation and rapid progression to bulbar involvement. The main factor impacting functional decline and survival is the onset of bulbar dysfunction.
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http://dx.doi.org/10.1080/21678421.2021.1910309DOI Listing
July 2021

Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers' Lives.

Brain Sci 2021 Jun 4;11(6). Epub 2021 Jun 4.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs ( = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r = -0.555, < 0.001, 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], < 0.001) and was interrelated with the CGs' depression (r = 0.627, < 0.001, 234), anxiety (r = 0.550, < 0.001, 234), and poorer physical condition (r = -0.362, < 0.001, 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r = -0.280, < 0.001, 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.
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http://dx.doi.org/10.3390/brainsci11060748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228206PMC
June 2021

Caregivers' divergent perspectives on patients' well-being and attitudes towards hastened death in Germany, Poland and Sweden.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jun 30:1-11. Epub 2021 Jun 30.

Department of Neurology, University of Ulm, Ulm, Germany.

During the course of amyotrophic lateral sclerosis (ALS), patients and their families are faced with existential decisions concerning life-prolonging and -shortening measures. Correct anticipation of patient's well-being and preferences is a prerequisite for patient-centered surrogate decision making. : In Germany ( = 84), Poland ( = 77) and Sweden ( = 73) patient-caregiver dyads were interviewed. Standardized questionnaires on well-being (ADI-12 for depressiveness; ACSA for global quality of life) and wish for hastened death (SAHD) were used in ALS patients. Additionally, caregivers were asked to fill out the same questionnaires by anticipating patients' perspective (surrogate perspective). : Caregivers significantly underestimated patients' well-being in Germany and Poland. For Swedish caregivers, there were just as many who underestimated and overestimated well-being. The same was true for wish for hastened death in all three countries. For Swedish and Polish patients, caregivers' estimation of well-being was not even associated with patients' responses and the same was true for estimation of wish for hastened death in all three countries. Older caregivers and those with the most frequent encounter with the patient were the closest in their rating of well-being and wish for hastened death to the patients' actual state, while caregivers with chronic disease him/herself were more likely to underestimate patient's well-being. : Despite distinct cultural differences, there was a clear discrepancy between patients' and caregivers' perspective on patients' well-being and preferences towards life in all three countries. This possible bias in caregivers' judgment needs to be taken into account in surrogate decision making.
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http://dx.doi.org/10.1080/21678421.2021.1936064DOI Listing
June 2021

Brain activity is contingent on neuropsychological function in a functional magnetic resonance imaging study of verbal working memory in amyotrophic lateral sclerosis.

Eur J Neurol 2021 09 29;28(9):3051-3060. Epub 2021 Jun 29.

Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.

Background And Purpose: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that causes progressive degeneration of neurons in motor and non-motor brain regions, affecting multiple cognitive domains such as memory. A functional magnetic resonance imaging (fMRI) study was performed to explore working memory function in ALS.

Methods: To contribute to the growing research field that employs structural and functional neuroimaging to investigate the effect of ALS on different working memory components, the localization and intensity of alterations in neural activity was explored using fMRI. Being the first study to specifically address verbal working memory via fMRI in the context of ALS, the verbal n-back task with 0-back and 2-back conditions was employed.

Results: Despite ALS patients showing unimpaired accuracies (p = 0.724) and reaction times (p = 0.0785), there was significantly increased brain activity of frontotemporal and parietal regions in the 2-back minus 0-back contrast in patients compared to controls (using nonparametric statistics with 5000 permutations and a T threshold of 2.5).

Discussion: Increased brain activity of the frontotemporal and parietal regions during working memory performance was largely associated with better neuropsychological function within the ALS group, suggesting a compensatory effect during working memory execution. This study therefore adds to the current knowledge on neural correlates of working memory in ALS and contributes to a more nuanced understanding of hyperactivity during cognitive processes in fMRI studies of ALS.
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http://dx.doi.org/10.1111/ene.14957DOI Listing
September 2021

Treatment expectations and perception of therapy in adult patients with spinal muscular atrophy receiving nusinersen.

Eur J Neurol 2021 08 16;28(8):2582-2595. Epub 2021 Jun 16.

Department of Neurology, Center for ALS, SMA and other Motor Neuron Disorders, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background And Purpose: This was an investigation of treatment expectations and of the perception of therapy in adult patients with 5q-associated spinal muscular atrophy (5q-SMA) receiving nusinersen.

Methods: A prospective, non-interventional observational study of nusinersen treatment in adult 5q-SMA patients was conducted at nine SMA centers in Germany. The functional status, treatment expectations and perceived outcomes were assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-extended (ALS-FRS-ex), the Measure Yourself Medical Outcome Profile (MYMOP2), the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the Net Promoter Score (NPS).

Results: In all, 151 patients were included with a median age of 36 years (15-69 years). SMA type 3 (n = 90, 59.6%) prevailed, followed by type 2 (33.8%) and type 1 (6.6%). In SMA types 1-3, median ALS-FRS-ex scores were 25, 33 and 46 (of 60 scale points), respectively. MYMOP2 identified distinct treatment expectations: head verticalization (n = 13), bulbar function (n = 16), arm function (n = 65), respiration (n = 15), trunk function (n = 34), leg function (n = 76) and generalized symptoms (n = 77). Median symptom severity decreased during nusinersen treatment (median observational period 6.1 months, 0.5-16 months) from 3.7 to 3.3 MYMOP2 score points (p < 0.001). The convenience of drug administration was critical (49.7 of 100 TSQM-9 points, SD 22); however, the overall treatment satisfaction was high (74.3, SD 18) and the recommendation rating very positive (NPS +66).

Conclusions: Nusinersen was administered across a broad range of ages, disease durations and motor function deficits. Treatment expectations were highly differentiated and related to SMA type and functional status. Patient-reported outcomes demonstrated a positive perception of nusinersen therapy in adult patients with 5q-SMA.
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http://dx.doi.org/10.1111/ene.14902DOI Listing
August 2021

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling.

Neurotherapeutics 2021 Apr 15. Epub 2021 Apr 15.

Department of Neurology, University Hospital Regensburg, Regensburg, Germany.

Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor-Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"-"NVP-13"), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.
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http://dx.doi.org/10.1007/s13311-021-01045-2DOI Listing
April 2021

Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients.

Brain Sci 2021 Mar 13;11(3). Epub 2021 Mar 13.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.
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http://dx.doi.org/10.3390/brainsci11030367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998943PMC
March 2021

A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany.

Brain Sci 2021 Mar 14;11(3). Epub 2021 Mar 14.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = -1.96 per increase of one point in the ALSFRS-R score, < 0.001). "Limb-onset" ALS (ALS) was associated with a better QoL than "bulbar-onset" ALS (ALS) (mean ALSAQ-5 total score 55.46 versus 60.99, = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = -7.60, = 0.001), being tracheostomized (β = -14.80, = 0.004) and using non-invasive ventilation (β = -5.71, = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, = 0.007), and increasing age (β = 0.18, = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
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http://dx.doi.org/10.3390/brainsci11030372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998410PMC
March 2021

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.

Ann Clin Transl Neurol 2021 05 31;8(5):1049-1063. Epub 2021 Mar 31.

Department of Neurology, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Objective: To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA).

Methods: Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months.

Results: CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05).

Interpretation: Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.
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http://dx.doi.org/10.1002/acn3.51340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108420PMC
May 2021

Treatment satisfaction in 5q-spinal muscular atrophy under nusinersen therapy.

Ther Adv Neurol Disord 2021 5;14:1756286421998902. Epub 2021 Mar 5.

Department of Neurology, Hannover Medical School, Hannover, Germany.

Background: Nusinersen was the first approved disease-modifying therapy for all 5q-spinal muscular atrophy (SMA) patients regardless of age or disease severity. Its efficacy in adults has recently been demonstrated in a large cohort by motor outcome measures, which were only partially suitable to detect changes in very mildly or severely affected patients. Patient-reported outcome measures (PROs) have been suggested as a valuable addition. Here, we aimed to assess treatment satisfaction and investigate whether it may be a useful PRO to monitor SMA patients.

Methods: We enrolled 91 mainly adult 5q-SMA patients treated with nusinersen in a national, multicenter, cross-sectional observational study. 21 patients underwent longitudinal follow up. Patients' satisfaction with treatment in four dimensions (global, effectiveness, convenience, side effects) was assessed by the Treatment Satisfaction Questionnaire for Medication German version 1.4 (TSQM-1.4) and related to clinical parameters, motor scores, and treatment duration.

Results: More than 90% of SMA patients were consistently satisfied over a median treatment duration of 10 months. Highest mean scores were observed in the dimensions 'side effects,' 'global satisfaction,' and 'effectiveness' (93.5 ± 14.8 73.1 ± 21.0 and 64.8 ± 20.6, respectively). Patients' satisfaction with the convenience of treatment was considerably lower (43.6 ± 20.2). Interestingly, satisfaction with the effectiveness was higher in ambulatory ( = 0.014) compared with non-ambulatory patients and directly correlated to motor outcome measures. Five non-ambulatory patients withdrew from therapy. All of them presented with a deterioration of motor outcome measures and reported dissatisfaction with treatment effectiveness and convenience.

Conclusion: Most patients were satisfied with nusinersen treatment effectiveness. Less severely affected patients indicated higher satisfaction. The TSQM-1.4 helped to identify therapy non-responders, who mainly addressed dissatisfaction with effectiveness and convenience. We suggest introducing the TSQM-1.4 as an additional PRO in SMA into clinical practice.
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http://dx.doi.org/10.1177/1756286421998902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940734PMC
March 2021

Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients.

Brain Sci 2021 Feb 26;11(3). Epub 2021 Feb 26.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.
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http://dx.doi.org/10.3390/brainsci11030296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996901PMC
February 2021

Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 12;22(3-4):276-286. Epub 2021 Feb 12.

Department of Neurology, Ulm University, Ulm, Germany.

Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. : Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients ( = 65). Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 ( = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients' progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. : CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.
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http://dx.doi.org/10.1080/21678421.2020.1861023DOI Listing
May 2021

Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers.

Exp Neurol 2021 05 23;339:113620. Epub 2021 Jan 23.

Institute of Experimental Epileptology and Cognition Research, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ (5 μM for 3 weeks) or Trolox (300 μM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors.
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http://dx.doi.org/10.1016/j.expneurol.2021.113620DOI Listing
May 2021

Clinically Applicable Quantitative Magnetic Resonance Morphologic Measurements of Grey Matter Changes in the Human Brain.

Brain Sci 2021 Jan 5;11(1). Epub 2021 Jan 5.

Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, 30625 Hannover, Germany.

(1) Purpose: Quantitative magnetic resonance imaging (qMRI) measurements can be used to sensitively estimate brain morphological alterations and may support clinical diagnosis of neurodegenerative diseases (ND). We aimed to establish a normative reference database for a clinical applicable quantitative MR morphologic measurement on neurodegenerative changes in patients; (2) Methods: Healthy subjects (HCs, = 120) with an evenly distribution between 21 to 70 years and amyotrophic lateral sclerosis (ALS) patients ( = 11, mean age = 52.45 ± 6.80 years), as an example of ND patients, underwent magnetic resonance imaging (MRI) examinations under routine diagnostic conditions. Regional cortical thickness (rCTh) in 68 regions of interest (ROIs) and subcortical grey matter volume (SGMV) in 14 ROIs were determined from all subjects by using Computational Anatomy Toolbox. Those derived from HCs were analyzed to determine age-related differences and subsequently used as reference to estimate ALS-related alterations; (3) Results: In HCs, the rCTh (in 49/68 regions) and the SGMV (in 9/14 regions) in elderly subjects were less than those in younger subjects and exhibited negative linear correlations to age ( < 0.0007 for rCTh and < 0.004 for SGMV). In comparison to age- and sex-matched HCs, the ALS patients revealed significant decreases of rCTh in eight ROIs, majorly located in frontal and temporal lobes; (4) Conclusion: The present study proves an overall grey matter decline with normal ageing as reported previously. The provided reference may be used for detection of grey matter alterations in neurodegenerative diseases that are not apparent in standard MR scans, indicating the potential of using qMRI as an add-on diagnostic tool in a clinical setting.
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http://dx.doi.org/10.3390/brainsci11010055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824828PMC
January 2021

FUS Is Not Mislocalized in Spinal Motor Neurons Derived From Human Induced Pluripotent Stem Cells of Main Non-FUS ALS Subtypes.

J Neuropathol Exp Neurol 2021 Aug;80(7):720-722

Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.

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http://dx.doi.org/10.1093/jnen/nlaa154DOI Listing
August 2021

Cardiovascular comorbidities in amyotrophic lateral sclerosis.

J Neurol Sci 2021 Feb 25;421:117292. Epub 2020 Dec 25.

Instituto de Fisiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Departamento de Neurociências e Saúde Mental, Hospital de Santa Maria - Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.

Background: The role of cardiovascular risk factors in amyotrophic lateral sclerosis (ALS) is controversial. A favourable profile has been found in ALS patients, but previous studies have not specifically considered the profile in different disease phenotypes.

Methods: Demographic data, smoking habits, lifetime exercise, and medical history including diabetes mellitus, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, stroke, and cardiac events, were analysed in ALS patients and in controls with other neurological disorders, utilising a standardized questionnaire applied by the same neurologist. In ALS patients the results were analysed according to their different phenotypes. Univariate analyses and multinomial logistic models were applied to estimate the odds ratios (ORs) and confidence intervals (CIs) for covariates, to test potential modifiers and their effects.

Results: 500 consecutively assessed adult ALS patients (mean age 65.6, 47% women, and 136 bulbar-onset) and 327 age and gender-matched controls were studied. Patients with spinal-onset ALS took more exercise (p = 0.012), reported less hypertension (p = 0.002) and had fewer cardiac events (p = 0.012). Multinomial regression analysis showed that men without hypertension have a higher risk of having spinal-onset ALS (p < 0.001) while female with hypertension have a higher risk of having bulbar-onset ALS (p = 0.033).

Conclusions: Risk-factors in ALS can be influenced by gender and phenotype. This study suggests that men with spinal ALS are healthier, exercise more and have lower rate of hypertension, but females with bulbar-onset ALS are more prone to hypertension. The complex interplay between exercise, diet and comorbidities with ALS phenotype requires further investigation.
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http://dx.doi.org/10.1016/j.jns.2020.117292DOI Listing
February 2021

Executive function is inversely correlated with physical function: the cognitive profile of adult Spinal Muscular Atrophy (SMA).

Orphanet J Rare Dis 2021 01 6;16(1):10. Epub 2021 Jan 6.

Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.

Background: Spinal muscular atrophy (SMA) issues from mutations in the survival of motor neuron (SMN) 1 gene. Loss or reduction of the SMN protein results in progressive muscle weakness. Whether this protein deficiency also affects cortical function remains unclear. While no data on adult patients exists so far, prior studies in children with SMA indicate cognitive abilities equal or even superior to healthy controls. This may suggest a possible compensatory-neuropsychological and interactional-process. The goal of this study was to assess the cognitive profile of adult patients with SMA, with a special focus on social cognition as a potential candidate for enhanced cognitive function through compensatory processes.

Methods: In a cross-sectional design, N = 31 adult SMA patients (types II and III) were assessed for language, verbal fluency, memory, visuospatial abilities and executive function with the Edinburgh Cognitive and Behavioural ALS Screen and for social cognition with the Reading the Mind in the Eyes Test. Physical function was evaluated using the Hammersmith Functional Motor Scale Expanded. N = 19 neurologically healthy controls were matched with patients for age, sex and years of education.

Results: In none of the abovementioned cognitive domains significant differences between SMA patients and controls were found. Among patients, no differences between type II SMA and type III SMA were detected for any domain. However, a trend towards better social cognition in patients with type II SMA, compared to those with type III SMA was observed. Furthermore, a significant inverse correlation of physical function and executive function was detected: lower motor function was associated with a better executive function.

Conclusions: This study shows cognitive abilities in adult SMA in the normal range for all assessed domains. Thus, reduction of SMN protein has no obvious negative impact on cognitive function. Executive functions are identified as the only cognitive domain correlated with disease severity. Therefore, executive functions may play a role in the adaptation to physical restrictions in SMA, making them a promising target for future research.
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http://dx.doi.org/10.1186/s13023-020-01661-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789267PMC
January 2021

Longitudinal clinical and neuroanatomical correlates of memory impairment in motor neuron disease.

Neuroimage Clin 2021 25;29:102545. Epub 2020 Dec 25.

Department of Neurology, Otto-von-Guericke University Magdeburg, Germany; Leibniz Institute for Neurobiology, Magdeburg, Germany; Kliniken Schmieder, Heidelberg, Germany.

Memory impairment in motor neuron disease (MND) is still an underrecognized feature and has traditionally been attributed to executive dysfunction. Here, we investigate the rate of memory impairment in a longitudinal cohort of MND patients, its relationship to other cognitive functions and the underlying neuroanatomical correlates. 142 patients with MND and 99 healthy controls (HC) underwent comprehensive neuropsychological testing and structural MRI at 3T up to four times over a period of 18 months. Linear-mixed effects models were fitted to identify changes at baseline and over time in episodic memory function (learning, immediate and delayed recall, recognition), composed cognitive scores (memory, verbal fluency, executive function), and memory-related structural brain regions (hippocampus, entorhinal cortex, parahippocampal gyrus). Associations between episodic memory performance and volumetric or cortical thickness changes of these regions were computed using Pearson's r. Learning, immediate and delayed recall, as well as recognition performance were significantly reduced in MND when compared to controls at baseline. Performances in these subtests improved over time although MND showed less improvement than controls. This relationship did not change when only "classical" ALS patients were considered. Patients with MND showed thinning of the right parahippocampal gyrus (PhG) in comparison to controls that was progressing over time. Bilateral hippocampal atrophy was observed in MND patients with memory impairment after splitting the group according to their overall episodic memory performance, with the right hippocampus shrinking over time. In MND patients, the bilateral hippocampal atrophy was associated with impairment in learning, recall, and recognition at baseline. In contrast, left PhG thinning was associated with a poorer learning performance. These results show that episodic memory impairment in MND is a frequent cognitive dysfunction. Since deficits are not clearly declining with disease course, an early involvement of this cognitive domain in the disease seems probable. The memory performance-dependent atrophy of the hippocampus and PhG provide evidence for a widespread involvement of these non-motor cortical areas in disease pathology.
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http://dx.doi.org/10.1016/j.nicl.2020.102545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786131PMC
June 2021

Cognitive Performance of Patients with Adult 5q-Spinal Muscular Atrophy and with Amyotrophic Lateral Sclerosis.

Brain Sci 2020 Dec 23;11(1). Epub 2020 Dec 23.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Motor neuron diseases, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), share several clinical similarities while differing substantially in etiology, disease onset and progression. Cognitive dysfunction, a clinically relevant non-motor feature in a substantial proportion of ALS patients, has been less frequently investigated in SMA. In this prospective multicenter cross-sectional study, cognitive function was assessed by the Edinburgh Cognitive (and Behavioural) ALS Screen (ECAS) and a German vocabulary test (Wortschatztest, WST) in 34 adult patients with SMA types 2-4 and in 34 patients with ALS. Demographic and clinical parameters were assessed to identify factors that potentially influence cognitive function. While SMA and ALS patients were comparable in the vocabulary test, on average, SMA patients performed better than ALS patients in the cognitive domains of memory, language and executive function. Better cognitive abilities in SMA patients seemed to be related to the early onset, rather than the extent or the duration, of their physical handicap. Future studies should focus on disease-specific cognitive functions in SMA.
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http://dx.doi.org/10.3390/brainsci11010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822456PMC
December 2020

Peripheral neuropathy in ALS: phenotype association.

J Neurol Neurosurg Psychiatry 2021 Oct 28;92(10):1133-1134. Epub 2020 Dec 28.

Faculdade de Medicina-Instituto de Medicina Molecular, Universidade de Lisboa. Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal.

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http://dx.doi.org/10.1136/jnnp-2020-325164DOI Listing
October 2021

The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on .

Neurology 2020 12 3;95(24):e3163-e3179. Epub 2020 Nov 3.

From the Friedrich-Baur-Institute (J.S., B.S.-W., M.W.), Department of Neurology, LMU Munich, Germany; DNA Laboratory (P.L., P.S.), Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic; Neuromuscular Unit (D.K., A.K.), Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland; Dr. John T. Macdonald Foundation Department of Human Genetics (L.A., A.R., S.Z.), John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL; Neurogenetics Group (J.B., T.D., P.D.J.), Center for Molecular Neurology, University of Antwerp; Institute Born-Bunge (J.B., T.D., P.D.J.), University of Antwerp; Neuromuscular Reference Centre (J.B., P.D.J.), Department of Neurology, Antwerp University Hospital, Belgium; Department of Clinical Chemistry and Laboratory Medicine (C.B.), Jena University Hospital; Centogene AG (C.B.), Rostock, Germany; Department of Medical Genetics (G.J.B., H.H.), Telemark Hospital Trust, Skien, Norway; Neurology Department (D.B., A.L., J. Weishaupt), Ulm University, Germany; Department of Neurology (J.D., D. Walk), University of Minnesota, Minneapolis; Department of Neurology (L.D.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Department of Sleep Medicine and Neuromuscular Diseases (B.D., A.S., P.Y.), University of Münster; Institute of Human Genetics (K.E., I.K.), Medical Faculty, RWTH Aachen University, Germany; Sydney Medical School (M.E., M.K., G.N.), Concord Hospital, Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, Australia; Department of Orthopaedics and Trauma Surgery (C.F., K.K., D. Weinmann, R.W., S.T., M.A.-G.), Medical University of Vienna, Austria; AP-HP (T.S.), Institut de Myologie, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, G-H Pitié-Salpêtrière, Paris, France; Department of Neurology (D.N.H.), University of Rochester, NY; Department of Clinical Neurosciences (R.H.), University of Cambridge School of Clinical Medicine, UK; Department of Neurology (S.I.), Konventhospital der Barmherzigen Brüder Linz; Karl Chiari Lab for Orthopaedic Biology (K.K., D. Weinmann, S.T.), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Austria; Stanford Center for Undiagnosed Diseases (J.N.K.), Stanford, CA; Undiagnosed Diseases Network (UDN) (J.N.K., S.Z.); Centre for Medical Research (N.G.L., R.O., G.Ravenscroft), University of Western Australia, Nedlands; Harry Perkins Institute of Medical Research (N.G.L., R.O., G. Ravenscroft), Nedlands; Neurogenetic Unit (P.J.L.), Royal Perth Hospital, Perth, Australia; Department of Neurology (W.N.L., J. Wanschitz), Medical University of Innsbruck, Austria; Department of Neurosciences and Behavior (W.M.), Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Department of Neurology (S.P.), Hannover Medical School, Germany; Department of Clinical and Experimental Medicine (G. Ricci), University of Pisa, Italy; Institute of Human Genetics (S.R.-S.), Medical University of Innsbruck, Austria; Department of Neurodegenerative Diseases Hertie-Institute for Clinical Brain Research and Center of Neurology (L.S., R.S., M.S.), University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (L.S., R.S., M.S.), Tübingen, Germany; AP-HP (B.F.), Laboratoire de génétique moléculaire, pharmacogénétique et hormonologie, Hôpital de Bicêtre; Le Kremlin-Bicêtre, France; Institute of Human Genetics (T.M.S.), Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg; Institute for Human Genetics (T.M.S.), Technical University Munich; and Institut für Klinische Genetik (J. Wagner), Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Germany.

Objective: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.

Methods: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and single-gene sequencing (n = 104). We further queried WES repositories for variants and measured blood levels of the -encoded protein neprilysin.

Results: In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance.

Conclusions: A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.
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http://dx.doi.org/10.1212/WNL.0000000000011132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836667PMC
December 2020

An observational cohort study on impact, dimensions and outcome of perceived fatigue in adult 5q-spinal muscular atrophy patients receiving nusinersen treatment.

J Neurol 2021 Mar 7;268(3):950-962. Epub 2020 Oct 7.

Department of Neurology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.

Background: Efficacy of nusinersen in adult 5q-spinal muscular atrophy (SMA) patients regarding motor function has recently been demonstrated. However, additional outcome measures are needed to capture non-motor improvements. Fatigue is a common and disabling symptom in neurologic diseases, but little is known about its frequency, characteristics and associated factors in SMA.

Objective: To characterize fatigue in SMA patients receiving nusinersen, identify associated factors and evaluate fatigue as potential patient-reported outcome measure (PRO).

Methods: We assessed fatigue in adults with genetically confirmed 5q-SMA in a prospective longitudinal monocentric study using the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI). Factors associated with fatigue including health-related quality of life (HRQOL) were evaluated.

Results: 75% of participants were abnormally fatigued with highest scores in the dimensions physical, followed by general fatigue and reduced activity. 53% agreed that fatigue was among their three most disabling symptoms. Reduced activity was reported more extensively by participants with ≥ 4 copies of the survival of motor neuron 2 gene and better motor function. General and mental fatigue correlated positively with age and disease duration. HRQOL was inversely correlated with physical fatigue, which was not associated with disease or participant characteristics. During 14 months of nusinersen treatment, fatigue measures remained mostly stable with a trend towards improvement in reduced activity, general and physical fatigue.

Conclusion: Fatigue is a frequent and relevant complaint in adult SMA patients. Fatigue should be taken into consideration as additional outcome measure, but needs further evaluation in a larger patient cohort over a longer observation period.
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http://dx.doi.org/10.1007/s00415-020-10227-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914247PMC
March 2021

Emotional Lability at Disease Onset Is an Independent Prognostic Factor of Faster Disease Progression in Amyotrophic Lateral Sclerosis.

Aging Dis 2020 Oct 1;11(5):1021-1028. Epub 2020 Oct 1.

1Department of Neurology, University Clinical Centre of Medical University of Warsaw, Warsaw, Poland.

Amyotrophic lateral sclerosis (ALS) is a fast progressing neurodegenerative disease leading to quadriplegia, anarthria and respiratory insufficiency. A large variety of phenotypes and disability progression requires individually tailored management. Identification of predictors of poor prognosis may not only improve management, but also allow for more precise patients' stratification for clinical trials or research studies. The aim of the study was to investigate the influence of emotional lability present at disease onset on ALS progression by exploring its direct impact on the decay of the ALS Functional Rating Scale-Revised (ALSFRS-R). The study was performed in a group of 1145 patients from Germany, Poland, Portugal and Turkey between 2014 and 2018. The analysis showed that the presence of emotional lability at ALS onset was linked to a faster decline of ALSFRS-R (0.70 vs 0.50, p<0.0001), in case of either bulbar (0.80 vs 0.65, p<0.05) or limb disease onset (0.59 vs 0.46, p <0.01). It was most prominent in the bulbar subscore of ALSFRS-R. A multiple regression analysis showed a direct influence of emotional lability at ALS onset on disease progression, regardless of age, gender, site of onset, weight loss, cognitive impairment and diagnosis delay (β=0.071; p=0.019). It can therefore be concluded that the presence of emotional lability at the disease onset is an independent factor of faster disease progression in ALS.
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http://dx.doi.org/10.14336/AD.2019.1120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505264PMC
October 2020

ALS and fertility: does ALS affect number of children patients have?

Amyotroph Lateral Scler Frontotemporal Degener 2021 02 8;22(1-2):94-100. Epub 2020 Sep 8.

Institute of Physiology, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Objective: Amyotrophic Lateral Sclerosis is one major disease in the group of neurodegenerative conditions. As with most other neurodegenerative diseases, clinical signs of the disease usually show among the elderly population, and most commonly around 60-65 years of age. Therefore the disease is not expected to impact the fertility of ALS patients. When examined from an evolutionary medicine and evolutionary biology perspective, there should be no selection pressure on the patient population due to the late onset of ALS. : In this study, we tested the hypothesis that ALS does not affect fertility on a group of patients with ALS that we collected in a multi-center study. We recruited 511 patients diagnosed with ALS according to the revised El Escorial criteria, and 236 control cases without a neurodegenerative disease. We compared the ALS group's number of offspring with the control group in three consecutive generations. : No statistically significant difference was found between the number of siblings of ALS and control groups ( = 0.44). A statistically significant difference was found between the number of children of ALS and control groups ( < 0.001), indicating ALS patients had more children than controls. When the number of children is assessed by gender, for women, there was no statistically significant difference between the number of children of ALS and control groups ( = 0.067). : This finding supports the view that ALS does not have a negative selection pressure on the patient population's fertility.
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http://dx.doi.org/10.1080/21678421.2020.1813313DOI Listing
February 2021

Cell culture media notably influence properties of human mesenchymal stroma/stem-like cells from different tissues.

Cytotherapy 2020 11 24;22(11):653-668. Epub 2020 Aug 24.

Department of Orthopaedic Surgery, Graded Implants and Regenerative Strategies, Hannover Medical School, Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), Hannover, Germany. Electronic address:

Background Aims: Mesenchymal stroma/stem-like cells (MSCs) are a popular cell source and hold huge therapeutic promise for a broad range of possible clinical applications. However, to harness their full potential, current limitations in harvesting, expansion and characterization have to be overcome. These limitations are related to the heterogeneity of MSCs in general as well as to inconsistent experimental protocols. Here we aim to compare in vitro methods to facilitate comparison of MSCs generated from various tissues.

Methods: MSCs from 3 different tissues (bone marrow, dental pulp, adipose tissue), exemplified by cells from 3 randomly chosen donors per tissue, were systematically compared with respect to their in vitro properties after propagation in specific in-house standard media, as established in the individual laboratories, or in the same commercially available medium.

Results: Large differences were documented with respect to the expression of cell surface antigens, population doubling times, basal expression levels of 5 selected genes and osteogenic differentiation. The commercial medium reduced differences in these parameters with respect to individual human donors within tissue and between tissues. The extent, size and tetraspanin composition of extracellular vesicles were also affected.

Conclusions: The results clearly demonstrate the extreme heterogeneity of MSCs, which confirms the problem of reproducibility of results, even when harmonizing experimental conditions, and questions the significance of common parameters for MSCs from different tissues in vitro.
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http://dx.doi.org/10.1016/j.jcyt.2020.07.005DOI Listing
November 2020

A Computational Study of Executive Dysfunction in Amyotrophic Lateral Sclerosis.

J Clin Med 2020 Aug 11;9(8). Epub 2020 Aug 11.

Department of Neurology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.

Executive dysfunction is a well-documented, yet nonspecific corollary of various neurological diseases and psychiatric disorders. Here, we applied computational modeling of latent cognition for executive control in amyotrophic lateral sclerosis (ALS) patients. We utilized a parallel reinforcement learning model of trial-by-trial Wisconsin Card Sorting Test (WCST) behavior. Eighteen ALS patients and 21 matched healthy control participants were assessed on a computerized variant of the WCST (cWCST). ALS patients showed latent cognitive symptoms, which can be characterized as bradyphrenia and haphazard responding. A comparison with results from a recent computational Parkinson's disease (PD) study (Steinke et al., 2020, J Clin Med) suggests that bradyphrenia represents a disease-nonspecific latent cognitive symptom of ALS and PD patients alike. Haphazard responding seems to be a disease-specific latent cognitive symptom of ALS, whereas impaired stimulus-response learning seems to be a disease-specific latent cognitive symptom of PD. These data were obtained from the careful modeling of trial-by-trial behavior on the cWCST, and they suggest that computational cognitive neuropsychology provides nosologically specific indicators of latent facets of executive dysfunction in ALS (and PD) patients, which remain undiscoverable for traditional behavioral cognitive neuropsychology. We discuss implications for neuropsychological assessment, and we discuss opportunities for confirmatory computational brain imaging studies.
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http://dx.doi.org/10.3390/jcm9082605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463664PMC
August 2020
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