Positive effects of fampridine on cognition, fatigue and depression in patients with multiple sclerosis over 2 years

OBJECTIVE: To assess the effects of PR-fampridine on cognitive functioning, fatigue and depression in patients with multiple sclerosis (PwMS). METHODS: Thirty-two PwMS were included in this trial. Cognitive performance was assessed in an open-label and randomized double-blind, placebo-controlled study design using a comprehensive neuropsychological test battery as well as questionnaires examining depression and fatigue. RESULTS: We found significant improvements in cognitive measures assessing alertness (tonic alertness, p = 0.0244 and phasic alertness, p = 0.0428), psychomotor speed (p = 0.0140) as well as verbal fluency (p = 0.0002) during open-label treatment with PR-fampridine. These effects of performance were paralleled by patients' perception of reduced fatigue (physical, p = 0.0131; cognitive, p = 0.0225; total, p = 0.0126). Fampridine-induced improvements in phasic alertness (p = 0.0010) and measures of fatigue (physical, p = 0.0014; cognitive, p = 0.0003; total, p = 0.0005) were confirmed during randomized, double-blind, placebo-controlled assessment in the second year. In addition, we found positive effects of PR-fampridine on depressive symptoms (p = 0.0049). We demonstrated persisting beneficial effects of PR-fampridine on fatigue in PwMS over a period of more than 2 years. Drug responsiveness regarding cognitive performance and fatigue was not limited to walking responders. CONCLUSIONS: Our data demonstrate significant positive effects of treatment with PR-fampridine over 2 years on different cognitive domains as well as fatigue and depression in a cohort of PwMS. These findings imply that PR-fampridine should be considered as symptomatic treatment improving aspects of cognition, fatigue and depression in PwMS

Galcanezumab bei episodischem und chronischem Clusterkopfschmerz

Zusammenfassung Hintergrund Der Clusterkopfschmerz (CK) ist eine schwerwiegende Kopfschmerzerkrankung mit heftigen unilateralen Schmerzattacken, begleitet von ipsilateralen autonomen Symptomen. Pathophysiologisch wird u. a. dem „calcitonin gene-related peptide“ (CGRP) eine wichtige Rolle beigemessen. Fragestellung Prophylaktische Wirksamkeit und Verträglichkeit des Anti-CGRP-Antikörpers Galcanezumab bei episodischem (eCK) und chronischem CK (cCK), Diskussion der Studienergebnisse und der Herausforderungen bei der Entwicklung von Medikamenten für die prophylaktische Behandlung des Clusterkopfschmerzes. Material und Methoden In zwei Phase-III-Studien wurde Galcanezumab (300 mg subkutan alle 4 Wochen) mit Placebo verglichen. Der Doppelblindphase (8 Wochen bei eCK, 12 Wochen bei cCK) ging jeweils eine Baseline-Phase voraus. Primärer Endpunkt war der Rückgang der wöchentlichen Attackenhäufigkeit. Ergebnisse und Diskussion In der Studie bei eCK wurden 106 Patienten randomisiert (49 Galcanezumab, 57 Placebo). In der Galcanezumabgruppe ging im Durchschnitt der ersten 3 Wochen die Häufigkeit von Kopfschmerzattacken um 52 % zurück, in der Placebogruppe um 27 % (p = 0,036). In der Studie beim cCK wurden 237 Patienten randomisiert (117 Galcanezumab, 120 Placebo). Hier wurde der primäre Studienendpunkt verfehlt (Rückgang der mittleren wöchentlichen Attackenhäufigkeit um 5,4 mit Galcanezumab vs. 4,6 mit Placebo; p = 0,334). In beiden Studien war Galcanezumab gut verträglich. Schlussfolgerungen Galcanezumab hat beim eCK eine prophylaktische Wirkung, nicht aber beim cCK. Mögliche Gründe für diese Diskrepanz werden diskutiert. Abstract Background Cluster headache (CH) is a highly debilitating headache disorder characterized by frequent attacks of excruciating unilateral pain accompanied by cranial autonomic symptoms. Calcitonin gene-related peptide (CGRP) is implicated in the pathophysiology of CH. Objectives Preventive efficacy and tolerability of the anti-CGRP antibody galcanezumab in patients with episodic (eCH) and chronic CH (cCH). Review of the study results and the challenges in developing drugs for the preventive treatment of CH. Materials and methods In two international multicenter phase III trials galcanezumab 300 mg given subcutaneously every 4 weeks was compared with placebo. The double-blind study period (8 weeks in eCH, 12 weeks in cCK) was preceded by a baseline period in both trials. The primary endpoint was the reduction in weekly attack frequency. Results In the eCH trial, 106 patients were randomized to either galcanezumab (n = 49) or placebo (n = 57). The mean weekly attack frequency during the first 3 weeks decreased by 52% in the galcanezumab group compared with 27% in the placebo group (p = 0.036). In the cCH trial, 237 patients were randomized to galcanezumab (n = 117) or placebo (n = 120). The primary endpoint was not met in this study. The reduction in mean weekly attack rate was 5.4 with galcanezumab versus 4.6 with placebo (p = 0.334). Galcanezumab was well tolerated in both studies. Conclusions Galcanezumab had a significant effect in the prevention of eCH attacks but not in cCH. Possible reasons for this discrepancy are discussed

Subcortical Shape Changes, Hippocampal Atrophy and Cortical Thinning in Future Alzheimer's Disease Patients

Efficacy of future treatments depends on biomarkers identifying patients with mild cognitive impairment at highest risk for transitioning to Alzheimer's disease. Here, we applied recently developed analysis techniques to investigate cross-sectional differences in subcortical shape and volume alterations in patients with stable mild cognitive impairment (MCI) (n = 23, age range 59-82, 47.8% female), future converters at baseline (n = 10, age range 66-84, 90% female) and at time of conversion (age range 68-87) compared to group-wise age and gender matched healthy control subjects (n = 23, age range 61-81, 47.8% female; n = 10, age range 66-82, 80% female; n = 10, age range 68-82, 70% female). Additionally, we studied cortical thinning and global and local measures of hippocampal atrophy as known key imaging markers for Alzheimer's disease. Apart from bilateral striatal volume reductions, no morphometric alterations were found in cognitively stable patients. In contrast, we identified shape alterations in striatal and thalamic regions in future converters at baseline and at time of conversion. These shape alterations were paralleled by Alzheimer's disease like patterns of left hemispheric morphometric changes (cortical thinning in medial temporal regions, hippocampal total and subfield atrophy) in future converters at baseline with progression to similar right hemispheric alterations at time of conversion. Additionally, receiver operating characteristic curve analysis indicated that subcortical shape alterations may outperform hippocampal volume in identifying future converters at baseline. These results further confirm the key role of early cortical thinning and hippocampal atrophy in the early detection of Alzheimer's disease. But first and foremost, and by distinguishing future converters but not patients with stable cognitive abilities from cognitively normal subjects, our results support the value of early subcortical shape alterations and reduced hippocampal subfield volumes as potential markers for the early detection of Alzheimer's disease

Characterizing cognitive-motor impairments in patients with myotonic dystrophy type 1

Myotonic Dystrophy Type 1 (DM1) is the most frequent hereditary, adult-onset muscular dystrophy. Nevertheless, DM1-associated cognitive-motor impairments have not been fully characterized so far. This study aimed at profiling cognitive and locomotor dysfunctions in these patients. In addition, cognitive-motor interactions were assessed using a dual-task paradigm. Comprehensive cognitive-motor impairment profiles were generated for 19 patients with DM1 and 19 healthy subjects by thorough clinical, biomechanical and neuropsychological examinations. Detailed gait analysis was performed using a 3D motion capture system, whereas cognitive function was assessed using a standardized neuropsychological test battery. Patients with DM1 showed impaired functional mobility, gait velocity and endurance. DM1-related gait pathology was mainly characterized by enhanced dynamic instability, gait variability, and restricted ankle dorsiflexion. Patients' cognitive impairments particularly concerned attentional functions. Dual-task conditions induced gait deviations that slightly differed between patients and controls. DM1-associated cognitive impairments correlated with reduced functional mobility and impaired ankle dorsiflexion. Patients with DM1 revealed significant impairments of walking function, balance and cognitive performance. Differential cognitive-motor interference and significant interactions between cognitive and motor dysfunctions point towards a prominent role of cognition in gait performance of patients with DM1