Wiebke Schrempf

Glatiramer acetate: mechanisms of action in multiple sclerosis.

Glatiramer acetate (GA), formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids resembling the myelin basic protein (MSP). GA has been shown to be highly effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Therefore, it was tested in several clinical studies and so approved for the immunomodulatory treatment of relapsing-type MS. In contrast to other immunomodulatory MS therapies, GA has a distinct mechanism of action: GA demonstrates an initial strong promiscuous binding to major histocompatibility complex molecules and consequent competition with various (myelin) antigens for their presentation to T cells. In addition, antigen-based therapy generating a GA-specific immune response seems to be the prerequisite for GA therapy. GA treatment induces an in vivo change of the frequency, cytokine secretion pattern and the effector function of GA-specific CD4+ and CD8+ T cells, probably by affecting the properties of antigen-presenting cells such as monocytes and dendritic cells. As demonstrated extensively in animal experiments, GA-specific, mostly, T helper 2 cells migrate to the brain and lead to in situ bystander suppression of the inflammatory process in the brain. Furthermore, GA-specific cells in the brain express neurotrophic factors like the brain-derived neurotrophic factor (BDNF) in addition to anti-inflammatory T helper 2-like cytokines. This might help tip the balance in favor of more beneficial influences because there is a complex interplay between detrimental and beneficial factors and mediators in the inflammatory milieu of MS lesions.

Neurological disability, psychological distress, and health-related quality of life in MS patients within the first three years after diagnosis.

Background Psychological distress and psychiatric co-morbidity are common in multiple sclerosis (MS) and is often associated with neurological disability as well as reduced quality of life. Objectives This study aimed to investigate psychological distress and the possible association with quality of life as well as neurological disability in MS patients within the first 3 years after diagnosis. Methods Psychological distress was measured using a standardized questionnaire (Symptom-Check-List-90-R; SCL-90-R) in 31 relapsing–remitting MS patients and 24 sex- and age-matched healthy controls. Results Psychological distress was significantly more pronounced in MS patients when compared to healthy controls. Interpersonal sensitivity and psychoticism were positively associated with neurological disability (Expanded Disability Status Scale [EDSS]). A high EDSS group (median split EDSS; 1.5) expressed significantly more psychological distress when compared to the low EDSS group and healthy controls. MS patients with minimal to no neurological disability (low EDSS group) also expressed significantly more emotional distress when compared to healthy controls. MS-related quality of life was positively associated with neurological disability as well as SCL-90-R scores. After adjusting for neurological disability, psychological distress was still significantly associated with quality of life. Conclusions Early stage MS patients significantly differ in their psychological distress when compared to healthy controls. Psychological distress in these patients is associated with neurological disability, but it is also present in patients with minimal to no neurological disability. Psychological distress was identified as an independent predictor for MS-related quality of life.

Sleep disorders in Parkinson's disease.

Sleep disorders in patients with Parkinsons disease (PD) are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless-legs syndrome (RLS) and REM-sleep behaviour disorder (RBD) are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, antiparkinsonian (e.g., levodopa and dopamine agonists) and concomitant medication (e.g., antidepressants) as well as comorbidities or other non-motor symptoms (such as depression) are discussed as causative factors. For the diagnosis of sleep disturbances we recommend regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS), for evaluating daytime sleepiness we would suggest to use the Epworth Sleepiness Scale (ESS), the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) antiparkinsonian therapy followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of REM-sleep behaviour disorder (RBD) as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies of neurodegenerative diseases, and particularly PD.

Potassium channel blocker 4‐aminopyridine is effective in interictal cerebellar symptoms in episodic ataxia type 2 — A video case report

Episodic ataxia type 2 (EA2) is an autosomal‐dominant hereditary disorder clinically characterized by recurrent attacks of vertigo, imbalance and ataxia. Studies have shown that 4‐aminopyridine (4‐AP) is capable to prevent these attacks. However, there are no reports whether 4‐AP is able to attenuate interictal cerebellar ataxia. Using the scale for assessment and rating of ataxia (SARA), we examined the efficacy of 4‐AP on interictal ataxia in a 63‐year‐old female patient who suffered from EA2 since the age of 57. EA2 was diagnosed based on clinical criteria and not genetically proven. When treatment with 4‐AP was paused the patient was suffering from marked gait and stance ataxia. After re‐initiation of treatment with 5 mg 4‐AP t.i.d., there was pronounced improvement in gait and stance ataxia. Within 24 hours SARA score lowered from 8.5 to 4.5 points. We conclude that 4‐AP may be beneficial for interictal cerebellar ataxia in late onset EA2.

Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease

ABSTRACT Parkinsons disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinsons disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3′-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction. Summary: Complexin 1 is a prodromal biomarker and risk factor for REM sleep behavior disorder and PARK4-associated Parkinsons disease.

Neurophysiological mechanisms of circadian cognitive control in RLS patients - an EEG source localization study

The circadian variation of sensory and motor symptoms with increasing severity in the evening and at night is a key diagnostic feature/symptom of the restless legs syndrome (RLS). Even though many neurological diseases have shown a strong nexus between motor and cognitive symptoms, it has remained unclear whether cognitive performance of RLS patients declines in the evening and which neurophysiological mechanisms are affected by the circadian variation. In the current study, we examined daytime effects (morning vs. evening) on cognitive performance in RLS patients (n = 33) compared to healthy controls (n = 29) by analyzing flanker interference effects in combination with EEG and source localization techniques. RLS patients showed larger flanker interference effects in the evening than in the morning (p = .023), while healthy controls did not display a comparable circadian variation. In line with this, the neurophysiological data showed smaller N1 amplitudes in RLS patients compared to controls in the interfering task condition in the evening (p = .042), but not in the morning. The results demonstrate diurnal cognitive changes in RLS patients with intensified impairments in the evening. It seems that not all dopamine-regulated cognitive processes are altered in RLS and thus show daytime-dependent impairments. Instead, the daytime-related cognitive impairment emerges from attentional selection processes within the extra-striate visual cortex, but not from later cognitive processes such as conflict monitoring and response selection.

Impairment in Respiratory Function Contributes to Olfactory Impairment in Amyotrophic Lateral Sclerosis

Background Nonmotor symptoms are very common in neurodegenerative diseases. In patients suffering from amyotrophic lateral sclerosis (ALS), olfactory dysfunction was first reported more than 20 years ago; however, its pathophysiological correlates and further implications remain elusive. Methods In this so far largest case–control study, we analyzed olfactory performance with the “Sniffin’ Sticks,” a validated olfactory testing kit used in clinical routine. This test kit was designed to investigate different qualities of olfaction including odor threshold, odor discrimination, and odor identification. Results ALS patients were mildly but significantly impaired in TDI score, the composite of the three subtests (ALS 27.7 ± 7.9, Controls 32.3 ± 5.8). In contrast to Parkinson’s disease, ALS patients did not show impaired performance in the suprathreshold tests identification and discrimination. However, the odor threshold was markedly decreased (ALS 6.0 ± 3.4, Controls 8.77 ± 3.6). This pattern of olfactory loss resembles sinonasal diseases, where olfactory dysfunction results from impeded odorant transmission to the olfactory cleft. The evaluation of medical history and clinical data of ALS patients showed that patients with perception of dyspnea (TDI 25.7 ± 8.0) performed significantly worse in olfactory testing compared to those who did not (TDI 30.0 ± 7.4). In line with that, we found that in patients with preserved respiratory function (vital capacity >70% of index value), olfactory performance did not differ from healthy controls. Conclusion These findings suggest that the mild impairment of olfaction in patients suffering from ALS should at least partly be considered as a consequence of impaired respiratory function, and odor threshold might be a marker of respiratory dysfunction in ALS.

RLS patients show better nocturnal performance in the Simon task due to diminished visuo-motor priming

OBJECTIVE The restless legs syndrome (RLS) is characterized by sensory-motor symptoms which usually occur predominantly at rest in the evening and at night. It is assumed that this circadian rhythm is caused by low dopamine levels in the evening. Yet, it has never been investigated whether RLS patients show diurnal variations in cognitive functions modulated by dopamine and what neurophysiological and functional neuroanatomical processes underlie such modulations. METHODS We used a Simon task combined with EEG and source localization to investigate whether top-down response selection and/or automatic visuo-motor priming are subject to diurnal changes in RLS patients, as compared to matched healthy controls. RESULTS We found that RLS patients showed better task performance due to reduced visuo-motor priming in the evening, as reflected by smaller early lateralized readiness potential (e-LRP) amplitudes and decreased activation of the superior parietal cortex and premotor cortex. Top-down response selection and early attentional processing were unaffected by RLS. CONCLUSIONS Counterintuitively, RLS patients show enhanced task performance in the evening, i.e. when experiencing dopaminergic deficiency. Yet, this may be explained by deficits in visuo-motor priming that lead to reduced false response tendencies. SIGNIFICANCE This study reveals a counterintuitive circadian variation of cognitive functions in RLS patients.

Role of the IL-6-Receptor expression in CD14+ monocytes in modulating sleep in patients with bipolar disorder

OBJECTIVE Bipolar disorder is a severe mental disorder associated with persistent sleep disturbances and elevated levels of mRNA coding for pro-inflammatory cytokines within peripheral monocytes. The mechanisms causing and sustaining a reduced sleep quality remain elusive. The pro-inflammatory cytokine receptor IL-6R is known to negatively affect sleep quality and architecture. Since elevations in IL-6R have repeatedly been demonstrated in bipolar disorder the association of sleep quality and architecture with levels of mRNA coding for IL-6R in monocytes was to be tested. METHODS Euthymic patients with bipolar disorder (n = 24) and healthy control subjects (n = 25) were assessed using all night polysomnography (PSG) and six day actigraphy. CD14+ monocytes were isolated on the evening of PSG assessment and levels of mRNA coding for IL-6R and other cytokines were determined using hybridization based assays. Interactions between IL-6R and sleep measures were calculated using linear regression models, adjusting for potential confounders. RESULTS Patients with bipolar disorder were found to have a reduced subjective sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) and more frequent arousals and short changes to wake during sleep. Both PSQI and the frequency of arousals were significantly predicted by levels of IL-6R. Contrary to previous publications, elevated levels of mRNA coding for pro-inflammatory cytokines in peripheral CD14+ monocytes of patients with bipolar disorder could not be replicated. LIMITATIONS Participants were only investigated with one night of PSG which may have given rise to first night effects. CONCLUSIONS Reduced sleep quality in euthymic patients with bipolar disorder may be related to an increased expression of IL-6R by peripheral monocytes.

Rasagiline improves polysomnographic sleep parameters in patients with Parkinson's disease: a double-blind, baseline-controlled trial

The aim was to study the effects of rasagiline on sleep quality in patients with Parkinsons disease (PD) with sleep disturbances. Sleep disorders are common in PD. Rasagiline is widely used in patients with PD, but double‐blind polysomnographic trials on its effects on sleep disturbances are missing.