Botulinum toxin type D blocks autonomic cholinergic synapses in humans: discussion of a potential therapeutic use Abstract Based on epidemiological data it was believed that botulinumtoxin type D (BT-D) may not block human cholinergic synapses. We wanted to investigate BT-D’s effect on the autonomic cholinergic synapse in humans. For this, we compared in four volunteers intraindividually the hypohidrotic effect of intradermal BT-D and BT-A in Minor’s iodine starch sweat test. Altogether, we studied BT-D in doses of 4, 8, 16 and 32MU and BT-A in doses of 2, 4, 8 and 16MU at weekly intervals throughout a period of 13 weeks. All BT doses were diluted in 0.2 ml 0.9% NaCl/H2O. Overall 704 data points were collected. Combined over all four subjects and all four doses BT-D’s hypohidrotic effect intensity was half of BT-A’s. BT-D’s effect peaked around 5 weeks, BT-A’s around 7 weeks. BT-D’s effect duration was around 12 weeks, of BT-A’s was around 14 weeks. For both BT types the hypohidrotic effect was dose dependent. BT-D, when injected intradermally, can block autonomic cholinergic synapses in humans. Compared to BT-A, BT-D’s effect intensity was half and its effect duration was some 2 weeks shorter. With its weaker and shorter effect BT-D does not seem to promise therapeutic effects superior to BT-A.

IncobotulinumtoxinA for hypersalivation in patients with amyotrophic lateral sclerosis: an open-label single-centre study Abstract The objective of this study is to discover whether incobotulinumtoxinA (inco) can reduce relative hypersalivation in patients with amyotrophic lateral sclerosis (ALS). 14 patients with ALS (8 males and 6 females, age 55.4 ± 16.3 years) received ultrasound-guided injection of inco 100 MU in both parotid glands and inco 50 MU in both submandibular glands. Saliva production was gravimetrically measured with three cotton rolls placed in the mouth. Weight increase after 5 min was measured on an electronic scale. Subjective saliva production was registered with drooling frequency scale (DFS) and drooling severity scale (DSS). Saliva production was gravimetrically reduced at week 4 (p = 0.04), week 8 (p = 0.01) but not after week 12 after BT application. DFS was reduced at week 4 (p = 0.04), week 8 (p = 0.02), but not after week 12. DSS was reduced at week 4 (p = 0.03), week 8 (p = 0.04) and week 12 (p = 0.04). Patients in our study did not experience changes in their swallowing patterns or any other safety-relevant events. Inco is effective and well tolerated for saliva reduction in patients with ALS for 8–12 weeks.

Extremely low frequency magnetic field induces human neuronal differentiation through NMDA receptor activation Abstract Magnetic fields with different frequency and intensity parameters exhibit a wide range of effects on different biological models. Extremely low frequency magnetic field (ELF MF) exposure is known to augment or even initiate neuronal differentiation in several in vitro and in vivo models. This effect holds potential for clinical translation into treatment of neurodegenerative conditions such as autism, Parkinson’s disease and dementia by promoting neurogenesis, non-invasively. However, the lack of information on underlying mechanisms hinders further investigation into this phenomenon. Here, we examine involvement of glutamatergic Ca2+ channel, N-methyl-d-aspartate (NMDA) receptors in the process of human neuronal differentiation under ELF MF exposure. We show that human neural progenitor cells (hNPCs) differentiate more efficiently under ELF MF exposure in vitro, as demonstrated by the abundance of neuronal markers. Furthermore, they exhibit higher intracellular Ca2+ levels as evidenced by c-fos expression and more elongated mature neurites. We were able to neutralize these effects by blocking NMDA receptors with memantine. As a result, we hypothesize that the effects of ELF MF exposure on neuronal differentiation originate from the effects on NMDA receptors, which sequentially triggers Ca2+-dependent cascades that lead to differentiation. Our findings identify NMDA receptors as a new key player in this field that will aid further research in the pursuit of effect mechanisms of ELF MFs.

Allopregnanolone reversion of estrogen and progesterone memory impairment: interplay with serotonin release Abstract Previously, we found out that in ovariectomized female rats, estrogen and progesterone produce a memory deficit which is reverted by the intrahippocampal administration of allopregnanolone. Here, we study the possible interplay between allopregnanolone and hippocampal serotonergic activity. Ovariectomized rats injected subcutaneously with estrogen and progesterone were subsequently injected in the dorsal hippocampus with vehicle, allopregnanolone alone or allopregnanolone shortly after 8OH-DPAT, a predominantly 5HT1A-7 receptor agonist. Then, the subjects were sequentially tested in: (1) an inhibitory avoidance task and (2) K+-evoked [3H]-serotonin ex vivo release through superfusion experiments. Allopregnanolone increased the K+-evoked [3H]-serotonin release compared to control. 8OH-DPAT infusions reversed the effects of allopregnanolone on memory and K+-evoked [3H]-serotonin release. These results suggest that allopregnanolone memory improvement could be mediated, at least in part, through modulation of the hippocampal serotonergic system reactivity.

The contribution of cerebrovascular risk factors, metabolic and inflammatory changes to cognitive decline in Parkinson’s disease: preliminary observations Abstract To determine whether systemic medical factors, such as vascular risk factors, metabolic and inflammatory markers contribute to cognitive decline in Parkinson’s disease (PD); if confirmed to determine whether a clinically applicable risk factor model can predict the conversion from normal cognition (NC) to mild cognitive impairment (MCI). 58 patients who met the UK Brain Bank Criteria for PD underwent clinical and laboratory assessment at study entry; 47 patients were re-assessed after 2 years. Medical history, vascular risk (QRISK2), blood metabolic and inflammatory factors, brain vessel examinations, activity of daily living, and neuropsychological testing were performed. Forty patients had NC and 18 patients had MCI at baseline. Patients with MCI had higher level of interleukin 6, folic acid below normal range and higher l-dopa equivalent dose compared to cognitive normal patients at baseline. Patients with NC at baseline were classified into two groups: patients who remained cognitively normal (non-converters, n = 23) and patients who progressed to MCI (converters, n = 11). MCI converters were older at baseline and had higher QRISK2 than the non-converters. Patients with higher QRISK2, lower uric acid level and lower activity of daily living scale at baseline had a higher risk of converting from NC to MCI with a sensitivity of 72.2%, a specificity of 87%, and an overall accuracy of 82.4%. Systemic medical factors are associated with cognitive impairment in PD both cross-sectionally and longitudinally. A risk factor model predicting the decline from NC to MCI could be constructed.

Effect fingerprints of antipsychotic drugs on neural networks in vitro Abstract We compared the acute effect of typical (haloperidol) and atypical (aripiprazole, clozapine, olanzapine) antipsychotic drugs (APDs) on spontaneous electrophysiological activity of in vitro neuronal networks cultured on microelectrode arrays (MEAs). Network burst analysis revealed a “regularizing” effect of all APDs at therapeutic concentrations, i.e., an increase of network-wide temporal synchronization. At supratherapeutic concentrations, all APDs but olanzapine mediated a decrease of burst and spike rates, burst duration, number of spikes in bursts, and network synchrony. The rank order of potency of APDs was: haloperidol > aripiprazole > clozapine > olanzapine (no suppression). Disruption of network function was not due to enhanced cell death as assessed by trypan blue staining. APDs promoted distinct concentration-dependent alterations yielding acute effect fingerprints of the tested compounds. These effects were rather characteristic for individual compounds than distinctive for typical vs. atypical APDs. Thus, this dichotomy may be of value in distinguishing clinical features but has no apparent basis on the network or local circuitry level.

Discussing sexuality with Parkinson’s disease patients: a multinational survey among neurologists Abstract Sexual dysfunction is a major non-motor feature of Parkinson’s disease (PD) that may affect the quality of life of many patients. In a Dutch survey, we demonstrated that neurologists often fail to discuss sexuality with their patients. Our objective was to determine to which extent neurologists in Spain and Germany address sexuality with their patients and whether cross-cultural differences exist. A 30-item questionnaire was sent out to 1650 German and 460 Spanish neurologists. The questionnaire addressed attitudes, knowledge, barriers, and feelings of responsibility regarding sexuality in PD. 160 German and 32 Spanish respondents completed and returned the questionnaire. The majority of German and Spanish participants discuss sexual dysfunction ‘regularly’ with male patients (61.7% and 78.9%, respectively), but ‘seldom’ with female patients (68.8% and 78.1%, respectively). Important barriers for German and Spanish respondents to discuss sexual dysfunction were patients not expressing sexual complaints spontaneously (52.9% and 75.0%, respectively) and insufficient consultation time (32.2% and 71.9%, respectively). Sexual dysfunction in PD was considered important by 68.3% of German and 96.9% of Spanish participants. German and Spanish neurologists do not routinely discuss sexual dysfunction with their patients, although many of them consider it important to address this topic. It is unclear why this lack of discussing sexual dysfunction is especially found for female patients and whether cultural aspects are involved. We recommend a self-assessment tool for patients to track their symptoms prior to consultation visits and advocate local guidelines that formulate who is responsible for discussing sexual dysfunction.

Higher zinc concentrations in hair of Parkinson’s disease are associated with psychotic complications and depression Abstract Parkinson’s disease (PD) is classically considered a motor disease; however, several non-motor symptoms are also present, including psychiatric complaints. In recent decades, the metals Ca, Fe, and Zn have gained prominence as potential etiologic factors in motoric signs of PD. However, metal alterations could be associated with the non-motor symptoms of PD. We wished to correlate the levels of these metals with the co-occurrence of depression, anxiety, and psychotic symptoms in PD patients. To this end, the Beck Depression Inventory, the Beck Anxiety Inventory, and the Scales for Outcomes in Parkinson’s disease-Psychiatric Complications (SCOPA-PC) were implemented to evaluate mood disorders and psychiatric complications. Flame atomic absorption spectrometry (FAAS) was used to assess concentrations of Ca, Fe, and Zn in hair samples collected from 22 clinically diagnosed PD patients, which represented the entire cohort of accessible patients in a Brazilian health registry, and 33 healthy individuals. While Ca and Fe alterations were not found to be associated with psychiatric complaints in the PD group, significantly higher levels of Zn were correlated in PD patients with depression and some psychotic symptoms. Within individual domains of the SCOPA-PC, significantly higher levels of Zn were correlated with the presence of hallucination, illusion, and paranoid ideation when compared to controls and PD patients who did not present these symptoms. Although our sample size is small and findings need to be replicated in larger and heterogeneous populations, our results provide a new perspective on the use of monitoring of Zn levels as a potential biomarker of psychiatric complaints, and may be useful in the development of more effective therapeutic approaches for the management of PD patients with co-occurrence of psychiatric disorders.

Basic processes as foundations of cognitive impairment in adult ADHD Abstract Attention deficit hyperactivity disorder (ADHD) in adulthood is associated with impairment of multiple aspects of cognition which adversely affect the individual’s everyday functioning. However, little is known about how these impairments are intertwined. This study explores whether impairments in basic processes (processing speed and distractibility) in adults with ADHD explain impairments in higher order functions, namely executive functions, memory, and complex attention. Furthermore, it is explored whether pharmacological treatment with methylphenidate (MPH) affects basic processes and higher order functions. A between-subjects design compared patients with ADHD without stimulant drug treatment (N = 55) and patients with ADHD treated with MPH (N = 31) with a healthy control group (N = 80). A neuropsychological test battery assessing basic processes and higher order functions was administered. Hierarchical logistic regression analyses were performed to evaluate the contribution of basic processes to impairments in higher order functions. Patients with ADHD not treated with MPH showed impairments in basic processes and higher order functions compared to controls. The impairments in basic processes explained 41–43% of impairments in executive functions, 27–29% in memory, and 56–74% in complex attention. In patients with ADHD treated with MPH, basic processes were not impaired and did not contribute significantly to impairments of higher order functions. Basic processes may constitute part of the foundation of cognitive impairments in adult ADHD. MPH may improve cognitive performance, presumably through improving basic processes. Applying this information could optimize neuropsychological assessments and inform treatment strategies by targeting basic processes.

Evaluation of potential cardiovascular risk protein biomarkers in high severity restless legs syndrome Abstract Restless legs syndrome (RLS) is a common sensorimotor disorder that, in case of severe symptoms, can be very distressing and negatively interfere with quality of life. Moreover, increasing evidences associate RLS with higher risk of cerebrovascular and cardiovascular disease (CVD). The purpose of this study was to quantify two proteins, previously identified by proteomics and potentially linked with CVD risk, namely kininogen-1 (KNG1) and alpha-1-antitrypsin (A1AT), in primary RLS patients at high severity grade (HS-RLS) in comparison to healthy control subjects. Proteins were quantified through enzyme-linked immunosorbent assay (ELISA) in plasma samples from 14 HS-RLS patients and 15 control individuals. The two groups were closely matched for age and gender. The expression level of KNG1 resulted significantly higher (p < 0.001), while A1AT was significantly decreased (p < 0.05) in HS-RLS patients compared to controls, confirming the relationship between these proteins and the disease severity. Furthermore, in patients group the association between the protein concentrations and the following parameters was further evaluated: age, disease onset and diagnosis, scores obtained from the RLS rating scales (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory) and smoking habit. All the considered variables resulted independent of protein levels, so the disease can be reasonably considered the main cause of protein changes. As emerged from the literature, high levels of KNG1 and low amounts of A1AT seem to be related with a highest probability to develop CVD. Consequently, these proteins may be reliable candidate biomarkers of CVD risk in patients with RLS at high severity grade.