Negative priming is diminished under high blood pressure in healthy subjects Abstract The ability to ignore distracting objects is a core mechanism in selective attention and has been analyzed particularly with respect to its clinical implications (e.g., depression, schizophrenia, or unhealthy life-style). Here, we investigated the correlation between an established experimental task to measure distractor-processing and participants’ blood pressure. We used the negative priming (NP) task in which participants show worse performance to target stimuli that were distractors in the previous trial. Notably, our participants were all healthy, young subjects but nevertheless we observed a correlation between blood pressure levels and NP effects, the higher the blood pressure the less NP was shown by participants. Our results suggest that processes modulated by higher blood pressure diminish the ability to successful ignore distracting objects not only at hypertension levels.

Do complexing proteins provide mechanical protection for botulinum neurotoxins? Abstract Botulinum toxin (BT) consists of botulinum neurotoxin and complexing proteins (CPs). CPs might provide mechanical protection for botulinum neurotoxin. As incobotulinumtoxinA (INCO, Xeomin®) does not contain CPs, we wanted to compare its mechanical stability to that of onabotulinumtoxinA (ONA, Botox®) containing CPs. For this, ONA and INCO were reconstituted without mechanical stress (NS) and with mechanical stress (WS) generated by a recently introduced stress test. Potencies were then measured by the paralysis times (PTs) in the mouse diaphragm assay. ONA-PT was 75.8 ± 10.3 min (n = 6) under NS and 116.7 ± 29.8 min (n = 6) under WS (two-tailed t test, p = 0.002). Mechanical stress increased the ONA-PT by 35.0% on the Growth Percentage Index. INCO-PT was 66.0 ± 7.0 min for NS and 76.0 ± 1.0 min for WS (t test, p = 0.129). Mechanical stress increased the INCO-PT by 13.2% on the Growth Percentage Index. Our data show that mechanical stress inactivates a CP-containing BT drug, but not a CP-free BT drug. We conclude that CPs do not provide protection against mechanical stress, supporting the view that CPs are not necessary for therapeutic purposes.

Nabilone for non-motor symptoms of Parkinson’s disease: a randomized placebo-controlled, double-blind, parallel-group, enriched enrolment randomized withdrawal study (The NMS-Nab Study) Abstract Although open-label observations report a positive effect of cannabinoids on non-motor symptoms (NMS) in Parkinson’s disease (PD) patients, these effects remain to be investigated in a controlled trial for a broader use in NMS in PD patients. Therefore, we decided to design a proof-of-concept study to assess the synthetic cannabinoid nabilone for the treatment of NMS. We hypothesize that nabilone will improve NMS in patients with PD and have a favorable safety profile. The NMS-Nab Study is as a mono-centric phase II, randomized, placebo-controlled, double-blind, parallel-group, enriched enrollment withdrawal study. The primary efficacy criterion will be the change in Movement Disorders Society-Unified Parkinson’s Disease-Rating Scale Part I score between baseline (i.e. randomization) and week 4. A total of 38 patients will have 80% power to detect a probability of 0.231 that an observation in the treatment group is less than an observation in the placebo group using a Wilcoxon rank-sum test with a 0.050 two-sided significance level assuming a true difference of 2.5 points between nabilone and placebo in the primary outcome measure and a standard deviation of the change of 2.4 points. The reduction of harm through an ineffective treatment, the possibility of individualized dosing, the reduction of sample size, and the possible evaluation of the influence of the placebo effect on efficacy outcomes justify this design for a single-centered placebo-controlled investigator-initiated trial of nabilone. This study should be the basis for further evaluations of long-term efficacy and safety of the use of cannabinoids in PD patients.

Impaired endothelial function may predict treatment response in restless legs syndrome Abstract While dopaminergic dysfunction is believed to be a crucial role in restless legs syndrome (RLS), changes in peripheral microvasculature system such as peripheral hypoxia and altered skin temperature, have been found. This study aimed to investigate whether patients with RLS would have a cerebral and peripheral endothelial dysfunction, and this may have association with treatment responsiveness. We evaluated cerebral endothelial function using breath-holding index (BHI) on transcranial Doppler in bilateral middle cerebral artery (MCA), posterior cerebral artery (PCA) and basilar artery (BA) and peripheral endothelial function using brachial flow-mediated dilation (FMD) in 34 patients with RLS compared with age and sex-matched controls. The values of BHI in both MCA and BA were significantly lower in RLS group than control group. The values of FMD also were significantly lower in RLS patients. There was a weak correlation between BHI and FMD (p = 0.038 in Rt MCA, p = 0.032 in Lt MCA, p = 0.362 in BA) in RLS, but not in controls. BHI differed according to treatment responsiveness. (p < 0.005). Our study suggests that RLS patients have poorer cerebral and peripheral endothelial function than controls, showing an underlying mechanism of RLS and further evidence of a possible association between RLS and cardiovascular disease.

Cholinergic transmission is impaired in patients with idiopathic normal-pressure hydrocephalus: a TMS study Abstract The pathophysiological mechanisms of cognitive and gait disturbances in subjects with normal-pressure hydrocephalus (NPH) are still unclear. Cholinergic and other neurotransmitter abnormalities have been reported in animal models of NPH. The objective of this study was to evaluate the short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain, in subjects with idiopathic NPH (iNPH). We applied SAI technique in twenty iNPH patients before ventricular shunt surgery. Besides SAI, also the resting motor threshold and the short intracortical inhibition to paired stimulation were assessed. A significant reduction of the SAI (p = 0.016), associated with a less pronounced decrease of the resting motor threshold and the short latency intracortical inhibition to paired stimulation, were observed in patients with iNPH at baseline evaluation. We also found significant (p < 0.001) correlations between SAI values and the gait function tests, as well as between SAI and the neuropsychological tests. These findings suggest that the impairment of cholinergic neurons markedly contributes to cognitive decline and gait impairment in subjects with iNPH.

High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer’s disease Abstract Various studies report discordant results regarding the efficacy, parameters, and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) on Alzheimer’s disease (AD). The objective of the study was to assess the effect of rTMS-CT on cognition, the activities of daily life, neuropsychiatric behavioral symptoms, and metabolite levels beneath the stimulated areas of the brain in patients with AD and to investigate the correlation of metabolic changes (measured with proton magnetic resonance spectroscopy [1H-MRS]) with clinical outcomes after treatment. Thirty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS with CT (i.e., real group) and (2) sham rTMS with CT (i.e., sham group). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then to stimulate the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment at baseline (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). The ratios of N-acetylaspartate/creatine (NAA/Cr), myoinositol/creatine (mI/Cr), and choline/creatine (Cho/Cr) in the stimulated cortex were measured using 1H-MRS at T0 and T1. Twenty-eight patients were treated with rTMS-CT for 4 weeks. Two patients in the sham group withdrew after being treated several times. Compared with the sham group, the cognitive function and behavior in the real rTMS group improved significantly at T1 and T2. In the real group, compared with the sham group, the NAA/Cr ratio in the left DLPFC was significantly elevated (p = 0.045); however, in the left LTL, it only showed a tendency toward increase (p = 0.162). The change in the NAA/Cr ratio in the left DLPFC was negatively correlated with the change in the cognitive scales of the Alzheimer’s Disease Assessment Scale (ADAS-cog). This study indicated a possible modest effect of rTMS-CT on preventing clinical and neuronal functional deterioration in the left DLPFC of patients with AD. The left DLPFC is a better candidate area than the left LTL.

A novel single-sensor-based method for the detection of gait-cycle breakdown and freezing of gait in Parkinson’s disease Abstract Objective measurement of walking speed and gait deficits are an important clinical tool in chronic illness management. We previously reported in Parkinson’s disease that different types of gait tests can now be implemented and administered in the clinic or at home using Ambulosono smartphone-sensor technology, whereby movement sensing protocols can be standardized under voice instruction. However, a common challenge that remains for such wearable sensor systems is how meaningful data can be extracted from seemingly “noisy” raw sensor data, and do so with a high level of accuracy and efficiency. Here, we describe a novel pattern recognition algorithm for the automated detection of gait-cycle breakdown and freezing episodes. Ambulosono-gait-cycle-breakdown-and-freezing-detection (Free-D) integrates a nonlinear m-dimensional phase-space data extraction method with machine learning and Monte Carlo analysis for model building and pattern generalization. We first trained Free-D using a small number of data samples obtained from thirty participants during freezing of gait tests. We then tested the accuracy of Free-D via Monte Carlo cross-validation. We found Free-D to be remarkably effective at detecting gait-cycle breakdown, with mode error rates of 0% and mean error rates < 5%. We also demonstrate the utility of Free-D by applying it to continuous holdout traces not used for either training or testing, and found it was able to identify gait-cycle breakdown and freezing events of varying duration. These results suggest that advanced artificial intelligence and automation tools can be developed to enhance the quality, efficiency, and the expansion of wearable sensor data processing capabilities to meet market and industry demand.

Treatment of patients with geriatric depression with repetitive transcranial magnetic stimulation Abstract Repetitive transcranial magnetic stimulation (rTMS) has become a useful tool to treat different neuropsychiatric conditions such as depression, dementia and extrapyramidal syndromes insufficiently responding to conventional treatment. In this SHAM-controlled exploratory study safety, symptom improvement as well as changes in inflammation markers and neurotransmitter precursor amino acids availability were studied after a prefrontal cortex (PFC) stimulation using rTMS as add-on treatment in 29 patients with geriatric depression. Out of these, ten patients received SHAM treatment. Treatment was well tolerated, no serious adverse effects were observed. A clear improvement in symptoms of depression with a significant decrease in the HAMD-7 (U = 3.306, p = 0.001) was found by rTMS treatment. In parallel, serum phenylalanine dropped significantly (U = 2.340, p < 0.02), and there was a decline of tryptophan and of Phe/Tyr concentrations, both the effects, however, failed to reach the levels of statistical significance. In the patients who underwent SHAM treatment, no significant changes of HAMD-7 or the concentrations of any biomarker in the study could be found. In addition to the significant effect of rTMS on depression scores, these results point to a possible influence of rTMS on the enzyme phenylalanine hydroxylase (PAH), which plays a crucial role in the biosynthesis of neurotransmitter precursors related to geriatric depression.

Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update—I. Hypokinetic-rigid movement disorders Abstract Extrapyramidal movement disorders include hypokinetic rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits. The functional anatomy of the BG, the cortico-BG–thalamocortical, and BG–cerebellar circuit connections are briefly reviewed. Pathophysiologic classification of extrapyramidal movement disorder mechanisms distinguish (1) parkinsonian syndromes, (2) chorea and related syndromes, (3) dystonias, (4) myoclonic syndromes, (5) ballism, (6) tics, and (7) tremor syndromes. Recent genetic and molecular–biologic classifications distinguish (1) synucleinopathies (Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease–dementia, and multiple system atrophy); (2) tauopathies (progressive supranuclear palsy, corticobasal degeneration, FTLD-17; Guamian Parkinson–dementia; Pick’s disease, and others); (3) polyglutamine disorders (Huntington’s disease and related disorders); (4) pantothenate kinase-associated neurodegeneration; (5) Wilson’s disease; and (6) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood, but is suggested to result from an interaction between genetic and environmental factors. Multiple etiologies and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, and chronic neuroinflammation) are more likely than a single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. We present a timely overview of the neuropathology and pathogenesis of the major extrapyramidal movement disorders in two parts, the first one dedicated to hypokinetic-rigid forms and the second to hyperkinetic disorders.

Neuropathology and pathogenesis of extrapyramidal movement disorders: a critical update. II. Hyperkinetic disorders Abstract Extrapyramidal movement disorders comprise hypokinetic-rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits that have been briefly reviewed in part 1 of the papers on neuropathology and pathogenesis of extrapyramidal movement disorders. The classification of hyperkinetic forms distinguishes the following: (1) chorea and related syndromes; (2) dystonias (dyskinesias); (3) tics and tourette disorders; (4) ballism; (5) myoclonic and startle disorders; and (6) tremor syndromes. Recent genetic and molecular classification distinguishes the following: (1) polyglutamine disorders (Huntington’s disease and related disorders); (2) pantothenate kinase associated neurodegeneration; (3) Wilson’s disease and related disorders; and (4) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood but is suggested to result from an interaction between genetic and environmental factors, multiple etiologies, and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, chronic neuroinflammation), being more likely than one single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. A timely overview of the neuropathology and pathogenesis of the major hyperkinetic movement disorders is presented.