Journal of Neural Transmission最新文献

Aim of this review is to discuss the value of current ongoing research initiatives in Parkinson's disease from the clinicians' point of view. The repeat, recent failures on progress slowing reflect the drifting apart between initially promising experimental and then disappointing clinical outcomes in the translational trials with well selected Parkinson's disease patients. A similar development concerns the emerging gap between novel developed drugs with improved pharmacokinetic behaviour and their limited use in the clinical practice following approval. Restricted regional different worldwide availability and direct, respectively indirect budget limitations for neurologists in private practice are essential hurdles. They prevent the widespread prescription of these compounds. As a result return of investment for the pharmaceutical industry becomes more and more uncertain. The interest for research on novel treatment approaches for the amelioration of motor and non motor symptoms declines. Clinicians crucially scrutinize the claim for an optimum patient care by payers and regulators.

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disease that manifests with a triad of symptoms including motor dysfunctions, cognitive deficits, and prominent neuropsychiatric symptoms, the most common of which is depression, with a prevalence between 30 and 70%. Depressive symptoms occur in all stages of HD, beginning in presymptomatic HD gene carriers, and are strongly associated with suicidal ideation and suicidality, but their relationship with other clinical dimensions in HD is controversial and the underlying pathophysiology is poorly understood. Analysis of the available literature until November 2023 concerned the prevalence, clinical manifestations, neuroimaging, transgenic models, and treatment options of HD depression. While it was believed that depression in HD is due to psychosomatic factors in view of the fatal disease, studies in transgenic models of HD demonstrated molecular changes including neurotrophic and serotonergic dysregulation and disorders of the hypothalamic-pituitary-adrenal axis inducing depression-like changes. While relevant neuropathological data are missing, recent neuroimaging studies revealed correlations between depressive symptoms and dysfunctional connectivities in the default mode network, basal ganglia and prefrontal cortex, and changes in limbic and paralimbic structures related to the basic neurodegenerative process. The impact of response to antidepressants in HD patients is controversial; selective serotonin reuptake inhibitors are superior to serotonin-norepinephrine reuptake inhibitors, while electroconvulsive therapy may be effective for pharmacotherapy resistant cases. Since compared to major depressive disorder and depression in other neurodegenerative diseases, our knowledge of the molecular basis in HD depression is limited, further studies to elucidate the heterogeneous pathogenesis in this fatal disorder are warranted.

Neurodegenerative disorders are typically featured by the occurrence of neuronal inclusions. In the case of Parkinson's disease (PD) these correspond to Lewy bodies (LBs), which are routinely defined as proteinaceous inclusions composed of alpha-synuclein (alpha-syn). In turn, alpha-syn is considered to be the key protein in producing PD and fostering its progression. Recent studies challenged such a concept and emphasized the occurrence of other proteins such as p62 and poly-ubiquitin (Poly-ub) in the composition of LBs, which are also composed of large amounts of tubulo-vesicular structures. All these components, which accumulate within the cytosol of affected neurons in PD, may be the consequence of a dysfunction of major clearing pathways. In fact, autophagy-related systems are constantly impaired in inherited PD and genetic models of PD. The present study was designed to validate whether a pharmacological inhibition of autophagy within catecholamine cells produces cell damage and accumulation of specific proteins and tubulo-vesicular structures. The stoichiometry counts of single proteins, which accumulate within catecholamine neurons was carried out along with the area of tubulo-vesicular structures. In these experimental conditions p62 and Poly-ub accumulation exceeded at large the amounts of alpha-syn. In those areas where Poly-ub and p62 were highly expressed, tubulo-vesicular structures were highly represented compared with surrounding cytosol. The present study confirms new vistas about LBs composition and lends substance to the scenario that autophagy inhibition rather than a single protein dysfunction as key determinant of PD.

Millions of individuals around the world are afflicted with Parkinson's disease (PD), a prevalent and incapacitating neurodegenerative disorder. Dr. Reichmann, a distinguished professor and neurologist, has made substantial advancements in the domain of PD research, encompassing both fundamental scientific investigations and practical applications. His research has illuminated the etiology and treatment of PD, as well as the function of energy metabolism and premotor symptoms. As a precursor to a number of neurotransmitters and neuromodulators that are implicated in the pathophysiology of PD, he has also investigated the application of tryptophan (Trp) derivatives in the disease. His principal findings and insights are summarized and synthesized in this narrative review article, which also emphasizes the challenges and implications for future PD research. This narrative review aims to identify and analyze the key contributions of Reichmann to the field of PD research, with the ultimate goal of informing future research directions in the domain. By examining Reichmann's work, the study seeks to provide a comprehensive understanding of his major contributions and how they can be applied to advance the diagnosis and treatment of PD. This paper also explores the potential intersection of Reichmann's findings with emerging avenues, such as the investigation of Trp and its metabolites, particularly kynurenines, which could lead to new insights and potential therapeutic strategies for managing neurodegenerative disorders like PD.

In Parkinson's disease (PD), impaired gait and cognition affect daily activities, particularly in the more advanced stages of the disease. This study investigated the relationship between gait parameters, cognitive performance, and brain morphology in patients with early untreated PD. 64 drug-naive PD patients and 47 healthy controls (HC) participated in the study. Single- and dual-task gait (counting task) were examined using an expanded Timed Up & Go Test measured on a GaitRite walkway. Measurements included gait speed, stride length, and cadence. A brain morphometry analysis was performed on T1-weighted magnetic resonance (MR) images. In PD patients compared to HC, gait analysis revealed reduced speed (p < 0.001) and stride length (p < 0.001) in single-task gait, as well as greater dual-task cost (DTC) for speed (p = 0.007), stride length (p = 0.014) and cadence (p = 0.029). Based on the DTC measures in HC, PD patients were further divided into two subgroups with normal DTC (PD-nDTC) and abnormally increased DTC (PD-iDTC). For PD-nDTC, voxel-based morphometric correlation analysis revealed a positive correlation between a cluster in the left primary motor cortex and stride-length DTC (r = 0.57, p = 0.027). For PD-iDTC, a negative correlation was found between a cluster in the right lingual gyrus and the DTC for gait cadence (r=-0.35, p_FWE = 0.018). No significant correlations were found in HC. The associations found between brain morphometry and gait performance with a concurrent cognitive task may represent the substrate for gait and cognitive impairment occurring since the early stages of PD.

In this narrative review, we address mild cognitive impairment, a frequent complication of Parkinson's disease (PD) and atypical parkinsonian disorders (APDs). Recent diagnostic criteria have blurred the lines between PD and dementia with Lewy bodies (DLB), particularly in the cognitive domain. Additionally, atypical parkinsonian syndromes like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) often present with significant cognitive decline. Even multiple system atrophy (MSA) can be associated with cognitive impairment in some cases. Several biomarkers, including imaging techniques, such brain magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET), as well as pathological proteins either of the cerebrospinal fluid (CSF), such as Tau, amyloid beta, and synuclein, or of the serum, such as neurofilament light chain (Nfl) are more and more often utilized in the early differential diagnosis of APDs. The complex interplay between these conditions and the evolving understanding of their underlying pathologies highlight the need for further research to refine diagnostic criteria, possibly incorporate the new findings from the biomarker's field into the diagnostic criteria and develop targeted therapeutic strategies.

Deep brain stimulation can influence the speech and voice quality in Parkinson´s disease (PD). This controlled, randomized, double-blind, cross-over clinical trial was conducted in 15 PD patients with bilateral subthalamic deep brain stimulation (DBS) to compare the effects of STN-DBS with combined subthalamic and nigral stimulation (STN + SNr-DBS) and DBS OFF on speech and voice parameters in PD patients. Speech and voice were analyzed subjectively using questionnaires (voice/pronunciation quality VAS, VHI, SHI) and objectively using audio analysis (maximum phonation time, AVQI, mean F0, intonation, syllable rate, reading time). Both stimulation conditions, STN + SNr-DBS and STN-DBS, revealed heterogeneous effects on speech and voice production with a slight beneficial effect on the voice quality of individual patients compared to DBS OFF, but not in the whole group. Small, but not significant effects were seen only in subjective voice quality on the VAS and intonation (both stimulation conditions compared to DBS OFF). No significant changes of the objective speech parameters during the audio analysis could be observed (both stimulation conditions compared to DBS OFF). There were no significant differences between STN + SNr-DBS and STN-DBS in any speech and voice domain. The beneficial effects on speech and voice production are minor in most patients compared to the motor improvements by DBS. Both STN-DBS and STN + SNr-DBS were safe, with comparable effects between both DBS modes, and represent no contraindications from the perspective of the voice specialist.

This study aimed to analyze the transferability of non-invasive brain stimulation (NIBS) interventions in individuals with major depressive disorder (MDD) based on the FIELD model (Function, Implementation, Ecology, Level, and Duration), encompassing function, implement, ecology, level, and duration. A systematic search of electronic databases yielded a total of 21 eligible studies, comprising 12 transcranial direct current stimulation (tDCS) and 9 transcranial magnetic stimulation (TMS) trials, involving 1029 individuals with MDD. The meta-analysis of effect sizes revealed positive transfer effects across all domains of the FIELD model, suggesting that NIBS interventions have potential efficacy in improving various facets of MDD. The subgroup analysis highlighted that bilateral dlPFC stimulation exhibited the highest effect size for transferability, indicating greater transferability for rTMS, a higher dose of stimulation, and the integration of additional interventions. Additionally, the study discusses the implications of bilateral dorsolateral prefrontal cortex (dlPFC) stimulation and the integration of complementary therapies for optimizing treatment efficacy.

Essential tremor (ET) is characterized by upper limbs action tremor, sometimes extending to other body parts. However, ET can present with additional neurological features known as "soft signs." These signs of uncertain clinical significance are not sufficient to suggest an alternative neurological diagnosis, and include, among others, questionable dystonia and subtle voluntary movement alterations, i.e., bradykinesia and related features. This study aimed to explore the prevalence and relationship between questionable dystonia and subtle bradykinesia features in ET. Forty ET patients were video-recorded during clinical examination. Five movement disorder experts reviewed the videos to identify soft motor signs, i.e., dystonia and movement alterations during finger-tapping namely, (i) bradykinesia (reduced velocity), (ii) dysrhythmia, and (iii) sequence effect. Inter-rater agreement was quantified using the Fleiss' Kappa index. Data analysis was performed using nonparametric tests. We found a fair inter-rater agreement for upper limb dystonia (Fleiss' K = 0.27). Inter-rater agreement was higher (moderate) for head dystonia (Fleiss' K = 0.49) and finger-tapping assessment (Fleiss' K = 0.45). Upper limb dystonia was identified in 70% of patients, head dystonia in 35%, and finger-tapping alterations (in variable combinations) were observed in 95% of individuals (P < 0.001 by Fisher's exact test), including subtle bradykinesia and related features. No significant concordance or correlation was found between the soft signs. Subtle bradykinesia and related features are the most easily identifiable and frequent soft signs in ET, appearing in a higher percentage of patients than subtle dystonia. These findings provide insights into the clinical and pathophysiological understanding of ET.