Apolipoprotein E Gene in α-Synucleinopathies: A Narrative Review.

In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer's disease-AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of APOE4 on LB pathology were summarized. We found robust evidence that APOE4 carriage constitutes a risk factor for PDD-APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that APOE4 copies confer an increased hazard towards DLB, as well. Again APOE2 and APOE3 appear unrelated to the risk of conversion. Of note, in individuals with DLB APOE4, carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; APOE-PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the APOE gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive-neuropsychiatric- motor-, and sleep-related manifestations) between APOE alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.

Rituximab as a sole steroid-sparing agent in generalized myasthenia gravis: Long-term outcomes.

BACKGROUND: Rituximab, a B-cell depleting monoclonal antibody, represents an option for the treatment of refractory myasthenia gravis (MG). Its use is more established in muscle-specific tyrosine kinase positive (MuSK +) patients, while its role in managing acetylcholine receptor positive (AChR +), or double seronegative (DSN) patients, remains less clear. This study evaluates the long-term effectiveness and safety of rituximab in MG of various serotypes. METHODS: We conducted an open-label study of MG patients receiving rituximab. Adults with generalized refractory MG, either anti-AChR + or DSN, and anti-MuSK + , refractory or not, who had follow-up > 12 months were selected. Change in quantitative myasthenia gravis (QMG) score at last follow-up, compared with baseline was a primary outcome, as well as factors affecting response to treatment. Secondary outcomes included, long-term safety, the steroid-sparing effect and relapse rates post-rituximab. RESULTS: Thirty patients (16 anti-AChR + , 6 anti-MuSK + , 8 DSN) followed for a mean of 33.3 months were included. Mean scores pre-rituximab compared to last follow-up significantly decreased (p < 0.001), from 11 ± 4.1 to 4.3 ± 3.8, and from 1.9 to 0.3 regarding QMG and relapse rate per patient/year, respectively, while in 93.1% a daily steroid dose ≤ 10 mg was achieved. Antibody status was the only factor independently influencing several endpoints. Throughout the study period no crises or deaths occurred. CONCLUSION: The present study supports that rituximab is an effective and well tolerated treatment for refractory anti-AChR + and DSN MG patients, while anti-MuSK + remains the group experiencing the greater benefits.

Effects of Transcutaneous Electrical Nervous Stimulation (TENS) on Dysphonic Patients: A Systematic Review Study.

Background and Objectives: Transcutaneous electrical nerve stimulation (TENS), a pain-alleviating and muscle-relaxing treatment used in physio-therapeutic clinical practice, has recently appeared to be just as effective in dysphonia. This review aimed at clarifying whether TENS can be an effective practice in dysphonia therapy and/or management on its own or combined with other types of interventions and, hence, whether its practice can be a useful, more widespread establishment to speech and language therapy intervention methods. Materials and Methods: A search was conducted on the PubMed database using specific terms based on the PICO search strategy. Eventually, four randomized controlled studies and four clinical trials were included. The methodological quality of the included studies was evaluated using the physiotherapy evidence-based database (PEDro) assessment tool, and this indicated high-quality research with an average score of 8.43. Results: The studies utilized various TENS devices, predominantly the Dualpex 961 device (frequency of 10 Hz, phase of 200 ms). The assessment methods varied, including auditory perception, vocal therapy, electrostimulation, audio and video perceptual assessments, and laryngeal evaluations. The clinical outcomes of TENS showed a reduction in musculoskeletal pain in various areas, while the acoustic analysis results were significant in only one study. TENS was compared to manual laryngeal therapy (LMT), placebo TENS, and vocal therapy in different studies with mixed results. Conclusions: This review supports the idea that a multidimensional approach, incorporating various therapeutic modalities (TENS, LMT, speech therapy, and vocal training) can yield positive outcomes for patients with voice disorders. Further research is needed to explore the specific mechanisms of action and optimal treatment protocols for TENS in voice therapy.

Speech deficits in multiple sclerosis: a narrative review of the existing literature.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating autoimmune disease. MS patients deal with motor and sensory impairments, visual disabilities, cognitive disorders, and speech and language deficits. The study aimed to record, enhance, update, and delve into our present comprehension of speech deficits observed in patients with MS and the methodology (assessment tools) studies followed. The method used was a search of the literature through the databases for May 2015 until June 2022. The reviewed studies offer insight into speech impairments most exhibited by MS patients. Patients with MS face numerous communication changes concerning the phonation system (changes observed concerning speech rate, long pause duration) and lower volume. Moreover, the articulation system was affected by the lack of muscle synchronization and inaccurate pronunciations, mainly of vowels. Finally, there are changes regarding prosody (MS patients exhibited monotonous speech). Findings indicated that MS patients experience communication changes across various domains. Based on the reviewed studies, we concluded that the speech system of MS patients is impaired to some extent, and the patients face many changes that impact their conversational ability and the production of slower and inaccurate speech. These changes can affect MS patients' quality of life.

Adenosine A2A receptors are required for glutamate mGluR5- and dopamine D1 receptor-evoked ERK1/2 phosphorylation in rat hippocampus: involvement of NMDA receptor.

Interaction between mGluR5 and NMDA receptors (NMDAR) is vital for synaptic plasticity and cognition. We recently demonstrated that stimulation of mGluR5 enhances NMDAR responses in hippocampus by phosphorylating NR2B(Tyr1472) subunit, and this reaction was enabled by adenosine A2A receptors (A2A R) (J Neurochem, 135, 2015, 714). In this study, by using in vitro phosphorylation and western blot analysis in hippocampal slices of male Wistar rats, we show that mGluR5 stimulation or mGluR5/NMDARs co-stimulation synergistically activate ERK1/2 signaling leading to c-Fos expression. Interestingly, both reactions are under the permissive control of endogenous adenosine acting through A2A Rs. Moreover, mGluR5-mediated ERK1/2 phosphorylation depends on NMDAR, which however exhibits a metabotropic way of function, since no ion influx through its ion channel is required. Furthermore, our results demonstrate that mGluR5 and mGluR5/NMDAR-evoked ERK1/2 activation correlates well with the mGluR5/NMDAR-evoked NR2B(Tyr1472) phosphorylation, since both phenomena coincide temporally, are Src dependent, and are both enabled by A2A Rs. This indicates a functional involvement of NR2B(Tyr1472) phosphorylation in the ERK1/2 activation. Our biochemical results are supported by electrophysiological data showing that in CA1 region of hippocampus, the theta burst stimulation (TBS)-induced long-term potentiation coincides temporally with an increase in ERK1/2 activation and both phenomena are dependent on the tripartite A2A , mGlu5, and NMDARs. Furthermore, we show that the dopamine D1 receptors evoked ERK1/2 activation as well as the NR2B(Tyr1472) phosphorylation are also regulated by endogenous adenosine and A2A Rs. In conclusion, our results highlight the A2A Rs as a crucial regulator not only for NMDAR responses, but also for regulating ERK1/2 signaling and its downstream pathways, leading to gene expression, synaptic plasticity, and memory consolidation.

Insights into the molecular mechanisms of stress and inflammation in ageing and frailty of the elderly.

Frailty is a natural state of physical, cognitive and mental decline that is expected in the elderly. The role of inflammation in the pathogenesis of frailty has been hypothesized, and so far many studies have been performed in order to understand the mechanism of action underlying this association. Recent studies support this hypothesis and show a clear association between inflammation, frailty, and age-related disease. Chronic inflammation is key pathophysiologic process that contributes to the frailty directly and indirectly through other intermediate physiologic systems, such as the musculoskeletal, endocrine, and hematologic systems. The complex multifactorial etiologies of frailty also include obesity and other age-related specific diseases. Herein, we investigate the link between chronic inflammation and frailty of the older people. In particular, we present an up-to-date review of the role of cytokines, interleukins, cardiovascular abnormalities, chronic high blood pressure, hyperlipidemia and diabetes in relation to the severity of frailty in the elderly.

Age and education adjusted normative data and discriminative validity for Rey's Auditory Verbal Learning Test in the elderly Greek population.

Rey's Auditory Verbal Learning Test (RAVLT) is a widely used neuropsychological test to assess episodic memory. In the present study we sought to establish normative and discriminative validity data for the RAVLT in the elderly population using previously adapted learning lists for the Greek adult population. We administered the test to 258 cognitively healthy elderly participants, aged 60-89 years, and two patient groups (192 with amnestic mild cognitive impairment, aMCI, and 65 with Alzheimer's disease, AD). From the statistical analyses, we found that age and education contributed significantly to most trials of the RAVLT, whereas the influence of gender was not significant. Younger elderly participants with higher education outperformed the older elderly with lower education levels. Moreover, both clinical groups performed significantly worse on most RAVLT trials and composite measures than matched cognitively healthy controls. Furthermore, the AD group performed more poorly than the aMCI group on most RAVLT variables. Receiver operating characteristic (ROC) analysis was used to examine the utility of the RAVLT trials to discriminate cognitively healthy controls from aMCI and AD patients. Area under the curve (AUC), an index of effect size, showed that most of the RAVLT measures (individual and composite) included in this study adequately differentiated between the performance of healthy elders and aMCI/AD patients. We also provide cutoff scores in discriminating cognitively healthy controls from aMCI and AD patients, based on the sensitivity and specificity of the prescribed scores. Moreover, we present age- and education-specific normative data for individual and composite scores for the Greek adapted RAVLT in elderly subjects aged between 60 and 89 years for use in clinical and research settings.

Adenosine A2A receptors permit mGluR5-evoked tyrosine phosphorylation of NR2B (Tyr1472) in rat hippocampus: a possible key mechanism in NMDA receptor modulation.

A great body of evidence points toward a functional interaction between metabotropic glutamate 5 receptors (mGluR5) and NMDA receptors (NMDAR) that enhances synaptic plasticity and cognition. However, the molecular mechanism underlying this interaction remains unclear. Here, we show that co-activation of mGluR5 and NMDAR in hippocampal slices synergistically leads to a robust phosphorylation of NR2B (Tyr1472), which is Src kinase dependent and is enabled by endogenous adenosine acting on A2A receptors. As it is well known, NR2B (Tyr1472) phosphorylation anchors NR2B-containing NMDARs to the surface of post-synaptic membranes, preventing their internalization. This is supported by our electrophysiological experiments showing that co-activation of mGluR5 and NMDARs robustly enhances NMDAR-dependent neuronal excitability recorded in CA1 hippocampal region, which temporally coincides with the robust increase in NR2B (Tyr1472) phosphorylation, depends on Src kinases and is also permitted by A2A receptors. Thus, we strongly suggest that NR2B (Tyr1472) phosphorylation constitutes, at least to some extent, the molecular mechanism underlying the mGluR5-mediated enhancement of NMDAR-dependent responses, which is modulated by A2A receptors. A better understanding of the molecular basis of mGluR5/NMDAR interaction would elucidate their role in synaptic plasticity processes as well as in pathological conditions. We propose the following molecular mechanism by which metabotropic Glutamate Receptor 5 (mGluR5) potentiate ionotropic Glutamate N-Methyl-D-Aspartate Receptor (NMDAR) responses in rat hippocampus. Co-activation of mGLUR5/NMDAR activates Src kinases, leading to NR2B(Tyr1472) phosphorylation, which anchors NR2B-containing NMDAR to the plasma membrane, thus inducing a robust increase in the NMDA-dependent excitability. Interestingly, adenosine A2A receptors license the mGluR5-induced NR2B(Tyr1472) phosphorylation.