Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is an invariably fatal neurodegenerative disorder affecting 1.5 cases per million individuals per year. About 10–15
Myasthenia Gravis, traditionally known as a purely motor disease, has been recently associated also with non-motor symptoms, including psychological and cognitive symptoms. However, the presence of cognitive impairment in Myasthenia Gravis remains unclear due to limited and heterogeneous findings. This systematic review and meta-analysis aims to clarify the relationship between Myasthenia Gravis and cognitive performances. Following PRISMA guidelines, we systematically searched PubMed, Web of Science, and SCOPUS for original researches published between January 2000 and December 2024 assessing cognitive functioning in people with MG compared to healthy controls. Pooled standardized mean differences and 95
Idiopathic inflammatory myopathies (IIMs) are autoimmune muscle diseases with distinct clinical, histopathological, and molecular features. Among them, inclusion body myositis (IBM) is refractory to immunotherapy and characterized by combined inflammatory and degenerative changes. Polymyositis with mitochondrial pathology (PM-Mito) has been proposed as a prodromal stage of IBM, but molecular profile underlying this spectrum remains poorly defined. Skeletal muscle biopsies from 38 IBM, 14 PM-Mito, 5 anti-synthetase syndrome (ASyS), 3 dermatomyositis (DM), 5 immune-mediated necrotizing myopathy (IMNM), and 7 non-diseased controls (NDC) were analyzed by label-free mass spectrometry and validated by bulk RNA sequencing. Dimensionality reduction was performed using sparse Partial Least Squares Discriminant Analysis (sPLS-DA), followed by differential protein analysis. IBM exhibited a homogeneous and distinct proteomic signature compared with other IIM subtypes, driven by upregulation of MHC class I (e.g. HLA-A) and II (e.g. HLA-DRB1, CD74) molecules, and cytoskeletal proteins (e.g. PDCL3). Comparing IBM to other types of IIM, we also detected increased level of specific histone variants (e.g. HIST2H2AA3, H1FX). Enrichment analysis of the differential proteins underscored increased antigen presentation and T-cell–mediated immunity pathways, with concomitant depletion of mitochondrial respiratory chain, RNA processing, and oxidative phosphorylation components in IBM. PM-Mito shared a proteomic profile with IBM with reduced MT-ND2 levels and increases in lipid storage regulator PLIN1 and extracellular matrix protein COL14A1, among others. In contrast to IBM, PM-Mito preserved type 2 myofiber markers (e.g. MYH2). A specific protein change to PM-Mito was an increase in the cytochrome c oxidase subunit III (MT-CO3), implicating mitochondrial remodelling. Transcriptomic analysis validated the proteomic changes in COL14A1, IGLL4, PLIN1, MT-ND2, SMDT1, and TIMM21, all of which were shared between IBM and PM-Mito. IBM exhibits a unique proteomic landscape distinct from other IIMs. The overlap with PM-Mito suggests that these conditions share molecular features, supporting an interpretation that places PM-Mito in the broader spectrum of IBM. Novel protein markers, including histone variants and cytoskeletal regulators, highlight potential pathways for future research. These findings underscore the need for longitudinal studies exploring therapeutic targets in early disease stages.
BACKGROUND:Management of deep brain stimulation (DBS) in late-stage Parkinson's disease (LSPD) remains challenging, particularly when deciding whether to continue or discontinue stimulation, and evidence on risk-benefit considerations is limited. OBJECTIVES:To identify key factors to improve decision-making in DBS management for LSPD patients. METHODS:We retrospectively analyzed demographic, clinical and stimulation parameters in LSPD patients (Hoehn and Yahr ≥4; Schwab and England ≤50) who either maintained best medical therapy (BMT) or required unscheduled device-aided therapy (DAT) implantation up to 1 year after DBS discontinuation. RESULTS:From 2005 to 2022, 94 patients with bilateral subthalamic nucleus DBS were reviewed and among the 31 patients who have transitioned to LSPD, 15 patients remained on BMT, while 10 required rescue DAT (6 unscheduled implantable pulse generator replacements and 4 Levodopa-Carbidopa Intestinal Gel) within 3 months after discontinuation. Significant differences were observed in years of DBS (12.4 vs. 8.5), modified Falls Efficacy Scale (12.5 vs. 21.2), and months since the last parameter adjustment (30.3 vs. 23.2), with a trend toward less ΔMDS-UPDRS III worsening after stimulation was switched off (7.6 vs. 10.9). Longer DBS duration was inversely associated with rescue DAT (OR 0.529; 95% CI, 0.284-0.986), with a cutoff of 10.5 years. CONCLUSION:In selected LSPD patients, a transition from DBS to BMT alone can be attempted with long-term stability, whereas in others a more conservative approach is advisable, and stimulation should be continued. Clinical, therapeutic, and care-related factors should guide decisions when discontinuation is being considered.
Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice is a great challenge, especially during early disease stages with subtle or mild symptoms of cognitive decline. Moreover, robust and more accessible blood-based screening tests for early diagnosis are needed. In this study, we investigated the core AD blood biomarkers — amyloid beta 42 (Aβ42) and 40 (Aβ40) peptides, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-Tau) — and extracellular vesicle (EVs) size and concentration in individuals characterized by different stages of cognitive decline to identify biochemical markers of dementia for early diagnosis. A total of n = 800 human plasma samples were analyzed. Plasma levels of NfL, t-Tau, p-Tau181, Aβ42, Aβ40 and plasma EVs were evaluated in n = 217 elderly healthy subjects (CTRL), in individuals with subjective cognitive complaints (SCC, n = 48), pre-mild cognitive impairment (pre-MCI, n = 58) and mild cognitive impairment (MCI, n = 426), and in n = 51 probable AD dementia patients (AD-dem), using ultrasensitive Single Molecule Array technology (Simoa®) and nanoparticle tracking analysis (NTA). Logistic regression and Receiver Operating Characteristic (ROC) analyses were employed. Plasma NfL displayed increased levels in AD-dem and MCI patients, while p-Tau181, Aβ42/Aβ40 ratio, Aβ42/p-Tau181 ratio, and EVs plasma levels were altered since the early stages of the pathology: in particular, p-Tau181 levels increased as cognitive symptoms worsened, already in the SCC and pre-MCI groups compared to CTRL, while the ratio of EVs concentration and size (EVs ratio) was decreased in all groups compared to CTRL. Plasma p-Tau181 best classified AD-dem patients from CTRL with an area under the curve (AUC) equal to 0.87, while EVs ratio best differentiated SCC from CTRL (AUC = 0.78). Combining p-Tau181 and EVs ratio with Aβ42/Aβ40 ratio and NfL, respectively, significantly improved the classification of pre-MCI and MCI from CTRL (AUCcomb = 0.79 and AUCcomb = 0.85). Combining biomarkers did not improve accuracy in discriminating MCI from SCC, pre-MCI and AD-dem. p-Tau181 and EVs ratio are promising biomarkers for the identification of individuals at risk of degenerative dementia. Combining the core AD plasma biomarkers with EVs ratio can aid in diagnosing the early stages of AD dementia.
