Abstract

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.

Keywords: C9orf72; GRN; cathepsin D; endo-lysosomal pathway; extracellular vesicles; frontotemporal dementia; frontotemporal lobar degeneration; lysosomal protease; plasma.

Abstract

Background and objectives: alemtuzumab is a monoclonal anti-CD52 antibody acting on B and T cells in highly active multiple sclerosis (MS). We analyzed changes in lymphocyte subsets after alemtuzumab administration in relation to disease activity and autoimmune adverse events.

Methods: lymphocyte subset counts were assessed longitudinally using linear mixed models. Subset counts at baseline and during follow-up were correlated with relapse rate, adverse events, or magnetic resonance (MRI) activity.

Results: we recruited 150 patients followed for a median of 2.7 years (IQR: 1.9-3.7). Total lymphocytes, CD4, CD8, and CD20 significantly decreased in all patients over 2 years (p < 0.001). Previous treatment with fingolimod increased the risk of disease activity and adverse events (p = 0.029). We found a higher probability of disease reactivation in males and in patients with over three active lesions at baseline. Higher EDSS scores at baseline and longer disease duration predicted the switch to other treatments after alemtuzumab.

Discussion and conclusions: Our real-world study supports data from clinical trials in which lymphocyte subsets were not useful for predicting disease activity or autoimmune disease during treatment. The early use of an induction therapy such as alemtuzumab in patients with a lower EDSS score and short history of disease could mitigate the risk of treatment failure.

Keywords: alemtuzumab; induction treatment; lymphocyte subsets; multiple sclerosis.

Abstract

Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.

Keywords: C9orf72; GRN; biomarkers; complement proteins; endo-lysosomal pathway; extracellular vesicles; frontotemporal lobar degeneration; nanoparticle tracking analysis; neuronal ceroid lipofuscinosis; plasma.

Abstract

Mild cognitive impairment (MCI) is a transitional clinical stage prior to dementia. Patients with amnestic MCI have a high risk of progression toward Alzheimer's disease. Both amnestic mild cognitive impairment and sporadic Alzheimer's disease are multifactorial disorders consequential from a multifaceted cross-talk among molecular and biological processes. Non-coding RNAs play an important role in the regulation of gene expression, mainly long non-coding RNAs (lncRNAs), that regulate other RNA transcripts through binding microRNAs. Cross-talk between RNAs, including coding RNAs and non-coding RNAs, produces a significant regulatory network all through the transcriptome. The relationship of genes and non-coding RNAs could improve the knowledge of the genetic factors contributing to the predisposition and pathophysiology of MCI. The objective of this study was to identify the expression patterns and relevant lncRNA-associated miRNA regulatory axes in the blood of MCI patients, which includes lncRNA-SNHG16, lncRNA-H19, and lncRNA-NEAT1. Microarray investigations have demonstrated modifications in the expression of long non-coding RNAs (lncRNA) in the blood of patients with MCI compared with control samples. This is the first study to explore lncRNA profiles in mild cognitive impairment blood. Our study proposes RNAs targets involved in molecular pathways connected to the pathogenesis of MCI.

Keywords: Alzheimer’s disease; H19; MCI; NEAT1; SNHG16; lncRNAs; mild cognitive impairment.

Abstract

We present the case of a 48-year-old-woman with apparently isolated central nervous system Erdheim-Chester disease characterized by brainstem involvement. Erdheim-Chester disease is extremely rare and multisystem impairment should always be sought in the suspicion of such pathology.

Keywords: Bone lesions; Erdheim-Chester; MRI.

Abstract

Introduction: Covid-19 has been sweeping over the world for more than a year. People with Multiple Sclerosis (MS) might be particularly vulnerable either for the disease iteself or for the ongoing immune treatment. The aim of this review is to understand the impact of the Covid-19 pandemic and lockdown on patients with MS and to provide evidence-based advice to ensure them a high standard of care even during the pandemic.

Areas covered: Literature search was conducted in the Scopus, Web of Science, Pubmed electronic databases, and articles reference lists to investigate the effect of Covid-19 on MS patients' treatment, access to health-care services and mental-health.The search terms 'multiple sclerosis' AND 'Covid-19' were combined with each of the following term 'disease modifying treatment,' 'steroids,' 'vaccination,' 'mental health,' 'stress,' 'quality of life,' 'management,' 'impact,' 'recommendations,'.

Expert opinion: To ensure MS control during the pandemic, minimizing the risk of Covid-19 contagion, face-to-face visits may be implemented with televisits. Management of relapses and DMTs schedule should be adapted based on the specific benefit/risk ratio for each patient, considering disease activity, disability, comorbidities. Vaccination should be strongly recommended. Telerehabilitation and online psychological support programs should be encouraged to preserve motor performances and mental health.

Keywords: Covid-19; Multiple sclerosis; disease-modifying treatment; management; psychological stress; vaccination.

Abstract

Background: Cerebral microbleeds (CMBs) are small round/oval lesions seen in MRI-specific sequences. They are divided in deep and lobar according to their location. Lobar CMBs (L-CMBs) are commonly associated with amyloid angiopathy. Although CMBs have been considered clinically silent for a long time, a growing body of evidence has shown that they could play a crucial role in cognitive functioning.

Objective: The aim of this systematic review was to estimate the role of L-CMBs in cognitive performance.

Methods: We selected, from the Cochrane Library, Embase, PubMed, and ScienceDirect databases, clinical studies, published from January 2000 to January 2020 and focused on the association between L-CMBs and cognitive functions. The inclusion criteria were: 1) participants grouped according to presence or absence of CMBs, 2) extensive neuropsychological examination, 3) CMBs differentiation according to topographical distribution, and 4) MRI-based CMB definition (< 10 mm and low signal in T2*/SWI). The impact of L-CMBs was separately assessed for executive functions, visuospatial skills, language, and memory.

Results: Among 963 potentially eligible studies, six fulfilled the inclusion criteria. Four studies reported a greater reduction in executive performances in participants with L-CMB and two studies showed a statistically significant association between visuospatial dysfunction and L-CMBs. No association was found between hippocampal memory or language abilities and L-CMBs.

Conclusion: Lobar CMBs are associated with a reduction of processing speed and visuospatial performances, thus suggesting the contribution of vascular amyloid deposition to this cognitive profile. This occurrence enables us to suspect an underlying Alzheimer's disease pathology even in absence of typical hippocampal memory impairment.

Keywords: Alzheimer’s disease; cerebral microbleeds; cognitive impairment; executive functions; hippocampal memory.

Abstract

Ocrelizumab is a humanized monoclonal antibody designed to bind to the CD20 molecule, resulting in a rapid depletion of B-cells; however, it has been shown that lymphocyte subpopulations other than B-cells are affected by the drug. To review the effects of ocrelizumab on circulating lymphocytes and identify candidate biomarkers to predict and monitor treatment response. A literature search for the most relevant articles from 2006 to 2022 was conducted in PubMed and Scopus. The effect of ocrelizumab on the peripheral immune system goes beyond B-cells; it also depletes T CD20 + lymphocytes. Further, ocrelizumab reshapes the T-cell response toward a low inflammatory profile and induces an increase in T CD8 + regulatory cell percentage. A higher Body Mass Index and higher B-cell count at baseline have been associated with early B-cell reappearance. Serum neurofilament light chain reduction has been associated with treatment response. Ocrelizumab treatment exerts a broad immunomodulatory effect and may be tailored based on patients' clinical and biological profiles.

Keywords: Multiple sclerosis; biomarker; ocrelizumab.

Abstract

Posterior cortical atrophy (PCA) is a neurodegenerative disorder characterized by an early prominent deficit of visual functions associated with signs and symptoms that are the expression of dysfunction of posterior brain regions. Although PCA is commonly associated with Alzheimer's disease (AD), in recent years new pathological substrates have emerged. Among them, frontotemporal lobar degeneration (FTLD) is the most commonly reported but, to date, little is known about the clinical features of PCA due to FTLD. We conducted a systematic search in the main biomedical database MEDLINE. We searched for all clinical PCA reports that assessed the pathological basis of such syndrome with at least one of the following: (1) neuropathological examination, (2) cerebrospinal fluid biomarkers, (3) amyloid-PET imaging and (4) genetic testing. Of 369 potentially eligible studies, 40 fulfilled the inclusion criteria with an overall number of 144 patients (127 PCA-AD vs. 17 PCA-FTD/non-AD). We found that hallucinations/illusions were present in none of the probable PCA-FTD/non-AD subjects while were reported in 15 out of 97 PCA-AD individuals. Optic ataxia and Parkinsonism showed a significantly greater prevalence in probable PCA FTD/non-AD than in PCA-AD whereas myoclonus and disorientation in time and space were significantly more frequent in PCA-AD than in probable PCA FTD/non-AD. We also found a predominance of a left-side pattern of atrophy/hypometabolism in the probable PCA FTD/non-AD. Clinical features such as optic ataxia, Parkinsonism, myoclonus, hallucinations and disorientation in time and space suggest the underlying pathological basis of PCA and help in leading the diagnostic protocol consequently.

Keywords: Alzheimer’s disease; Gerstmann syndrome; frontotemporal lobar degeneration; hallucinations; myoclonus; posterior cortical atrophy.

Abstract

Background: Although migraine is recognized as one of the most common and disabling diseases in the world, it is nonetheless still underestimated, underdiagnosed, and undertreated. The fact that migraine patients often tend to access the Web to search for headache-related information hinders patient-doctor relationships and one should also bear in mind that, unfortunately, text readability and medical literacy in the overall population may be the reason why patients' understanding of health information is compromised.

Aim: We aimed to assess the readability of the home page of the top 10 patient - oriented migraine-related websites and the educational level required to be in a position to broach them.

Methods: On April 15, 2018, we conducted a descriptive study on the international version of Google by entering the words "headache" and "migraine." We then analyzed the overall level of readability of texts of the home pages of the top 10 patient-oriented websites, by means of the Simple Measure of Gobbledygook Readability Calculator.

Results: Entering "headache" on the home pages of the top 10 patient-oriented websites on Google we found that to understand these particular websites with ease, an average grade level of 12.4 (±1.5 standard deviation, SD) and an average 13.3 years of formal education (±1.7 SD) were required. Similarly, typing "migraine" on Google we found an average grade level of 10.8 (±1.2 SD) and an average of 12.5 years of formal education (±1.9 SD) were required. The most frequently viewed websites all failed to meet the USA National Institutes of Health guidelines, which recommend a range between 6th and 7th grade level readability.

Discussion: The present study shows the low readability level resulting from the top 10 patient-oriented headache/migraine websites and the consequent barrier this creates in the dissemination of headache/migraine-related medical information. Although the actual physicians, both primary care physicians and headache specialists are the principal source of understandable headache-related information, only a minority of people consult these professionals. Given the foregoing, the majority of migraine patients is, therefore, unable to obtain adequate comprehensible health information on the Web. Furthermore, the existing gap between migraine-related website content readability and the unmet need for migraine patients to obtain pertinent and correct information might well contribute to the worldwide neglect of migraine as a major public health problem.

Conclusion: Physician experts in headache and migraine should actively cooperate in planning informative material to establish what information patients need to know, how they should use it, and how readable that material actually is. Readability ought to be established before the final website publication. Plain language ought to be used and written messages should be supplemented with visual content such as simple drawings. We recommend the setting up of a new dynamic, modern, plain-talking, and efficient approach in communication aimed at catching the public's attention with its readability and thus satisfying a migraine and headache web scenario.