The relevance of the socio-emotional deficits in cerebral small vessels disease (CSVD): An exploratory study with sporadic CSVD and CADASIL patients.

Background: Cerebral Small Vessels Disease (CSVD) is categorized in different forms, the most common being the sporadic form and a genetic variant - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Amongst the most frequent clinical manifestations are the neuropsychological changes of cognitive, behavioral, and emotional nature, whose features are still under debate. Objective: This exploratory study aimed to compare the neuropsychological profile of a sporadic CSVD sample and a CADASIL sample with an age, education, and gender matched control group, between the ages of 30-65 YO (total sample mean age=51.16; SD=4.31). Methods: 20 patients with sporadic CSVD, 20 patients with CADASIL and 20 matched controls completed a neuropsychological assessment battery. Global cognitive state, processing speed, working memory, attention, executive dysfunction, episodic memory, social cognition, impulsivity, apathy, alexithymia, depression, and anxiety were measured. White matter hyperintensities (WMH) volume were quantified and measured as lesion burden. Results: The cognitive differences found between the clinical groups combined (after confirming no differences between the two clinical groups) and matched controls were restricted to speed processing scores (d = 0.32 95 % CI [.12-.47]). The socio-emotional and behavioral profile revealed significantly higher levels of depression (d = 0.21, 95 % CI [.16-.33]). and anxiety (d = 0.25 95 % CI [.19-.32]) in CADASIL and sporadic CSVD groups, and the same for the alexithymia score (d = 0.533 95 % CI [.32-.65]) were the clinical groups revealed impoverished emotional processing compared to controls. WMH only significantly correlated with the cognitive changes and age. Conclusions: In our study, CADASIL and sporadic cSVD patients combined, present multiple emotional-behavioral symptoms - alexithymia, anxiety, depression, and in a lower extent apathy and impulsivity - suggesting for the presence of emotion dysregulation behaviors, present independently of age and of the presence of cognitive deficits. Despite of the small sample size that could underpower some findings, this exploratory research supported that these symptoms may have a significant impact in disease monitoring, progression, and prognosis, requiring further investigation regarding their neurophysiological substrates.

Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon's Syndrome of Unknown Cause.

BACKGROUND: The association that exists between livedo reticularis (LR) and stroke is known as Sneddon's syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). METHODS: ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. RESULTS: A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. CONCLUSION: Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.

Impairment of autophagy by TTR V30M aggregates: in vivo reversal by TUDCA and curcumin.

Transthyretin (TTR)-related amyloidoses are diseases characterized by extracellular deposition of amyloid fibrils and aggregates in tissues composed of insoluble misfolded TTR that becomes toxic. Previous studies have demonstrated the ability of small compounds in preventing and reversing TTR V30M deposition in transgenic mice gastrointestinal (GI) tract as well as lowering biomarkers associated with cellular stress and apoptotic mechanisms. In the present study we aimed to study TTR V30M aggregates effect in autophagy, a cellular mechanism crucial for cell survival that has been implicated in the development of several neurodegenerative diseases. We were able to demonstrate in cell culture that TTR V30M aggregates cause a partial impairment of the autophagic machinery as shown by p62 accumulation, whereas early steps of the autophagic flux remain unaffected as shown by autophagosome number evaluation and LC3 turnover assay. Our studies performed in TTR V30M transgenic animals demonstrated that tauroursodeoxycholic acid (TUDCA) and curcumin effectively reverse p62 accumulation in the GI tract pointing to the ability of both compounds to modulate autophagy additionally to mitigate apoptosis. Overall, our in vitro and in vivo studies establish an association between TTR V30M aggregates and autophagy impairment and suggest the use of autophagy modulators as an additional and alternative therapeutic approach for the treatment of TTR V30M-related amyloidosis.

Glucocerebrosidase involvement in Parkinson disease and other synucleinopathies.

Mutations in both copies (homozygous or compound heterozygous) of the gene encoding the lysosomal enzyme glucocerebrosidase, which cleaves the glycolipid glucocerebroside into glucose and ceramide cause Gaucher disease. However, multiple independent studies have also reported an association between GBA mutations and Parkinsonism with an increased frequency of heterozygous GBA mutations in various cohorts of patients with parkinsonism and other Lewy body disorders. Furthermore, GBA mutation carriers exhibit diverse parkinsonian phenotypes and present a diffuse pattern of Lewy body distribution in the cerebral cortex. This review provides an overview of the genetic basis for this association in various diseases with dysfunction of the central nervous system in which affected individuals developed Parkinsonian symptoms. The emerging clinical, pathological, and genetic studies in neuronal synucleinopathies suggest a common underlying mechanism in the etiology of these neurodegenerative disorders.

Epilepsy and recreational scuba diving: an absolute contraindication or can there be exceptions? A call for discussion.

Recreational scuba diving is a popular sport, and people with epilepsy often ask physicians whether they may engage in diving. Scuba diving is not, however, without risk for anyone; apart from the risk of drowning, the main physiological problems, caused by exposure to gases at depth, are decompression illness, oxygen toxicity, and nitrogen narcosis. In the United Kingdom, the Sport Diving Medical Committee advises that, to dive, someone with epilepsy must be seizure free and off medication for at least 5 years. The reasons for this are largely theoretical. We review the available evidence in the medical literature and diving websites. The risk of seizures recurring decreases with increasing time in remission, but the risk is never completely abolished. We suggest that people with epilepsy who wish to engage in diving, and the physicians who certify fitness to dive, should be provided with all the available evidence. Those who have been entirely seizure-free on stable antiepileptic drug therapy for at least 4 years, who are not taking sedative antiepileptic drugs and who are able to understand the risks, should then be able to consider diving to shallow depths, provided both they and their diving buddy have fully understood the risks.

The binding of xanthone derivatives to transthyretin.

A series of xanthone derivatives, isolated from Calophyllum teysmannii var. inophylloide, have been evaluated for their binding affinity to transthyretin. Transthyretin is a plasma protein involved in the transport of thyroxine (T4) and also implicated in amyloid diseases. Using competition-binding studies with the protein natural ligand T4, we have identified one prenylated xanthone with a very strong affinity to transthyretin. Molecular docking simulations show that the flexible tail of the prenylated xanthone could allow favorable molecular interactions. Since this xanthone may play a role in the thyroxine metabolism and/or over the pathogenic process associated with the amyloid disease, these results may be explored for the design of new ligands.