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Introduction: Movement Disorder Society (MDS) new diagnostic criteria for Progressive Supranuclear palsy (PSP) identifying different disease phenotypes were recently released. The aim of the present study is to report on the cognitive and behavioral features of the different phenotypes diagnosed according to the MDS criteria. Methods: Forty-nine PSP patients underwent an extensive battery of clinical assessments. Differences between PSP subtypes were computed with χ2 or ANOVA tests. Using the z scores, subjects were classified as having normal cognition, mild cognitive impairment, single or multiple domain, and dementia. A logistic regression model was implemented to investigate the major determinants of PSP non-Richardson’s syndrome phenotype. Results: Half of the cohort presented Richardson’s syndrome (46.9%), followed by PSP with parkinsonism and corticobasal syndrome (22.4% and 14.2%, respectively). Richardson’s syndrome and PSP with corticobasal syndrome presented a similar burden of disease. The only cognitive testing differentiating the phenotypes weresemantic fluency and ideomotor apraxia. The majority of our cohort was either affected by dementia or presented normal cognition. Richardson’s syndrome presented the highest rate of dementia. The only marker of PSP non-Richardson’s syndrome phenotype was better performance in visuo-spatial testing, implying worse visuo-spatial abilities in PSP Richardson’s syndrome. Conclusion: Available clinical assessments hardly capture differences between PSP phenotypes. The cognitive testing differentiating the PSP phenotypes were semantic fluency and ideomotor apraxia. In PSP, mild cognitive impairment likely represents an intermediate step from normal cognition to dementia. The only marker of PSP non-Richardson’s syndrome phenotype was better performance in visuo-spatial testing.

Post-prandial hyperglycemia can be relevant in developing early manifestations of atherosclerosis. EVOO (Extra Virgin Olive Oil), rich in saturated fatty acids and commonly used in the Mediterranean diet, seems to control post-prandial hyperglycemia better than butter. Subjects with type 1 diabetes are at higher risk of developing cardiovascular disease and show endothelial dysfunction, an early manifestation of atherosclerosis in the first years of the disease. Our study aims to evaluate whether EVOO and butter influence endothelial function in subjects with type 1 diabetes when added to a single high glycemic index (HGI) meal. In this exploratory cross-over study, 10 subjects with type 1 diabetes and 6 healthy subjects were scheduled to receive two types of HGI meals: one enriched with EVOO and one with butter. Before and after each test meal at different time points, all subjects underwent the evaluation of endothelial function by flow-mediated dilation technique, glucose and lipids measurements, and gastric emptying assessment by ultrasound. Flow-mediated dilation significantly increased after EVOO-enriched meal compared with butter in subjects with type 1 diabetes (two-way-repeated measurements ANOVA, p = 0.007). In patients with type 1 diabetes, the add-on of EVOO to HGI meal improves vascular function compared to butter, which has detrimental effects.

Diet, visceral sensitivity, and psychological distress play an important role in Irritable Bowel Syndrome (IBS). This study focused on the relation between IBS severity, foods, visceral sensitivity, and anxiety/depression.Patients with IBS were investigated through (1) IBS-symptoms severity score (SSS), (2) self-reported food intolerance, (3) visceral sensitivity index (VSI), and (4) Hospital Anxiety and Depression Scale (HADS). Seventy-seven patients agreed to participate in the survey. Of them, 64 (83%) showed IBS according to Rome IV criteria and were included in the final analysis. Patients with IBS-D were 30 (47%), with IBS-C 27 (42%), and with IBS-M 7 (11%).Fifty-eight patients (90%) considered at least one foodstuff as IBS trigger. Amine-rich foods represented a symptom trigger for 77% of patients, those with lectin for 70%, IACs by 48%, and capsaicin by 37%. Overweight was significantly associated with amine-rich foods (p=0.015), age45 years (p=0.001) and non-smoking condition (p=0.033) with lectin-rich foods, male gender (p=0.005) and overweight (p=0.027) with capsaicin-containing foods. A positive VSI score was found in 59% of patients, and non-smoking condition was significantly associated (OR 10.03; p=0.009). No factors were associated with a positive HADS score, shown by 80% of patients. Severe IBS was shown by 63% of patients, being amine-rich foods (p=0.024), overweight (p=0.020), and female gender (p=0.029) independent risk factors while marriage/cohabiting a protective one (p=0.038). Amine-rich foods are an independent risk factor for severe IBS, along with overweight and female gender.Clinicians should pay more attention to self-reported food intolerance in IBS patients. A personalized therapy including dietary advice as part of treatment could be of great benefit.

Objective To perform the genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome. Methods A Next Generation Sequencing – based targeted sequencing of 32 genes associated to various neurodegenerative phenotypes, plus a screening for SNCA Copy Number Variations and C9orf72 repeat expansion, was applied in a cohort of 85 Italian patients presenting with parkinsonism and cognitive and/or behavioral syndrome and a positive familial history for any neurodegenerative disorder (i.e., dementia, movement disorders, amyotrophic lateral sclerosis). Results Through this combined genetic approach, we detected potentially relevant genetic variants in 25.8% of patients with familial parkinsonism and cognitive and/or behavioral syndrome. Peculiar phenotypes are described (Cortico-basal syndrome with APP, Posterior Cortical Atrophy with GBA, Progressive Supranuclear Palsy-like with GRN, Multiple System Atrophy with TARDBP). The majority of patients presented a rigid-bradykinetic parkinsonian syndrome, while rest tremor was less common. Myoclonic jerks, pyramidal signs, dystonic postures and vertical gaze disturbances were more frequently associated with the presence of a pathogenic variant in one of the tested genes. Conclusions Given the syndromic approach adopted in our study, we were able to provide a detailed clinical description of patients beyond the boundaries of specific clinical diagnoses and describe peculiar phenotypes. This observation further supports the knowledge that genetic disorders present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria defining sharp boundaries between distinct conditions.

Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts' primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts' analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p

Cognitive deficits are common in Parkinson’s disease (PD) and many patients eventually develop dementia; however, its occurrence is unpredictable. Serum uric acid (UA) has been proposed as a biomarker of PD, both in the preclinical and clinical phase of the disease. The aim of this pilot study was to evaluate relationships between baseline serum UA levels and occurrence of mild cognitive impairment (MCI) at 4-year follow-up in a cohort of early PD patients. Early PD patients, not presenting concomitant diseases, cognitive impairment or treatment possibly interfering with UA levels, underwent neuropsychological testing at baseline and 4-year follow-up. UA levels were determined in serum at baseline. MCI was found in 23 out of 42 PD patients completing 4-year follow-up. Patients presenting MCI had significantly higher age at onset and lower Frontal Assessment Battery scores at baseline as compared with patients cognitively intact. Logistic regression analysis showed that both serum UA levels (OR = 0.54, p = 0.044) and age (OR = 1.16, p = 0.009) contribute to the occurrence of MCI at 4-year follow-up. Our pilot study suggests that lower levels of serum UA in the early disease stages are associated to the later occurrence of MCI. These results need to be confirmed by further studies on larger samples.

Chronic inflammatory pain is a major health problem worldwide with high prevalence in women. Cerebrolysin is a multimodal neuropeptide preparation that crosses the blood brain barrier and displays neuroprotective properties in aging and disease. Previously, we showed that cerebrolysin reduced mechanical allodynia in a model of persistent inflammation and pain. We aim to build upon the findings of our previous study by investigating the response to acute administration of cerebrolysin in two models of peripheral inflammation and assessing sex differences. We utilized the complete Freund's adjuvant (CFA) that produces maximal oedema and mechanical allodynia within days and carrageenan that produces similar effects within hours. Cerebrolysin reversed the mechanical allodynia in both sexes in CFA-treated rats. On the other hand, in rats treated with carrageenan, cerebrolysin was only effective in reducing mechanical allodynia in female rats. In conclusion, the present study shows that cerebrolysin effects may be sex-specific depending on different mechanisms that are at play in these two models of peripheral inflammatory pain. Further investigations are required to determine the factors contributing to sex differences.

Multiple system atrophy (MSA) is a neurodegenerative disease that belongs to the α synucleinopathies. Clinically, there is an overlap between MSA and Parkinson’s disease (PD), especially at the early disease stage. However, these two pathologies differ in terms of disease progression. Currently, no biomarker exists to differentiate MSA from PD. MicroRNAs are non-coding RNAs implicated in gene expression regulation. MiRNAs modulate cellular activity and they control a range of physiological and pathological functions. miRNAs are found in biofluids, such as blood, serum, plasma, saliva, and cerebrospinal fluid. Many groups, including ours, found that circulating miRNAs are differently expressed in blood, plasma, serum and cerebrospinal fluid of PD and MSA patients. In the present study, our primary aim was to determine if serum mir-30-5p and mir-148b-5p can be used as biomarkers for early diagnosis of PD and/or MSA. Our secondary goal was to determine if serum levels of those miRNAs can be correlated with the patients’ clinical profile. Using quantitative PCR (qPCR), we evaluated expression levels of miR-30c-5p and miR148b-5p in serum samples from PD (n = 56), MSA (n = 49), and healthy control (n = 50) subjects. We have found that miR-30c-5p is significantly upregulated in MSA if compared with PD and healthy control subjects. Moreover, serum miR-30c-5p levels correlate with disease duration in both MSA and PD. No significant difference was found in miR-148b-5p among MSA, PD and healthy control subjects. Our results suggest a possible role of serum miR-30-5p as a biomarker for diagnosis and progression of MSA.

Background: Prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD) is variable because different classification criteria are applied and there is lack of consensus about neuropsychological tests and cut-off used for cognitive profiling. Given the important therapeutic consequences for patient management, we aimed at identifying suitable diagnostic cognitive tests and respective screening cut-off values for MCI and dementia in PD (PDD). Methods: We evaluated 105 PD patients using an extensive neuropsychological battery categorized as PD without cognitive impairment (PD-CNT) (35%), PD-MCI (47%) and PDD (18%) based on established criteria and calculated Receiver Operating Characteristic (ROC) curves. Results: We found different sensitivity and specificity among neuropsychological tests in detecting PDMCI and PDD. In particular performance in attention/set shifting, verbal memory and language abilities, discriminated both PD-MCI and PDD from PD-CNT. Abilities involved mainly in semantic retrieval mechanisms discriminated PD-CNT from PD-MCI but also PD-MCI from PDD. Finally deficits in executive and visual-spatial abilities were only affected in PDD. Conclusion: Our data point to an independent and different load of each test in defining different PD cognitive statuses. These findings can help selection of appropriate cognitive batteries in longitudinal studies and definition of stage-specific therapeutic targets.

Prevalence of mild cognitive impairment (MCI) in Parkinson's disease (PD) is variable likely due to methodological differences in classification criteria and lack of consensus about neuropsychological tests used for cognitive profiling. The main objective of our study was to identify the most suitable neuropsychological tests and determine their screening and diagnostic cutoff scores for PD-MCI. A series of 104 consecutive PD patients performed an extensive neuropsychological evaluation. Individual test values were converted into Z-scores using relative published normative data. According to published criteria, PD patients were categorized as PD-CNT (PD without cognitive impairment), PD-MCI (patients performing -1.5 SDs below the mean score in at least one cognitive domain), and PDD. We used receiver operating characteristic (ROC) curves and K-means clustering analyses to calculate the best discriminating power of each neuropsychological tests in detecting PD-MCI. PD patients were categorized as follows: 55 PD-CNT (53 %), 34 PD-MCI (33 %), and 15 PDD (14 %). PD-MCI had lower education, longer disease duration and greater frequency of hallucinations than PD-CNT. We found that only the Trail Making test, Rey-Osterrieth Complex Figure Test (ROCF) copy, Frontal Assessment Battery (FAB), Digit Span Backward, and Rey's word auditory verbal learning test (RVLT) immediate recall reached significant screening and diagnostic validity in predicting PD-MCI (AUC 0.705-0.795) with cutoff scores calculated by ROC analyses lying within normal range for normative data. Specific neuropsychological tests covering verbal memory, attention/set-shifting, and visual-spatial deficits are the best predictors of MCI in PD if valid cutoff scores are used. These results have consequences for cognitive diagnosis and potentially in establishing the rate of PD cognitive decline.

In the present report we studied the safety, efficacy and efficiency of using an infrared laser to facilitate IVF by assessing fertilization, development and birth rates after laser-zona drilling (LZD) in 30 subfertile genetically modified (GM) mouse lines. We determined that LZD increased the fertilization rate four to ten times that of regular IVF, thus facilitating the derivation of 26 of 30 (86.7%) GM mouse lines. Cryopreserved two-cell stage embryos derived by LZD-assisted IVF were recovered and developed to blastocysts in vitro at the same rate as frozen–thawed embryos derived by regular IVF. Surprisingly after surgical transfer to pseudopregnant recipients the birth rate of embryos derived by LZD-assisted IVF was significantly lower than that of embryos derived by regular IVF. However this result could be completely mitigated by the addition of 0.25 M sucrose to the culture medium during LZD which caused the oocyte to shrink in volume relative to the perivitelline space. By increasing the distance from the laser target site on the zona pellucida, we hypothesize that the hyperosmotic effect of sucrose reduced the potential for laser-induced cytotoxic thermal damage to the underlying oocytes. With appropriate preparation and cautious application, our results indicate that LZD-assisted IVF is a safe, efficacious and efficient assisted reproductive technology for deriving mutant mouse lines with male factor infertility and subfertility caused by sperm–zona penetration defects.

Background: Whether the presence of the Apolipoprotein E e4 allele modulates hippocampal connectivity networks in abnormal ageing has yet to be fully clarified. Objective: Allele-dependent differences in this pattern of functional connectivity were investigated in patients with very mild neurodegeneration of the Alzheimer’s type, carriers and non-carriers of the e4 allele. Method: A seed-based connectivity approach was used. The two groups were similar in demographics, volumetric measures of brain structure, and cognitive profiles. Results: e4-carriers had increased connectivity between the seed area in the left hippocampus and 1) a left insular/lateral prefrontal region and 2) the contralateral right parietal cortex. Moreover, hippocampus- to-parietal connectivity in the group of e4 carriers was positively associated with memory performance, indicating that the between-group difference reflects compensatory processes. Retrospective analyses of functional connectivity based on patients from the ADNI initiative confirmed this pattern. Conclusion: We suggest that increased connectivity with areas external to the Default Mode Network (DMN) reflects both compensatory recruitment of additional areas, and pathological interwining between the DMN and the salience network as part of a global e4-dependent circuital disruption. These differences indicate that the e4 allele is associated with a more profound degree of DMN network breakdown even in the prodromal stage of neurodegeneration.

Previous functional neuroimaging studies in Parkinson's disease (PD) patients with impulse control disorders (ICDs) demonstrated dysfunction of the reward network, although the extent of anatomical changes is unclear. The aim of this study was to measure brain cortical thickness and subcortical volumes, and to assess their relationship with presence and severity of symptoms, in PD patients with and without ICDs. We studied 110 PD patients (N=58 with ICDs) and 33 healthy controls (all negative for ICDs) who underwent an extensive neurological, neuropsychological, and behavioral assessment as well as structural 1.5 Tesla magnetic resonance imaging (MRI). Between-group differences in brain cortical thickness and subcortical volumes, assessed with the FreeSurfer 5.1 tool, were analyzed. In patients with ICDs, we found significant cortical thinning in fronto-striatal circuitry, specifically in the right superior orbitofrontal, left rostral middle frontal, bilateral caudal middle frontal region, and corpus callosum, as well as volume reduction in the right accumbens and increase in the left amygdala. Finally, we observed a positive association relationship between severity of impulsive symptoms and left rostral middle frontal, inferior parietal, and supramarginal areas. These results support the involvement of both reward and response inhibition networks in PD patients with ICDs. Moreover, their severity is associated with alterations in brain regions linked with reward and top-down control networks. Increased understanding of the mechanisms underlying impulsive and compulsive behaviors might help improve therapeutic strategies for these important disorders.

Cold transport of epididymides from genetically modified mice is an efficient alternative to the shipment of live animals between research facilities. Mouse sperm from epididymides cold-stored for short periods can maintain viability. We previously reported that cold storage of mouse epididymides in Lifor® perfusion medium prolonged sperm motility and fertilization potential and that the sperm efficiently fertilized oocytes when reduced glutathione was added to the fertilization medium. Cryopreservation usually results in decreased sperm viability; an optimized protocol for cold storage of epididymides plus sperm cryopreservation has yet to be established. Here, we examined the motility and fertilization potential of cryopreserved, thawed (frozen-thawed) sperm from previously cold-stored mouse epididymides. We also examined the protective effect of sphingosine-1-phosphate (S1P) on sperm viability when S1P was added to the preservation medium during cold storage. We assessed viability of frozen-thawed sperm from mouse epididymides that had been cold-transported domestically or internationally and investigated whether embryos fertilized in vitro with these sperm developed normally when implanted in pseudo-pregnant mice. Our results indicate that frozen-thawed sperm from epididymides cold-stored for up to 48 hours maintained high fertilization potential. Fertilization potential was reduced after cold storage for 72 hours, but not if S1P was included in the cold storage medium. Live pups were born normally to recipients after in vitro fertilization using frozen-thawed sperm from cold-transported epididymides. In summary, we demonstrate an improved protocol for cold-storage of epididymides that can facilitate transport of genetically engineered-mice and preserve sperm viability after cryopreservation.

Hyperhomocysteinemia is a risk factor for Parkinson’s disease (PD) and may result from genetic mutations or/and environmental factors. 5,10-methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme that catalyzed remethylation of homocysteine (Hcy) and the MTHFR C677T polymorphism makes the MTHFR enzyme thermolabile causing hyperhomocysteinemia. In this study we analyzed whether two functional polymorphisms of MTHFR gene, A1298C and C677T, affect age of onset in PD. We enrolled 120 patients with sporadic PD. Patients were divided into three groups based on MTHFR C677T polymorphisms: (a) homozygotes wild type (CC) (b) heterozygotes (CT) and (c) homozygotes carriers of mutation (TT). MTHFR SNPs were analyzed using High-Resolution Melt analysis and ANOVA was performed to assess whether polymorphisms of MTHFR gene could influence age of onset. The MTHFR A1298C polymorphism had no effect on PD age at onset (p = 1.0) while there was a significant association with MTHFR C677T (p = 0.019 Bonferroni-adjusted post hoc) showing an earlier onset in CC as compared with TT. (p = 0.024). No differences were found for vascular load assessed with magnetic resonance imaging, pharmacological therapy and cognitive state for two MTHFR SNPs. Our results suggest a possible association of MTHFR C677T with age at onset of PD and may have important implications regarding the role of MTHFR.

Procedures for cryopreserving embryos vary considerably, each having its specific advantages and disadvantages in terms of technical feasibility, embryo survival yield, temperature permissibility and species- or strain-dependent applicability. Here we report a high osmolality vitrification (HOV) method that is advantageous in these respects. Cryopreservation by vitrification is generally very simple, but, unlike slow freezing, embryos should be kept at a supercooling temperature (below -130°C) to avoid cryodamage. We overcame this problem by using an HOV solution containing 42.5% (v/v) ethylene glycol, 17.3% (w/v) Ficoll and 1.0 M sucrose. This solution is more viscous than other cryopreservation solutions, but easy handling of embryos was assured by employing a less viscous equilibration solution before vitrification. Most (>80%) embryos cryopreserved in this solution survived at -80°C for at least 30 days. Normal mice were recovered even after intercontinental transportation in a conventional dry-ice package for 2-3 days, indicating that special containers such as dry shippers with liquid nitrogen vapor are unnecessary. The HOV solution could also be employed for long-term storage in liquid nitrogen, as with other conventional cryoprotectants. Finally, we confirmed that this new vitrification method could be applied successfully to embryos of all six strains of mice we have tested so far. Thus, our HOV method provides an efficient and reliable strategy for the routine cryopreservation of mouse embryos in animal facilities and biomedical laboratories, and for easy and cheap transportation.

Nutritional problems often result from malignancies and aggressive multimodal treatment. Early identification of reliable risk factors associated with malnutrition and need for nutritional support is necessary for development of preventative approaches. Nutritional and treatment-related characteristics were examined for 173 pediatric oncology patients referred for nutritional support and a comparison sample of 43 patients matched on treatment protocol and/or diagnosis who had never been referred for nutritional support. Abnormally low serum albumin levels, poor oral intake, mucositis, prior radiation therapy, and increased gastrointestinal toxicity were significantly more frequent among referred than non-referred patients. A discriminant function analysis indicated that poor oral intake was the single best predictor of need for nutritional support. Patients with solid tumors were more nutritionally depleted at the time of referral; all bone marrow transplant patients received nutritional support. Patients with central nervous system (CNS) tumors required nutritional support for longer time periods. We conclude that routine documentation of poor oral intake (i.e., observation of change in a child's eating patterns) is the most reliable indicator of children who eventually require nutritional support and who may benefit from interventions that could delay or prevent nutritional problems. Prophylactic interventions should be tailored to meet the specific needs of individual diagnostic groups.

Background The mechanisms underlying the development of impulse control disorders (ICDs) like compulsive gambling, buying, sexual, and eating behaviors in Parkinson’s disease (PD) are debated. We assessed whether allelic variants of dopamine D2 receptors (DRD2), catechol-O-methyltransferase (COMT) and dopamine transporter (DAT) were associated with the development of ICDs in PD. Method We enrolled 89 idiopathic PD patients (48 without ICDs and 41 with ICDs). All patients were screened with the Minnesota Impulsive Disorders Interview (MIDI) and fulfilled DSM-IV criteria for the ICD positive cohort. Differences in the frequency of the genotypes between ICDs and non-ICDs groups were assessed using the χ2 test. Results Genotyping was performed for variants of the DRD2 Taq1A (rs1800497), COMT Val158Met (rs4680), DAT1 (3′ UTR 40 bp VNTR). Variants of DRD2 Taq1A, COMT and DAT1 were not associated with the risk of developing ICDs. Conclusion In our study, there were no differences in the frequency of variant of DRD2 Taq1A, COMT and DAT1 between the two groups. Polymorphisms of dopaminergic genes do not play a relevant role in the development of ICD in PD suggesting that ICD originate from inability to filter inappropriate behaviors triggered by dopaminergic therapy.

article i nfo Cognitive and behavioral abnormalities are frequent in Parkinson's disease (PD) but their anatomical correlates are still uncertain. We assessed a cohort of 59 PD patients with and without impulse control disorders (PD-ICDs and PD-CNTR) with magnetic resonance imaging and a comprehensive neuropsycholog- ical battery. Thirty-five PD patients presented ICDs according to DSM-IV criteria and Minnesota Impulsive Disorders Interview. We found areas of significant brain atrophy in the middle and superior frontal gyrus in the whole cohort of 59 PD patients vs. healthy controls but there were no morphometric changes in PD-ICDs vs. PD-CNTR. This was consistent with cognitive findings of relatively preserved function in PD-ICDs with the exception for slower performance in the Trail Making Test B-A suggesting difficulties to maintain goal- directed tasks and suppress irrelevant responses. Voxel Based Morphometric regression analysis (VBM) carried out using TMTB-A as independent factor showed a negative gray matter correlation between high TMTB-A scores and left middle frontal cortex, right posterior cingulate area, anterior cingulate and supplementary motor area bilaterally. Our results suggest that PD is characterized by an overall loss of gray matter in pre-frontal regions. However, the contribution of these changes to the development of ICDs is marginal.