Search

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10 -12 , OR = 1.27) and APOE (rs6857; p = 1.31 × 10 -12 , OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10 -8 , OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex., Competing Interests: Declaration of interests O.A.A. has received speakers’ honoraria from Janssen, Lundbeck, and Sunovion and is a consultant to Cortechs.ai. C.C. received research support from GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of Vivid Genomics and Circular Genomics. M.A.N. and H.L.L. hold part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. currently serves on the scientific advisory board for Character Bio Inc. and Neuron23 Inc. I.R.M. receives license royalties for patent related to PGRN therapy and is a member of the scientific advisory committee for Prevail Therapeutics. H.R.M. is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics, and Amylyx; lecture fees/honoraria from BMJ, Kyowa Kirin, and Movement Disorders Society; and research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, and the Michael J. Fox Foundation. H.R.M. is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). R.P. has received honoraria for advisory boards and speaker engagements from Roche, EISAI, Eli Lilly, Biogen, Janssen-Cilag, Astra Zeneca, Schwabe, Grifols, Novo Nordisk, and Tabuk. R.S.-V. served in advisory board meetings for Wave Life Sciences, Ionis, and Novo Nordisk; has received personal fees for participating in educational activities from Janssen, Roche Diagnostics, and Neuraxpharm; and has received funding to her institution for research projects from Biogen and Sage Pharmaceuticals. S.W.S. received research support from Cerevel Therapeutics and is a member of the scientific advisory board of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. J.S.Y. serves on the scientific advisory board for the Epstein Family Alzheimer’s Research Collaboration. J.H. does consulting and gives talks for Eli-Lilly, Roche, and Eisai and is on the Ceracuity advisory board., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The role of tumor necrosis factor-α (TNF-α) in Alzheimer's disease (AD) has recently become a topic of debate. TNF-α levels increase in the blood of patients with AD, and amyloid beta (Aβ) plaques contain TNF-α deposits. The therapeutic efficacy of blocking TNF-α in patients with AD remains controversial as it is mostly based on preclinical studies. Thus, whether and how TNF-α contributes to amyloidogenic processes in AD is still an open question to be addressed. We analyzed plasma TNF-α and Aβ42 levels in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, and in healthy volunteers (HLT). In addition, we performed correlation analysis to evaluate whether changes in plasma TNF-α levels correlate with cognitive decline, Aβ42 levels, age, and BMI, which are all factors considered to contribute to or predispose individuals to AD. We found that TNF-α and Aβ42 plasma levels were higher in patients with AD than in HLT individuals. High TNF-α levels were also observed in patients with SCI, in whom TNF-α and Aβ42 levels were negatively correlated. Notably, TNF-α did not affect the amyloidogenic pathway in human microglial cultures exposed to 48 h of incubation, although it did trigger neuroinflammatory processes. These results imply that high TNF-α levels are more likely to be a clinical condition linked to AD than are direct contributors. Nonetheless, elevated levels of TNF-α in early-stage patients, like those with SCI and MCI, may provide a distinguishing feature for identifying clinical profiles that are at risk of having a poorer outcome in AD and could benefit from tailored therapies.

Recently, measurable peripheral biomarkers in the plasma of patients with Alzheimer's disease (AD) have gained considerable clinical interest. Several studies have identified one or more blood signatures that may facilitate the development of novel diagnostic and therapeutic strategies. For instance, changes in peripheral amyloid β42 (Aβ42) levels have been largely investigated in patients with AD and correlated with the progression of the pathology, although with controversial results. In addition, tumor necrosis factor α (TNFα) has been identified as an inflammatory biomarker strongly associated with AD, and several studies have consistently suggested the pharmacological targeting of TNFα to reduce systemic inflammation and prevent neurotoxicity in AD. Moreover, alterations in plasma metabolite levels appear to predict the progression of systemic processes relevant to brain functions. In this study, we analyzed the changes in the levels of Aβ42, TNFα, and plasma metabolites in subjects with AD and compared the results with those in healthy elderly (HE) subjects. Differences in plasma metabolites of patients with AD were analyzed with respect to Aβ42, TNFα, and the Mini-Mental State Examination (MMSE) score, searching for plasma signatures that changed simultaneously. In addition, the phosphorylation levels of the Tyr682 residue of the amyloid precursor protein (APP), which we previously proposed as a biomarker of AD, were measured in five HE and five AD patients, in whom the levels of Aβ42, TNFα, and two plasma lipid metabolites increased simultaneously. Overall, this study highlights the potential of combining different plasma signatures to define specific clinical phenotypes of patient subgroups, thus paving the way for the stratification of patients with AD and development of personalized approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interests in the subject matter or materials discussed in this manuscript. Competing Interests Authors have not a conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Although physical activity (PA) has been shown to enhance hypertension control, the impact of exercise on the potential decrease of the use of antihypertensive medications remains inadequately researched., Aim: The aim was to assess the impact of a two-year PA on the medication requirements of individuals with hypertension., Methods: A clinical trial was conducted, involving 130 participants with essential hypertension who took at least one antihypertensive medication. Participants were randomly assigned to either a control group (CG n = 65) or an experimental group (EG n = 65) that underwent a 24-month supervised PA program based on a combination of aerobic and resistance training. The antihypertensive drug load for each participant was determined by adding the ratios of the prescribed daily dose (PDD) to the defined daily dose (DDD) for all antihypertensive medications taken by the participants. The outcome measures were evaluated at 0, 6, 12, 18, and 24 months., Results: A total of 76 participants completed the 24-month assessment, and RM-ANOVA revealed a significantly lower antihypertensive drug load in the EG compared to the CG at 18 ( p < 0.017) and 24 months ( p < 0.003)., Conclusion: A long-term PA program can decrease the antihypertensive drug load in older adults with essential hypertension. The trend of improvement regarding the EG drug load intake and the trend of CG drug load increase, although not significant over time, results in a significant difference between the groups at 18 months and an even greater difference at 24 months. This trend certifies the protective value of PA against the aging process and its related health risk factors.

Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia in the elderly population. Since its original description, there has been intense debate regarding the factors that trigger its pathology. It is becoming apparent that AD is more than a brain disease and harms the whole-body metabolism. We analyzed 630 polar and apolar metabolites in the blood of 20 patients with AD and 20 healthy individuals, to determine whether the composition of plasma metabolites could offer additional indicators to evaluate any alterations in the metabolic pathways related to the illness. Multivariate statistical analysis showed that there were at least 25 significantly dysregulated metabolites in patients with AD compared with the controls. Two membrane lipid components, glycerophospholipids and ceramide, were upregulated, whereas glutamic acid, other phospholipids, and sphingolipids were downregulated. The data were analyzed using metabolite set enrichment analysis and pathway analysis using the KEGG library. The results showed that at least five pathways involved in the metabolism of polar compounds were dysregulated in patients with AD. Conversely, the lipid pathways did not show significant alterations. These results support the possibility of using metabolome analysis to understand alterations in the metabolic pathways related to AD pathophysiology.

Objective: Orexin-A (OX-A) is a neuropeptide produced selectively by neurons of the lateral hypothalamus. It exerts powerful control over brain function and physiology by regulating energy homeostasis and complex behaviors linked to arousal. Under conditions of chronic or acute brain leptin signaling deficiency, such as in obesity or short-term food deprivation, respectively, OX-A neurons become hyperactive and promote hyperarousal and food seeking. However, this leptin-dependent mechanism is still mostly unexplored. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) is known to be implicated in food consumption by promoting hyperphagia and obesity, and we and others demonstrated that OX-A is a strong inducer of 2-AG biosynthesis. Here, we investigated the hypothesis that, under acute (6 h fasting in wt mice) or chronic (in ob/ob mice) hypothalamic leptin signaling reduction, OX-A-induced enhancement of 2-AG levels leads to the production of the 2-AG-derived 2-arachidonoyl-sn-glycerol-3-phosphate (2-AGP), a bioactive lipid belonging to the class of lysophosphatidic acids (LPAs), which then regulates hypothalamic synaptic plasticity by disassembling α-MSH anorexigenic inputs via GSK-3β-mediated Tau phosphorylation, ultimately affecting food intake., Methods: We combined cell-type-specific morphological (CLEM and confocal microscopy), biochemical, pharmacological, and electrophysiological techniques to dissect the leptin- and OX-A/2-AGP-mediated molecular pathways regulating GSK-3β-controlled pT231-Tau production at POMC neurons of obese ob/ob and wild-type (wt) lean littermate mice and in an in vitro model of POMC neurons such as mHypoN41 neurons (N41)., Results: 2-AGP is overproduced in the hypothalamus of obese leptin-deficient, or lean 6 h food-deprived mice, and promotes food intake by reducing α-MSH-expressing synaptic inputs to OX-A neurons via lysophosphatidic acid type-1 receptor (LPA1-R) activation, and pT231-Tau accumulation in α-MSH projections. This effect is due to the activation of the Pyk2-mediated pTyr216-GSK3β pathway and contributes to further elevating OX-A release in obesity. Accordingly, we found a strong correlation between OX-A and 2-AGP levels in the serum of obese mice and of human subjects., Conclusions: Hypothalamic feeding pathways are endowed with 2-AGP-mediated synaptic plasticity according to their inherent functional activities and the necessity to adapt to changes in the nutritional status. These findings reveal a new molecular pathway involved in energy homeostasis regulation, which could be targeted to treat obesity and related disturbances., (Crown Copyright © 2023. Published by Elsevier GmbH. All rights reserved.)

Background: Whole-body electromyostimulation (WB-EMS) was never previously applied to Parkinson's disease (PD) patients. This randomized controlled study aimed to find the most effective and safe WB-EMS training protocol for this population., Methods: Twenty-four subjects (age: 72.13 ± 6.20 years), were randomly assigned to three groups: a high-frequency WB-EMS strength training group (HFG) (rectangular stimulation at 85 Hz, 350 μs, 4 s stimulation/4 s rest), a low-frequency WB-EMS aerobic training group (LFG) (rectangular stimulation 7 Hz, 350 μs, with a continuous pulse duration), and an inactive control group (CG). Participants of the two experimental groups underwent 24 controlled WB-EMS training sessions, with a duration of 20 min each, during 12-week intervention. Serum growth factors (BDNF, FGF-21, NGF and proNGF), α-synuclein, physical performance and Parkinson's Disease Fatigue Scale (PFS-16) responses were analyzed to evaluate the pre-post variation and differences among groups., Results: Significant interactions of Time*Groups were detected for BDNF (Time*Groups p = 0.024; Time*CG, b = -628, IC95% = -1,082/-174, p = 0.008), FGF-21 (Time*Groups p = 0.009; Time*LFG b = 1,346, IC95% = 423/2268, p = 0.005), and α-synuclein (Time*Groups p = 0.019; Time*LFG b = -1,572, IC95% = -2,952/-192, p = 0.026). Post hoc analyses and comparisons of ΔS (post-pre), performed independently for each group, showed that LFG increased serum BDNF levels (+ 203 pg/ml) and decreased α-synuclein levels (-1,703 pg/ml), while HFG showed the opposite effects (BDNF: -500 pg/ml; α-synuclein: + 1,413 pg/ml). CG showed a significant BDNF reduction over time. Both LFG and HFG showed significant improvements in several physical performance outcomes and the LFG showed better results than HFG. Concerning PFS-16, significant differences over time ( b = -0.4, IC95% = -0.8/-0.0, p = 0.046) and among groups (among all groups p < 0.001) were found, and the LFG exhibited better results than the HFG ( b = -1.0, IC95% = -1.3/-0.7, p < 0.001), and CG ( b = -1.7, IC95% = -2.0/-1.4, p < 0.001) with this last one that worsened over time., Conclusion: LFG training was the best choice for improving or maintaining physical performance, fatigue perception and variation in serum biomarkers., Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT04878679, identifier NCT04878679., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 di Cagno, Buonsenso, Centorbi, Manni, Di Costanzo, Casazza, Parisi, Guerra, Calcagno, Iuliano, Soligo and Fiorilli.)

A regular sleep-wake cycle plays a positive function that preserves synaptic plasticity and brain activity from neuropathological injuries. The hypothalamic neuropeptide orexin-A (OX-A) is central in sleep-wake regulation and has been found to be over-expressed in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) suffering from sleep disturbances. OX-A promotes the biosynthesis of 2-arachidonoylglycerol (2-AG), which, in turn, could be phosphorylated to 2-arachidonoyl lysophosphatidic acid (2-AGP). The reorganization of the actin cytoskeleton during neurite retraction is one of the best-characterized effects of lysophosphatidic acids. However, less information is available regarding the reorganization of the neuronal microtubule network in response to OX-A-induced 2-AG and, possibly consequent, 2-AGP production in AD patients. This is of special relevance also considering that higher 2-AG levels are reported in the CSF of AD patients. Here, we found a positive correlation between OX-A and 2-AGP concentrations in the plasma, and an increase of 2-AGP levels in the CSF of AD patients. Furthermore, a negative correlation between the plasmatic 2-AGP levels and the mini-mental state examination score is also revealed in AD patients. By moving from the human patients to in vitro and in vivo models of AD we investigated the molecular pathway linking OX-A, 2-AG and 2-AGP to the phosphorylation of pT231-Tau, which is a specific early plasma biomarker of this disorder. By LC-MS analysis we show that OX-A, via OX-1R, induces 2-AG biosynthesis via DAGLα, and in turn 2-AG is converted to 2-AGP in primary hippocampal neurons. By confocal microscopy and western blotting assay we found an OX-A- or 2-AGP-mediated phosphorylation of Tau at threonine 231 residue, in a manner prevented by LPA1R (2-AGP receptor) or OX1R (OX-A receptor) antagonism with AM095 or SB334867, respectively. Finally, by patch-clamp recording we documented that 2-AGP-mediated pT231-Tau phosphorylation impairs glutamatergic transmission in the mouse hippocampus. Although further additional research is still required to clarify the potential role of orexin signaling in neurodegeneration, this study provides evidence that counteraction of aberrant OX-A signaling, also via LPA-1R antagonism, may be beneficial in the mild-to-moderate age-related cognitive decline associated with sleep disturbances., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Forte, Fernández-Rilo, Palomba, Marfella, Piscitelli, De Girolamo, Di Costanzo, Di Marzo and Cristino.)

Background: Parkinson's Disease (PD) is the second most frequent degenerative disorder, the risk of which increases with age. A preclinical PD diagnostic test does not exist. We identify PD blood metabolites and metabolic pathways significantly correlated with age to develop personalized age-dependent PD blood biomarkers., Results: We found 33 metabolites producing a receiver operating characteristic (ROC) area under the curve (AUC) value of 97%. PCA revealed that they belong to three pathways with distinct age-dependent behavior: glycine, threonine and serine metabolism correlates with age only in PD patients; unsaturated fatty acids biosynthesis correlates with age only in a healthy control group; and, finally, tryptophan metabolism characterizes PD but does not correlate with age., Conclusions: The targeted analysis of the blood metabolome proposed in this paper allowed to find specific age-related metabolites and metabolic pathways. The model offers a promising set of blood biomarkers for a personalized age-dependent approach to the early PD diagnosis., (© 2022. The Author(s).)

Physical activity (PA) is a key element in the management of successful aging. The aim of this paper was to show the effects of PA on the quality of life perception, nutritional status, and daily life management of 178 older adults (aged 63.87 ± 8.17) randomly assigned to an Experimental Group (EG), which performed moderate-to-high intensity aerobic and strengthening training, and a Control Group (CG) which performed low-impact PA, assessed after 6, 12, and 24 months. The Short-Form Health Survey (SF-36), Mini Nutritional Assessment (MNA), and Physical Activity Scale for the Elderly (PASE) were used for the study. In the SF-36 assessment, EG showed a good quality of life perception maintained after 24 months, while CG showed a worsening in the same period (p = 0.018). The EG reported a significant better nutritional status as compared to pre-intervention assessment (p = 0.003) and to CG (p < 0.001). Regarding the PASE, the EG showed a higher level of weekly activities than the CG after 24 months (p = 0.011), while the CG showed a worsening after 12 months (p = 0.008). The prolonged engagement in moderate-to high-intensity PA allowed the maintenance of a good quality of life perception, a good level of nutritional status, and daily life activities.

The CD33 gene encodes for a member of the sialic-acid-binding immunoglobulin-type lectin (Siglec) family, and is one of the top-ranked Alzheimer’s disease (AD) risk genes identified by genome-wide association studies (GWAS). Many CD33 polymorphisms are associated with an increased risk of AD, but the function and potential mechanism of many CD33 single-nucleotide polymorphisms (SNPs) in promoting AD have yet to be elucidated. We recently identified the CD33 SNP rs2455069-A>G (R69G) in a familial form of dementia. Here, we demonstrate an association between the G allele of the rs2455069 gene variant and the presence of AD in a cohort of 195 patients from southern Italy. We carried out in silico analysis of the 3D structures of CD33 carrying the identified SNP to provide insights into its functional effect. Structural models of the CD33 variant carrying the R69G amino acid change were compared to the CD33 wild type, and used for the docking analysis using sialic acid as the ligand. Our analysis demonstrated that the CD33-R69G variant may bind sialic acid at additional binding sites compared to the wild type, thus potentially increasing its affinity/specificity for this molecule. Our results led to a new hypothesis of rs2455069-A>G SNP as a risk factor for AD, suggesting that a long-term cumulative effect of the CD33-R69G variant results from the binding of sialic acid, acting as an enhancer of the CD33 inhibitory effects on amyloid plaque degradation.

Lipidomics is strategic in the discovery of biomarkers of neurodegenerative diseases (NDDs). The skin surface lipidome bears the potential to provide biomarker candidates in the detection of pathological processes occurring in distal organs. We investigated the sebum composition to search diagnostic and, possibly, prognostic, biomarkers of Alzheimer's disease (AD) and Parkinson's disease (PD). The observational study included 64 subjects: 20 characterized as "probable AD with documented decline", 20 as "clinically established PD", and 24 healthy subjects (HS) of comparable age. The analysis of sebum by GCMS and TLC retrieved the amounts (µg) of 41 free fatty acids (FFAs), 7 fatty alcohols (FOHs), vitamin E, cholesterol, squalene, and total triglycerides (TGs) and wax esters (WEs). Distributions of sebum lipids in NDDs and healthy conditions were investigated with multivariate ANOVA-simultaneous component analysis (ASCA). The deranged sebum composition associated with the PD group showed incretion of most composing lipids compared to HS, whereas only two lipid species (vitamin E and FOH14:0) were discriminant of AD samples and presented lower levels than HS sebum. Thus, sebum lipid biosynthetic pathways are differently affected in PD and AD. The characteristic sebum bio-signatures detected support the value of sebum lipidomics in the biomarkers search in NDDs.

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disease without guidelines for early diagnosis or personalized treatment. Previous studies have highlighted a crucial role of increasing phosphorylation levels of the amyloid precursor protein (APP) Tyr682 residue in predicting neuronal deficits in AD patients. However, the lack of a method for the identification and quantification of Tyr682 phosphorylation levels prevents its potential clinical applications. Methods: Here we report a method to identify and quantify APP Tyr682 phosphorylation levels in blood mononuclear cells of AD patients by tandem mass spectrometry (tMS). Results: This method showed excellent sensitivity with detection and quantification limits set respectively at 0.035 and 0.082 ng injected for the phosphorylated peptide and at 0.02 and 0.215 ng injected for the non-phosphorylated peptide. The average levels of both peptides were quantified in transfected HELA cells (2.48 and 3.53 ng/μg of protein, respectively). Preliminary data on 3 AD patients showed quantifiable levels of phosphorylated peptide (0.10-0.15 ng/μg of protein) and below the LOQ level of non-phosphorylated peptide (0.13 ng/μg of protein). Conclusion: This method could allow the identification of patients with increased APP Tyr682 phosphorylation and allow early characterization of molecular changes prior to the appearance of clinical signs.

Background: Alzheimer's disease (AD) is one of the most common causes of dementia in old people. Neuronal deficits such as loss of memory, language and problem-solving are severely compromised in affected patients. The molecular features of AD are Aβ deposits in plaques or in oligomeric structures and neurofibrillary tau tangles in brain. However, the challenge is that Aβ is only one piece of the puzzle, and recent findings continue to support the hypothesis that their presence is not sufficient to predict decline along the AD outcome. In this regard, metabolomic-based techniques are acquiring a growing interest for either the early diagnosis of diseases or the therapy monitoring. Mass spectrometry is one the most common analytical platforms used for detection, quantification, and characterization of metabolic biomarkers. In the past years, both targeted and untargeted strategies have been applied to identify possible interesting compounds., Aim of Review: The overall goal of this review is to guide the reader through the most recent studies in which LC-MS-based metabolomics has been proposed as a powerful tool for the identification of new diagnostic biomarkers in AD. To this aim, herein studies spanning the period 2009-2020 have been reported. Advantages and disadvantages of targeted vs untargeted metabolomic approaches have been outlined and critically discussed., (© 2021. The Author(s).)

Alzheimer's disease is a neurodegenerative disorder whose pathological mechanisms, despite recent advances, are not fully understood. However, the deposition of beta amyloid -peptide and neuroinflammation, which is probably aggravated by dysbiotic microbiota, seem to play a key role. Anti-Gal are the most abundant xenoreactive natural antibodies. They are supposed to stem from immunization against the gut microbiota and have been implicated in the pathogenesis of several diseases, including multiple sclerosis. These antibodies target the alpha-Gal epitope, expressed on the terminal sugar units of glycoprotein or glycolipid of all mammals except apes, Old World monkeys and humans. The alpha-Gal is constitutively expressed in several bacteria constituting the brain microbiota, and alpha-Gal-like epitopes have been detected in gray matter, amyloid plaque, neurofibrillary tangles and corpora amylacea of the human brain, suggesting a potential link between anti-Gal and Alzheimer's disease etiopathogenesis. For the first time, our study searched for possible alterations of anti-Gal immunoglobulin levels in Alzheimer's disease patients. IgG and IgM blood levels were significantly lower, and IgA significantly higher in patients than in healthy subjects. These results suggest that such immunoglobulins might be implicated in Alzheimer's disease pathogenesis and open new scenarios in the research for new biomarkers and therapeutic strategies.

Parkinson's disease (PD) patients lead a sedentary lifestyle, being unable or unwilling to exercise conventionally, due to physical and mental limitations. The aim of this study was to assess the acute effects of a single session of whole-body electromyostimulation (WB-EMS) on the physical performances and serum levels of the neurotrophic factors in PD patients. Ten subjects (aged 72.60 ± 6.82) underwent 20 min of physical activity with superimposed WB-EMS and, after four weeks, the same protocol with no WB-EMS. WB-EMS was conducted with intermittent stimulation, with 4 s WB-EMS/4 s rest, at 85 Hz, 350 μs. A physical fitness assessment and blood samples collection, to evaluate neurotrophic factors' levels (BDNF, FGF21, proNGF, mNGF), were collected before and after the intervention. The RM-ANOVA showed significant improvements in sit-to-stand ( p < 0.01), arm curl ( p < 0.01), handgrip ( p < 0.01) and soda pop test ( p < 0.01) after the WB-EMS intervention. Higher proNFG serum levels were observed in the WB-EMS condition compared to the no WB-EMS after 60 min post-intervention ( p = 0.0163). The effect of WB-EMS confirmed the electrostimulation ability to modulate the proNGF quantity. The positive impact of the WB-EMS protocol on physical functioning, and eye-hand coordination, makes this intervention a promising strategy to improve motor and non-motor symptoms in PD patients.

Lippia citriodora is a plant traditionally used for its anti-inflammatory, antioxidant and antispasmodic effects, as well as for additional biological activities proven in cell culture, animal studies and a small number of human clinical trials. The plant has also shown a marked improvement in blood lipid profile in some animal species. In the present preliminary study, we investigated the effect of a leaf extract on lipid and oxidative blood profile of hypercholesterolemic volunteers. Twelve adults received Lippia citriodora extract caps, containing 23% phenylpropanoids, (100 mg, once a day) for 16 weeks. Selected blood lipids and plasma oxidative markers were measured at baseline and after 4, 8 and 16 weeks of treatment. Compared with baseline, total cholesterol levels significantly decreased and high-density lipoprotein cholesterol increased, while low-density lipoprotein cholesterol and triglycerides showed only a downward trend. Oxidative status was improved due to a decrease in the concentration of total oxidant status, reactive oxygen metabolites and malondialdehyde, and a significant increase in ferric reducing ability of plasma, vitamin A and vitamin E. These preliminary results suggest that dietary supplementation with Lippia citriodora extract can improve the lipid profile, enhance blood antioxidant power, and could be a valuable natural compound for the management of human hypercholesterolemia.

It is still debated whether non-specific preclinical symptoms of Alzheimer's disease (AD) can have diagnostic relevance. We followed the evolution from cognitively normal to AD by NMR-based metabolomics of blood sera. Multivariate statistical analysis of the NMR profiles yielded models that discriminated subjective memory decline (SMD), mild cognitive impairment (MCI) and AD. We validated a panel of six statistically significant metabolites that predicted SMD, MCI and AD in a blind cohort with sensitivity values ranging from 88 to 95% and receiver operating characteristic values from 0.88 to 0.99. However, lower values of specificity, accuracy and precision were observed for the models involving SMD and MCI, which is in line with the pathological heterogeneity indicated by clinical data. This excludes a "linear" molecular evolution of the pathology, pointing to the presence of overlapping "gray-zones" due to the reciprocal interference of the intermediate stages. Yet, the clear difference observed in the metabolic pathways of each model suggests that pathway dysregulations could be investigated for diagnostic purposes.

Sialic acid-binding immunoglobulin-type lectins, which are predominantly expressed in immune cells, represent a family of immunomodulatory receptors with inhibitory and activating signals, in both healthy and disease states. Genetic factors are important in all forms of dementia, especially in early onset dementia. CD33 was recently recognized as a genetic risk factor for Alzheimer disease (AD). Here, we present a 2-generation family with 4 members, the father and the 3 siblings, characterized by an early form of unusual dementia exhibiting a behavioral variant close to behavioral variant frontotemporal dementia phenotype and severe forms of memory loss suggestive of AD. We analyzed the CD33 gene in this family and identified 10 single nucleotide polymorphisms (SNPs) in a linkage disequilibrium block associated with the disease. We also identified a tag SNP, rs2455069-A>G, in CD33 exon 2 that could be involved with dementia risk. Additionally, we excluded the presence of C9orf72 expansion mutations and other mutations previously associated with sporadic FTD and AD. The tag SNP association was also analyzed in selected sporadic AD patients from the same Southern Italy region. We demonstrate that CD33 and SIGLECL1 have a significantly increased level of expression in these patients., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Silymarin, a mixture of flavonolignan and flavonoid polyphenolic compounds extractable from milk thistle ( Silybum marianum ) seeds, has anti-oxidant, anti-inflammatory, anti-cancer and anti-viral activities potentially useful in the treatment of several liver disorders, such as chronic liver diseases, cirrhosis and hepatocellular carcinoma. Equally promising are the effects of silymarin in protecting the brain from the inflammatory and oxidative stress effects by which metabolic syndrome contributes to neurodegenerative diseases. However, although clinical trials have proved that silymarin is safe at high doses (>1500 mg/day) in humans, it suffers limiting factors such as low solubility in water (<50 μg/mL), low bioavailability and poor intestinal absorption. To improve its bioavailability and provide a prolonged silymarin release at the site of absorption, the use of nanotechnological strategies appears to be a promising method to potentiate the therapeutic action and promote sustained release of the active herbal extract. The purpose of this study is to review the different nanostructured systems available in literature as delivery strategies to improve the absorption and bioavailability of silymarin., Competing Interests: The authors declare no conflict of interest.

Background: Several observational studies have shown that exercise reduces the risk of cognitive decline; however, evidences from long-term, well-conducted, randomized controlled trials are scanty. The principal aim of this study is to verify whether a long-term program of multimodal supervised exercise improves the cognitive function and/or reduces the rate of cognitive decline in older adults at different degrees of risk for dementia., Methods/design: EPD is a parallel group, double-blind, randomized controlled trial. Community-dwelling volunteers aged 50 years or more are being recruited from different community centers and screened for eligibility. Enrolled subjects are being divided in 3 groups: a) without subjective or objective cognitive impairment, b) with subjective memory complaints, and c) with mild cognitive impairments. Participants in each group (at least 180) are being randomly assigned (1:1) to an experimental group, performing a supervised training including aerobic and resistance exercises of moderate/high intensity, or to a control group. Primary outcome will be 48-months changes in Mini Mental State Examinations. Secondary outcomes will be changes in several cognitive tests including a composite cognitive score. Time points will be at baseline, and at 6, 12, 24, 36 and 48 months. Statistical analysis will be done as intention to treat, complete case and mixed model analysis., Discussion: EPD is the first trial to examine the effects of a long exercise program (48 months) on cognitive performances. If successful, this trial may provide evidence for using long-term and multimodal exercise interventions for dementia prevention programs in the aging population., Trial Registration: The study is registered at ClinicalTrials.gov with the code NCT02236416 .

Background: Although the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration., Methods: We have measured the levels of the inflammation-related cytokines and receptors of the IL-1 family in serum of subjects with AD, compared to mild cognitive impairment (MCI), subjective memory complaints (SMC), and normal healthy subjects (NHS). Using a custom-made multiplex ELISA array, we examined ten factors of the IL-1 family, the inflammation-related cytokines IL-1α, IL-1β, IL-18, and IL-33, the natural inhibitors IL-1Ra and IL-18BP, and the soluble receptors sIL-1R1, sIL-1R2, sIL-1R3, and sIL-1R4., Results: The inflammatory cytokines IL-1α and IL-1β, their antagonist IL-1Ra, and their soluble receptor sIL-1R1 were increased in AD. The decoy IL-1 receptor sIL-1R2 was only increased in MCI. IL-33 and its soluble receptor sIL-1R4 were also significantly higher in AD. The soluble form of the accessory receptor for both IL-1 and IL-33 receptor complexes, sIL-1R3, was increased in SMC and even more in AD. Total IL-18 levels were unchanged, whereas the inhibitor IL-18BP was significantly reduced in MCI and SMC, and highly increased in AD. The levels of free IL-18 were significantly higher in MCI., Conclusions: AD is characterised by a significant alteration in the circulating levels of the cytokines and receptors of the IL-1 family. The elevation of sIL-1R4 in AD is in agreement with findings in other diseases and can be considered a marker of ongoing inflammation. Increased levels of IL-1Ra, sIL-1R1, sIL-1R4, and IL-18BP distinguished AD from MCI and SMC, and from other inflammatory diseases. Importantly, sIL-1R1, sIL-1R3, sIL-1R4, and IL-18BP negatively correlated with cognitive impairment. A significant elevation of circulating sIL-1R2 and free IL-18, not present in SMC, is characteristic of MCI and disappears in AD, making them additional interesting markers for evaluating progression from MCI to AD.

This study aimed to evaluate the effects of different types of exercise on memory performance and memory complaint after a 12-week intervention. Eighty community-dwelling volunteers, aged 66.96 ± 11.73 years, were randomly divided into four groups: resistance, cardiovascular, postural, and control groups (20 participants for each group). All participants were tested for their cognitive functions before and after their respective 12-week intervention using Rey memory words test, Prose memory test, and Memory Complaint Questionnaire (MAC-Q). Statistical analysis showed that the three experimental groups significantly improved MAC-Q scores in comparison with the control group (p < .05). The variation of MAC-Q scores and the variations of Rey and Prose memory tests scores were not correlated. These results indicate that the 12-week interventions exclusively influenced memory complaint but not memory performance. Further investigations are needed to understand the relation between memory complaint and memory performance, and the factors that can influence this relationship.

Background/aims: Abnormalities in the plasma amino acid profile have been reported in Alzheimer disease (AD), but no data exist for the prodromal phase characterized by subjective memory complaint (SMC). It was our aim to understand if serum amino acid levels change along the continuum from normal to AD, and to identify possible diagnostic biomarkers., Methods: Serum levels of 15 amino acids and 2 organic acids were determined in 4 groups of participants - 29 with probable AD, 18 with mild cognitive impairment (MCI), 24 with SMC, and 46 cognitively healthy subjects (HS) - by electrospray tandem mass spectrometry., Results: Glutamate, aspartate, and phenylalanine progressively decreased, while citrulline, argi-ninosuccinate, and homocitrulline progressively increased, from HS over SMC and MCI to AD. The panel including these 6 amino acids and 4 ratios (glutamate/citrulline, citrulline/phenylalanine, leucine plus isoleucine/phenylalanine, and arginine/phenylalanine) discriminated AD from HS with about 96% accuracy. Other panels including 20 biomarkers discriminated SMC or MCI from AD or HS with an accuracy ranging from 88 to 75%., Conclusion: Amino acids contribute to a characteristic metabotype during the progression of AD along the continuum from health to frank dementia, and their monitoring in elderly individuals might help to detect at-risk subjects.

Objective: To find the optimal exercise program to be recommended in reducing adiposity and promoting long-term physical activity adherence in a sample of overweight adolescents., Methods: Forty-five overweight adolescents were randomly divided into three exercise groups, to perform two phases of physical activity as follows: in the first phase, the first group performed a 16-week moderate-intensity resistance training (RT), the second group performed a 16-week high-intensity RT, and the third group performed a 16-week aerobic training (AT); in the second phase, all groups performed a 6-week AT. Anthropometric body composition and fitness measures were considered as outcome measures., Results: After the second protocol, both RT groups showed a significant improvement in percentage of fat mass ( F 2,76 = 5.843; p = 0.004; h 2 = 0.133) and free fat mass ( F 2,76 = 6.254; p = 0.003; h 2 = 0.141), and in fitness tests ( p < 0.01). The VO 2 max values of the RT groups were significantly higher than those of the AT group ( F 2,38 = 4.264; p = 0.021; h 2 = 0.183). The rate of adherence to exercise was an average of 94% in both RT groups, whereas in the AT group, it was 83%. During the 12-week post-intervention follow-up, the number of participants who continued to perform physical activities was significantly higher in both the RT groups than in the AT group ( p < 0.05)., Conclusion: The present study provides preliminary evidence that moderate-to-intense RT, followed by AT, can be an effective treatment for overweight adolescents, and the positive effects are maintained even after 12 weeks of follow-up., Competing Interests: The authors report no conflicts of interest in this work.

Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia. To date, there are no definitive diagnostic tests that can predict or assess onset and progression of the disease. Blood biomarkers for AD are being sought for many years but their identification remains a challenging task. In this study, we investigated the potential relationship between AD and levels of acyl-peptide hydrolase (APEH) and proteasome in erythrocyte samples of 52 participants (26 AD and 26 cognitively healthy controls). A statistically significant decrease in proteasome and exopeptidase/endopeptidase APEH activities was found in AD samples compared to those of healthy controls. Moreover, in contrast to what was observed for proteasome transcripts, APEH activities reduction in AD patients was unrelated to its gene expression levels, suggesting the occurrence of posttranslational modifications or the expression of endogenous inhibitors that might impair enzyme activity. These preliminary data further support a relationship between the APEH-proteasome system and AD molecular players, providing the first evidence of its potential use as a novel blood-based indicator for the routine detection of AD.

This study aimed to determine the serum levels of free L-carnitine, acetyl-L-carnitine and 34 acyl-L-carnitine in healthy subjects and in patients with or at risk of Alzheimer's disease. Twenty-nine patients with probable Alzheimer's disease, 18 with mild cognitive impairment of the amnestic type, 24 with subjective memory complaint and 46 healthy subjects were enrolled in the study, and the levels of carnitine and acyl-carnitines were measured by tandem mass spectrometry. The concentrations of acetyl-L-carnitine progressively decreased passing from healthy subjects group (mean±SD, 5.6±1.3 μmol/L) to subjective memory complaint (4.3±0.9 μmol/L), mild cognitive impairment (4.0±0.53 μmol/L), up to Alzheimer's disease (3.5±0.6 μmol/L) group (p<0.001). The differences were significant for the comparisons: healthy subjects vs. subjective memory complaint, mild cognitive impairment or Alzheimer's disease group; and subjective memory complaint vs. Alzheimer's disease group. Other acyl-carnitines, such as malonyl-, 3-hydroxyisovaleryl-, hexenoyl-, decanoyl-, dodecanoyl-, dodecenoyl-, myristoyl-, tetradecenoyl-, hexadecenoyl-, stearoyl-, oleyl- and linoleyl-L-carnitine, showed a similar decreasing trend, passing from healthy subjects to patients at risk of or with Alzheimer's disease. These results suggest that serum acetyl-L-carnitine and other acyl-L-carnitine levels decrease along the continuum from healthy subjects to subjective memory complaint and mild cognitive impairment subjects, up to patients with Alzheimer's disease, and that the metabolism of some acyl-carnitines is finely connected among them. These findings also suggest that the serum levels of acetyl-L-carnitine and other acyl-L-carnitines could help to identify the patients before the phenotype conversion to Alzheimer's disease and the patients who would benefit from the treatment with acetyl-L-carnitine. However, further validation on a larger number of samples in a longitudinal study is needed before application to clinical practice.

Aim: The aim of this study was to investigate the effects of high-intensity aerobic training (AT) and high-intensity aerobic training combined with resistance training (ie, combined training [CT]) on cognitive function in patients with COPD., Methods: Twenty-eight Caucasian male patients (68.35±9.64 years; mean ± SD) with COPD were recruited and randomized into two groups, AT and CT. Both groups performed physical reconditioning for 4 weeks, with a frequency of five training sessions per week. The CT group completed two daily sessions of 30 minutes: one aerobic session and one strength session, respectively; The AT group performed two 30-minute aerobic endurance exercise sessions on treadmill. Physical and cognitive function tests were performed before and after the training intervention performances., Results: Exercise training improved the following cognitive functions: long-term memory, verbal fluency, attentional capacity, apraxia, and reasoning skills (P<0.01). Moreover, the improvements in the CT group were significantly greater than those in the AT group in long-term memory, apraxia, and reasoning skills (P<0.05)., Conclusion: CT may be a possible strategy to prevent cognitive decline and associated comorbidities in male patients with COPD.

Element profiling is an interesting approach for understanding neurodegenerative processes, considering that compelling evidences show that element toxicity might play a crucial role in the onset and progression of Alzheimer's disease (AD). Aim of this study was to profile 22 serum elements in subjects with or at risk of AD. Thirtyfour patients with probable AD, 20 with mild cognitive impairment (MCI), 24 with subjective memory complaint (SMC) and 40 healthy subjects (HS) were included in the study. Manganese, iron, copper, zinc, selenium, thallium, antimony, mercury, vanadium and molybdenum changed significantly among the 4 groups. Several essential elements, such as manganese, selenium, zinc and iron tended to increase in SMC and then progressively to decrease in MCI and AD. Toxic elements show a variable behavior, since some elements tended to increase, while others tended to decrease in AD. A multivariate model, built using a panel of six essential elements (manganese, iron, copper, zinc, selenium and calcium) and their ratios, discriminated AD patients from HS with over 90% accuracy. These findings suggest that essential and toxic elements contribute to generate a distinctive signature during the progression of AD, and their monitoring in elderly might help to detect preclinical stages of AD.

This study aimed to verify whether brain abnormalities, previously described in patients with myotonic dystrophy type 1 (DM1) by magnetic resonance imaging (MRI), progressed over time and, if so, to characterize their progression. Thirteen DM1 patients, who had at least two MRI examinations, were retrospectively evaluated and included in the study. The mean duration (± standard deviation) of follow-up was 13.4 (±3.8) years, over a range of 7-20 years. White matter lesions (WMLs) were rated by semi-quantitative method, the signal intensity of white matter poster-superior to trigones (WMPST) by reference to standard images and brain atrophy by ventricular/brain ratio (VBR). At the end of MRI follow-up, the scores relative to lobar, temporal and periventricular WMLs, to WMPST signal intensity and to VBR were significantly increased compared to baseline, and MRI changes were more evident in some families than in others. No correlation was found between the MRI changes and age, onset, disease duration, muscular involvement, CTG repetition and follow-up duration. These results demonstrated that white matter involvement and brain atrophy were progressive in DM1 and suggested that progression rate varied from patient to patient, regardless of age, disease duration and genetic defect., (© The Author(s) 2016.)

This study aimed to evaluate the effects of different types of exercise on cognition. Eighty participants, 32 males and 48 females, aged 66.96 ± 11.73, volunteered for this study. The participants were randomly divided into the four following groups: Resistance Group (RG; n=20), involved in high intensity strength training; Cardiovascular Group (CVG; n=20), involved in high intensity cardiovascular training; Postural Group (PG; n=20) involved in low intensity training, based on postural and balance exercises; and Control Group (CG; n=20). Exercises were performed over the course of 12 weeks. All participants were tested for their cognitive functions pre- and post-intervention using the following neurocognitive tests: the Attentive Matrices Test, Raven's Progressive Matrices, Stroop Color and Word Interference Test, Trail Making Test and Drawing Copy Test. Statistical analysis showed that the CVG group improved significantly in the Attentive Matrices Test and Raven's Progressive Matrices (both p=<0.05), whereas the RG group improved in Drawing Copy Test time (p=<0.05). These results confirm that different types of exercise interventions have unique effects on cognition. Cardiovascular training is effective in improving performance attentive and analytic tasks, whereas resistance training is effective in improving praxis. Further investigation is necessary to evaluate the combination of the two exercise types in order to ascertain if their respective effects can be summated when performed together., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The human requires attentive effort as assessed in dual-task experiments. Consistently, an attentive task can modify the walking pattern and a attention deficit and hyperactivity disorder (ADHD) is accompanied by gait modifications. Here we investigated the relationships between backward walking and attentive performances in ADHD children (n=13) and healthy age-, height and weight matched controls (n=17). We evaluated the attentive/impulsive profile by means of a Go/No-Go task and the backward and forward gait parameters by step length, cadence and Froude number. Moreover, to test the causal relationship between attention and gait parameters, we trained children to walk backward. The training program consisted of 10 min backward walking session, thrice a week for two months. Results showed a significant negative correlation between Froude number during backward walking and reaction time in the Go/No-Go test. Besides, after training with backward walking control children increased their cadence by 9.3% and their Froude number by 17% during backward walking. Conversely, ADHD children did not modify their walking parameters after training, and showed a significant reduction in their number of errors in the Go/No-Go task (-49%) compared to the score before the training. These data suggest that specific physical training with attention-demanding tasks may improve attentive performance.

Adiponectin (Acrp30) is an adipocyte-secreted hormone with pleiotropic metabolic effects, whose reduced levels were related to development and progression of several malignancies. We looked at the presence of Acrp30 receptors in human glioblastomas (GBM), hypothesizing a role for Acrp30 also in this untreatable cancer. Here we demonstrate that human GBM express Acrp30 receptors (AdipoR1 and AdipoR2), which are often co-expressed in GBM samples (70% of the analyzed tumors). To investigate the effects of Acrp30 on GBM growth, we used human GBM cell lines U87-MG and U251, expressing both AdipoR1 and AdipoR2 receptors. In these cells, Acrp30 treatment inhibits DNA synthesis and cell proliferation rate, inducing arrest in G1 phase of the cell cycle. These effects were correlated to a sustained activation of ERK1/2 and Akt kinases, upon Acrp30 treatment. Our results suggest that Acrp30 may represent a novel endogenous negative regulator of GBM cell proliferation, to be evaluated for the possible development of novel pharmacological approaches., (© 2014 Wiley Periodicals, Inc.)

Objective: The discrimination between recurrent glioma and radiation injury is often a challenge on conventional magnetic resonance imaging (MRI). We verified whether adding and combining proton MR spectroscopic imaging ((1)H-MRSI), diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) information at 3 Tesla facilitate such discrimination., Materials and Methods: Twenty-nine patients with histologically verified high-grade gliomas, who had undergone surgical resection and radiotherapy, and had developed new contrast-enhancing lesions close to the treated tumour, underwent MRI, (1)H-MRSI, DWI and PWI at regular time intervals. The metabolite ratios choline (Cho)/normal( n )Cho n , N-acetylaspartate (NAA)/NAA n , creatine (Cr)/Cr n , lactate/lipids (LL)/LL n , Cho/Cr n , NAA/Cr n , Cho/NAA, NAA/Cr and Cho/Cr were derived from (1)H-MRSI; the apparent diffusion coefficient (ADC) from DWI; and the relative cerebral blood volume (rCBV) from PWI., Results: In serial MRI, recurrent gliomas showed a progressive enlargement, and radiation injuries showed regression or no modification. Discriminant analysis showed that discrimination accuracy was 79.3 % when considering only the metabolite ratios (predictor, Cho/Cr n ), 86.2 % when considering ratios and ADC (predictors, Cho/Cr n and ADC), 89.7 % when considering ratios and rCBV (predictors, Cho/Cr n , Cho/Cr and rCBV), and 96.6 % when considering ratios, ADC and rCBV (predictors, Cho/Cho n , ADC and rCBV)., Conclusions: The multiparametric 3-T MR assessment based on (1)H-MRSI, DWI and PWI in addition to MRI is a useful tool to discriminate tumour recurrence/progression from radiation effects.

Purpose: This case report presents the diagnosis and management of an adult patient with cyclic esotropia, a rare and poorly understood form of strabismus, that is characterized by alternating periods of manifest strabismus and orthotropia. Few cases of adult-onset cyclic strabismus have been reported. The etiology, pathogenesis, and treatment for this condition are reviewed., Case Report: A 37-year-old man with high unilateral myopia and anisometropic amblyopia in his left eye developed cyclic esotropia 2 months after a scleral buckle procedure for a retinal detachment. A 48-hour cycle that consisted of a 24-hour period of orthotropia followed by a 24-hour period of constant left esotropia was present. Magnetic resonance imaging, electromyography, electroencephalography, and ocular and orbital echography were unremarkable, as was a neurological assessment that included fatigue and edrophonium testing. The patient was successfully managed with muscle surgery., Conclusions: The etiology and pathogenesis of adult-onset cyclic esotropia remain unknown. Cyclic esotropia should be considered in the differential diagnosis when an individual presents with a history of intermittent strabismus that is present some days and not others.

Background: Physical activity and occupational exposures appeared to play a relevant role in pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin., Materials and Methods: We aimed to make an overview of the clinical characteristics and lifestyle (occupation and sport) of a population of 395 patients with ALS from Campania, in southern Italy., Results: ALS onset resulted anticipated of about 11 years in industry workers, whilst the more frequent site of onset among farmers was upper limbs. Compared to non-athletes, athletes, particularly soccer players, showed a 7 years anticipation of ALS onset, with higher mortality after 5 years., Discussion and Conclusions: We suggest that subjects genetically prone to abnormal response to hypoxia during strenuous physical activity or exposed to neurotoxic agents, such as athletes, farmers or industry workers, might present increased risk to develop ALS. Future case-control and follow-up studies on our population should be implemented to deepen the present results.

The introduction of DNA microarrays and DNA sequencing technologies in medical genetics and diagnostics has been a challenge that has significantly transformed medical practice and patient management. Because of the great advancements in molecular genetics and the development of simple laboratory technology to identify the mutations in the causative genes, also the diagnostic approach to epilepsy has significantly changed. However, the clinical use of molecular cytogenetics and high-throughput DNA sequencing technologies, which are able to test an entire genome for genetic variants that are associated with the disease, is preparing a further revolution in the near future. Molecular Karyotype and Next-Generation Sequencing have the potential to identify causative genes or loci also in sporadic or non-familial epilepsy cases and may well represent the transition from a genetic to a genomic approach to epilepsy.

Objective: The hormone adiponectin exerts beneficial pleiotropic effects on biological and metabolic processes. Although a well-recognized insulin sensitizer, its characteristic has yet to be clearly defined. Myotonic dystrophy type 1 (DM1) is a rare genetic disorder that features muscle wasting and metabolic comorbidity, and patients have an increased risk of developing type 2 diabetes. We analyzed circulating levels of adiponectin and its oligomers to determine whether their expression correlates with metabolic alterations in DM1 patients., Design and Methods: We measured the anthropometric and biochemical features and three insulin resistance (IR) indices (homeostasis model assessment, quantitative insulin sensitivity check index, and McAuley) of 21 DM1 patients and of 82 age-, sex-, and weight-matched controls. In the blood samples of patients and controls, adiponectin levels were measured by ELISA, and its oligomers were characterized by using western blotting and gel filtration. The adiponectin gene was molecularly analyzed in patients., Results: DM1 patients had significantly higher body mass index, waist circumference, triglycerides (TGs), glucose, tumor necrosis factor α, and IR; conversely, they had significantly lower concentrations of total serum adiponectin with a selective, pronounced decrease of its high molecular weight (HMW) oligomers. There was a strong negative correlation between adiponectin and TGs in DM1 patients., Conclusions: Our results endorse the hypothesis that decreased expression of adiponectin together with a selective reduction of its HMW oligomers contributes to the worsening of IR and its metabolic complications in DM1 patients. These findings suggest that adiponectin and HMW oligomers may serve as biomarkers and are promising therapeutic agents for IR and its consequences in DM1.

Alzheimer's disease is a progressive and neurodegenerative disorder which involves multiple molecular mechanisms. Intense research during the last years has accumulated a large body of data and the search for sensitive and specific biomarkers has undergone a rapid evolution. However, the diagnosis remains problematic and the current tests do not accurately detect the process leading to neurodegeneration. Biomarkers discovery and validation are considered the key aspects to support clinical diagnosis and provide discriminatory power between different stages of the disorder. A considerable challenge is to integrate different types of data from new potent approach to reach a common interpretation and replicate the findings across studies and populations. Furthermore, long-term clinical follow-up and combined analysis of several biomarkers are among the most promising perspectives to diagnose and manage the disease. The present review will focus on the recent published data providing an updated overview of the main achievements in the genetic and biochemical research of the Alzheimer's disease. We also discuss the latest and most significant results that will help to define a specific disease signature whose validity might be clinically relevant for future AD diagnosis.

The congenital form of myotonic dystrophy type 1 (CDM1) has an almost exclusively maternal transmission and is characterized by mental retardation and by moderate/severe ventriculomegaly and white matter hyperintensities on brain magnetic resonance imaging (MRI). We report a 20-year-old case of CDM1 with paternal inheritance showing mental retardation and normal brain MRI, and presenting at birth with hypotonia, facial weakness and feeding difficulties. We reviewed the literature for studies addressing the brain neuroimaging in paternally transmitted CDM1 and found four studies reporting diffuse cerebral, frontal lobe or mild parietal cortical atrophy, or mild ventricular dilatation, without white matter abnormalities. To our knowledge, this is the first report describing normal brain MRI in a mentally retarded CDM1 patient with paternal transmission.

This study aimed to evaluate the usefulness of proton MR spectroscopic imaging ((1)H-MRSI) at 3 T in differentiating high- from low-grade gliomas, and tumour from necrosis, oedema or normal tissue. Forty-four patients with brain gliomas and four with meningiomas were retrospectively reviewed. The normalised metabolites choline (nCho), N-acetylaspartate (nNAA), creatine (nCr) and lactate/lipids (nLL), and the metabolite ratios Cho/NAA, NAA/Cr and Cho/Cr were calculated. Necrotic-appearing areas showed two spectroscopic patterns: "necrosis" with variable nCho and high nLL, and "cystic necrosis" with variable nLL or nonevident peaks. Peri-enhancing oedematous-appearing areas showed three spectroscopic patterns ("tumour" with abnormal Cho/NAA, "oedema" with normal Cho/NAA and "tumour/oedema" with normal nCho and abnormal Cho/NAA) in gliomas, and one ("oedema") in meningiomas. Peri-enhancing or peri-tumour normal-appearing areas showed two patterns ("infiltrated" with abnormal nCho and/or Cho/NAA and "normal" with normal spectra) in gliomas and one ("normal") in meningiomas. Discriminant analysis showed that classification accuracy between high- and low-grade glioma masses was better with normalised metabolites or all parameters together than metabolite ratios and that among peri-enhancing areas was much better with normalised metabolites. The analysis of spatial distribution of normalised metabolites by 3-T (1)H-MRSI helps to discriminate among different tissues, offering information not available with conventional MRI.

This study aimed to determine whether white matter lesions, previously described as a frequent feature in myotonic dystrophy type 1 (DM1), aggregate within DM1 families or are sporadic findings, and to explore the relationship between these lesions and clinical or genetic features. Brain MRI of 60 DM1 patients belonging to 22 families were evaluated and white matter lesions were rated according to a semiquantitative method. Presence and extent of lobar, temporal or periventricular lesions showed a significant association with the family history of lesions and the disease duration, and no association with the CTG repeat size. Furthermore, parent-offspring and sibling pairs showed a significant positive concordance for lesion severity. White matter lesions demonstrate familial aggregation in DM1 and no relationship with CTG repeat length. These findings suggest that other genetic causes and/or unknown environmental factors influence the occurrence and severity of lesions in patients carrying the DM1 genetic defect.

Background: Fatigue is a major problem in multiple sclerosis (MS), and its association with MRI features is debated., Objective: To study the correlation between fatigue and lesion load, white matter (WM), and grey matter (GM), in MS patients independent of disability., Methods: We studied 222 relapsing remitting MS patients with low disability (scores or=5; n=197) and low-fatigue groups (FSS

Proton magnetic resonance spectroscopy ((1)H-MRS) provides specific metabolic information not otherwise observable by any other imaging method. (1)H-MRS of the brain at 3 T is a new tool in the modern neuroradiological armamentarium whose main advantages, with respect to the well-established and technologically advanced 1.5-T (1)H-MRS, include a higher signal-to-noise ratio, with a consequent increase in spatial and temporal resolutions, and better spectral resolution. These advantages allow the acquisition of higher quality and more easily quantifiable spectra in smaller voxels and/or in shorter times, and increase the sensitivity in metabolite detection. However, these advantages may be hampered by intrinsic field-dependent technical issues, such as decreased T(2) signal, chemical shift dispersion errors, J-modulation anomalies, increased magnetic susceptibility, eddy current artifacts, challenges in designing and obtaining appropriate radiofrequency coils, magnetic field instability and safety hazards. All these limitations have been tackled by manufacturers and researchers and have received one or more solutions. Furthermore, advanced (1)H-MRS techniques, such as specific spectral editing, fast (1)H-MRS imaging and diffusion tensor (1)H-MRS imaging, have been successfully implemented at 3 T. However, easier and more robust implementations of these techniques are still needed before they can become more widely used and undertake most of the clinical and research (1)H-MRS applications.

Introduction: Contrast-enhanced MR imaging is the method of choice for routine assessment of brain tumors, but it has limited sensitivity and specificity. We verified if the addition of metabolic, diffusion and hemodynamic information improved the definition of glioma extent and grade., Methods: Thirty-one patients with cerebral gliomas (21 high- and 10 low-grade) underwent conventional MR imaging, proton MR spectroscopic imaging ((1)H-MRSI), diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI) at 3 Tesla, before undergoing surgery and histological confirmation. Normalized metabolite signals, including choline (Cho), N-acetylaspartate (NAA), creatine and lactate/lipids, were obtained by (1)H-MRSI; apparent diffusion coefficient (ADC) by DWI; and relative cerebral blood volume (rCBV) by PWI., Results: Perienhancing areas with abnormal MR signal showed 3 multiparametric patterns: "tumor", with abnormal Cho/NAA ratio, lower ADC and higher rCBV; "edema", with normal Cho/NAA ratio, higher ADC and lower rCBV; and "tumor/edema", with abnormal Cho/NAA ratio and intermediate ADC and rCBV. Perienhancing areas with normal MR signal showed 2 multiparametric patterns: "infiltrated", with high Cho and/or abnormal Cho/NAA ratio; and "normal", with normal spectra. Stepwise discriminant analysis showed that the better classification accuracy of perienhancing areas was achieved when regarding all MR variables, while (1)H-MRSI variables and rCBV better differentiated high- from low-grade gliomas., Conclusion: Multiparametric MR assessment of gliomas, based on (1)H-MRSI, PWI and DWI, discriminates infiltrating tumor from surrounding vasogenic edema or normal tissues, and high- from low-grade gliomas. This approach may provide useful information for guiding stereotactic biopsies, surgical resection and radiation treatment.

Proton magnetic resonance spectroscopy (1H-MRS) of the brain reveals specific biochemical information about cerebral metabolites, which may support clinical diagnoses and enhance the understanding of neurological disorders. The advantages of performing 1H-MRS at higher field strengths include better signal to noise ratio (SNR) and increased spectral, spatial and temporal resolution, allowing the acquisition of high quality, easily quantifiable spectra in acceptable imaging times. In addition to improved measurement precision of N-acetylaspartate, choline, creatine and myo-inositol, high-field systems allow the high-resolution measurement of other metabolites, such as glutamate, glutamine, gamma-aminobutyric acid, scyllo-inositol, aspartate, taurine, N-acetylaspartylglutamate, glucose and branched amino acids, thus extending the range of metabolic information. However, these advantages may be hampered by intrinsic field-dependent technical difficulties, such as decreased T2 signal, chemical shift dispersion errors, J-modulation anomalies, increased magnetic susceptibility, eddy current artifacts, limitations in the design of homogeneous and sensitive radiofrequency (RF) coils, magnetic field instability and safety issues. Several studies demonstrated that these limitations could be overcome, suggesting that the appropriate optimization of high-field 1H-MRS would expand the application in the fields of clinical research and diagnostic routine.

We reviewed the brain MRI of 66 patients with the adult form of myotonic dystrophy type 1 (DM1) to evaluate the extent and significance of white matter involvement and to look for a pattern of MRI abnormalities suggestive of DM1. White matter lesions (WMLs) and large Virchow Robin spaces (VRSs) were rated by semiquantitative methods and the signal intensity of white matter superior and posterior to the trigones (WMPST) by reference to standard images. Disease duration was correlated positively with WML and negatively with VRS scores. Patients were divided into four groups according to increasing severity of WMPST involvement: group A with mild WMPST hyperintensity, group B with large VRSs and mild or moderate WMPST hyperintensity, group C with moderate WMPST hyperintensity or mild WMPST hyperintensity with small WMLs, group D with severe WMPST hyperintensity or moderate WMPST hyperintensity with small WMLs. Disease duration, muscular impairment, lobar WMLs and brain atrophy significantly increased from groups A and B (not significantly different) to C and from C to D, while convexity VRSs significantly decreased from group B to C and from C to D. Lobar white matter involvement in DM1 seems progressive during the disease and may be characterized initially by large VRSs or mild WMPST hyperintensity, then by small WMLs or moderate WMPST hyperintensity, and finally by more extensive and confluent WMLs or diffuse white matter hyperintensity and by brain atrophy.

We investigated 30 patients with familial essential tremor (ET) for spinocerebellar ataxia type 12 (SCA-12) mutations. No patient presented a CAG repeat larger than 19, suggesting that familial ET and SCA-12 are distinct diseases., (Copyright 2002 Movement Disorder Society)