Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

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.

A Targeted Mass Spectrometry Approach to Identify Peripheral Changes in Metabolic Pathways of Patients with Alzheimer's Disease.

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.

CD33 rs2455069 SNP: Correlation with Alzheimer's Disease and Hypothesis of Functional Role.

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.

Challenges in LC-MS-based metabolomics for Alzheimer's disease early detection: targeted approaches versus untargeted approaches.

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 Aß deposits in plaques or in oligomeric structures and neurofibrillary tau tangles in brain. However, the challenge is that Aß 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.

Physical exercise for prevention of dementia (EPD) study: background, design and methods.

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 .

Formulation Strategies for Enhancing the Bioavailability of Silymarin: The State of the Art.

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.

Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression?

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-1ß, 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-1ß, 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.

Twelve-Week Exercise Influences Memory Complaint but not Memory Performance in Older Adults: A Randomized Controlled Study.

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.

Adiponectin as novel regulator of cell proliferation in human glioblastoma.

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.

Recurrent glioblastoma multiforme versus radiation injury: a multiparametric 3-T MR approach.

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.

TNF-α Levels Are Increased in Patients with Subjective Cognitive Impairment and Are Negatively Correlated with ß Amyloid-42.

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 (Aß) 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 Aß42 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, Aß42 levels, age, and BMI, which are all factors considered to contribute to or predispose individuals to AD. We found that TNF-α and Aß42 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 Aß42 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.

Adult-onset cyclic esotropia: a case report.

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.

Advances in peripheral blood biomarkers of patients with Alzheimer's disease: Moving closer to personalized 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 ß42 (Aß42) 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 Aß42, 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 Aß42, 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 Aß42, 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.

Long-Term Physical Activity Effectively Reduces the Consumption of Antihypertensive Drugs: A Randomized Controlled Trial.

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.

Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity.

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-3ß-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-3ß-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-GSK3ß 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.

Whole body-electromyostimulation effects on serum biomarkers, physical performances and fatigue in Parkinson's patients: A randomized controlled trial.

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.

Metabolomics of blood reveals age-dependent pathways in Parkinson's Disease.

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.

Long Term Physical Activity Improves Quality of Life Perception, Healthy Nutrition, and Daily Life Management in Elderly: A Randomized Controlled Trial.

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.

Positive association between plasmatic levels of orexin A and the endocannabinoid-derived 2-arachidonoyl lysophosphatidic acid in Alzheimer's disease.

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.