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BackgroundSarcopenic obesity (SO) is a clinical disorder characterized by increased adiposity and decreased muscle mass and function, commonly observed in older adults. However, most of the studies that investigated SO prevalence rates were not based on current standardized diagnostic methods. Thus, this study aims to estimate the prevalence rates of SO and their level of agreement using different instruments proposed by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) Consensus, in a sample of hospitalized older adults with severe obesity.MethodsA cross-sectional study with 90 older adults (≥ 60 years) with severe obesity (body mass index ≥ 35 kg/m/²) seeking an in-hospital multidisciplinary body weight reduction program. Skeletal muscle function was assessed using the five-repetition Sit-Stand test (5-SSt) and Handgrip Strength (HGS). Body composition was evaluated by high percentages of fat mass (FM), low appendicular lean mass (ALM/W), and skeletal muscle mass (SMM/W), adjusted to body weight. The stage of SO was assessed on the presence of at least one comorbidity and specific cut-offs were adopted for each step. All analyses were performed according to gender and age range.ResultsThe prevalence rates of SO in the total sample were 23.3%, 25.5%, 31.1%, and 40.0% considering altered values of 5-SSt+FM+ALM/W, HGS+FM+ALM/W, 5-SSt+FMSSM/W, and HGS+FM+SSM/W, respectively. Higher prevalence rates were observed among female and old elderly subgroups, regardless of the diagnostic combination. There were weak agreements between the muscle function tests (5-SSt versus HGS) using both muscle mass indexes in the total sample and all subgroups. Moderate agreements were observed between muscle mass indexes (SMM/W versus ALM/W) in the total sample, male and younger older adults (using 5-SSt), and strong agreements for men and younger older adults (using HGS).ConclusionThe discrepancies observed between the prevalence rates and their levels of agreement reinforce the need for new studies in similar populations aiming for better standardization of SO assessment.

BackgroundAlthough data on outdoor gamma radiation are available for many countries, they have generally been obtained with measurements performed in undisturbed environments instead of in urban areas where most of the population lives. Only one large national survey, with on-site measurements in urban areas, has been identified worldwide, probably due to high costs (e.g., personnel and instrumentation) and difficulties in selecting measuring points.MethodsA campaign of outdoor gamma radiation measurements has been carried out in the entire Italian territory. All measurement points were selected at the infrastructures of an Italian telecommunications company as representatives of all the possible situations of outdoor exposure to gamma radiation for population in urban areas. Ten replicates of portable gamma (X) detectors carried out all the measurements.ResultsApproximately 4,000 measurements have been performed. They are distributed across 2,901 Italian municipalities, accounting for 75% of the Italian population. The national population-weighted mean of the gamma ambient dose equivalent rate (ADER) is 117 nSv h−1, and it ranges from 62 to 208 nSv h−1 and from 40 to 227 nSv h−1 for 21 regions and 107 provinces, respectively. The average variability at the municipal level, in terms of the coefficient of variation (CV) is 21%, ranging from 3 to 84%. The impact of land coverage and the distance from a building on the outdoor gamma radiation level was assessed with complementary measurements, leading to differences ranging from −40 to 50% and to 50%, respectively.ConclusionA representative campaign of outdoor gamma dose rate measurements has been performed in Italy, only in urban areas, to assess the exposure effect due to outdoor gamma radiation on the population. It is the largest national campaign in urban areas worldwide, with a total of 3,876 on-site measurements. The land coverage and the distance from surrounding buildings were recognized to strongly affect outdoor gamma radiation levels, leading to high variability within small areas. The collaboration with a company that owns a network of facilities on a national territory as dense as the residing population made this survey feasible and affordable. Other countries might adopt this methodology to conduct national surveys in urban environments.

Ring Laser Gyroscopes, based on the Sagnac effect, are currently the most sensitive rotation sensors. GINGERINO, a RLG installed underground, shows a proved sensitivity that enters the few frad/s regime in about 2.5 days of integration time. On one hand, this sensitivity is well below the shot–noise–level as predicted applying to GINGERINO the so called independent beam model. On the other hand, it paves the way to the use of RLG in fundamental and quantum physics research. Indeed, high sensitivity rotation measurement opens to test general relativity and alternative theory of gravity. Moreover, it make possible to study the interplay between quantum effects in the optical domain and non-inertial reference frames.

The evaluation of pupillary light reflex (PLR) by chromatic pupillometry may provide a unique insight into specific photoreceptor functions. Chromatic pupillometry refers to evaluating PLR to different wavelengths and intensities of light in order to differentiate outer/inner retinal photoreceptor contributions to the PLR. Different protocols have been tested and are now established to assess in-vivo PLR contribution mediated by melanopsin retinal ganglion cells (mRGCs). These intrinsically photosensitive photoreceptors modulate the non-image-forming functions of the eye, which are mainly the circadian photoentrainment and PLR, via projections to the hypothalamic suprachiasmatic and olivary pretectal nucleus, respectively. In this context, chromatic pupillometry has been used as an alternative and non-invasive tool to evaluate the mRGC system in several clinical settings, including hereditary optic neuropathies, glaucoma, and neurodegenerative disorders such as Parkinson’s disease (PD), idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD), and Alzheimer’s disease (AD). The purpose of this article is to review the key steps of chromatic pupillometry protocols for studying in-vivo mRGC-system functionality and provide the main findings of this technique in the research setting on neurodegeneration. mRGC-dependent pupillary responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower and sustained compared with rod- and cone-mediated responses, driving the tonic component of the PLR during exposure to high-irradiance and continuous light stimulus. Thus, mRGCs contribute mainly to the tonic component of the post-illumination pupil response (PIPR) to bright blue light flash that persists after light stimulation is switched off. Given the role of mRGCs in circadian photoentrainment, the use of chromatic pupillometry to perform a functional evaluation of mRGcs may be proposed as an early biomarker of mRGC-dysfunction in neurodegenerative disorders characterized by circadian and/or sleep dysfunction such as AD, PD, and its prodromal phase iRBD. The evaluation by chromatic pupillometry of mRGC-system functionality may lay the groundwork for a new, easily accessible biomarker that can be exploited also as the starting point for future longitudinal cohort studies aimed at stratifying the risk of conversion in these disorders.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex genetic architecture, showing monogenic, oligogenic, and polygenic inheritance. In this study, we describe the case of a 71 years-old man diagnosed with ALS with atypical clinical features consisting in progressive ocular ptosis and sensorineural deafness. Genetic analyses revealed two heterozygous variants, in the SOD1 (OMIM*147450) and the TBK1 (OMIM*604834) genes respectively, and furthermore mitochondrial DNA (mtDNA) sequencing identified the homoplasmic m.14484T>C variant usually associated with Leber’s Hereditary Optic Neuropathy (LHON). We discuss how all these variants may synergically impinge on mitochondrial function, possibly contributing to the pathogenic mechanisms which might ultimately lead to the neurodegenerative process, shaping the clinical ALS phenotype enriched by adjunctive clinical features.

The safety of reclaimed urban wastewater (RUW) for the production of hydroponic barley forage (HBF) was evaluated in terms of effluent and forage characteristics, as well as the health and performance of lactating cows. The study was conducted on a dairy farm equipped with two hydroponic chambers producing approximately 620 kg/d of HBF as fed. For experimental purposes, HBF was produced using RUW collected from an aqueduct plant processing urban wastewater in a membrane bioreactor treatment chain. A feeding trial was carried out with HBF derived from RUW. Sixty lactating cows were randomly assigned to two balanced groups fed a standard total mixed ration (TMR) or a TMR in which 10 kg of HBF replaced 1 kg of oat hay and 0.5 kg of maize. The experimental period lasted 7 weeks, including a 2-week adaptation period, during which each cow underwent a physical examination, BCS scoring, blood sampling for a complete blood count and biochemical panel, recording of body weight and milk yield and quality, including fatty acid composition and heavy metal content. Ruminal pH was continuously monitored by reticulorumen boluses, and nutrient digestibility and N balance were determined at week 7. RUW showed an acceptable microbial load and an overall good quality as irrigation water, even though the supply of N and P did not influence the yield and quality of HBF. The characteristics of HBF reflected the quality of RUW supplied to the hydroponic chambers and no anomalous components (i.e., high ion concentration) were found. Feeding RW-derived HBF to lactating cows had no major positive or negative effects on animal health and production, including milk quality, ruminal pH, in vivo digestibility, and N balance. The use of RUW under the conditions tested appears to be safe for the health status of lactating cows and the quality of the milk obtained. Overall, the results do not reveal any major limitations for the use of tertiary wastewater as irrigation water for the hydroponic production of forage barley, so that a wider use of wastewater in hydroponic systems seems realistic.

BackgroundIn the last decade a large number of studies proposed and/or validated equations to estimate the Resting Energy Expenditure (REE) in adults and/or older adults, however, no equation currently available showed good accuracy for older adults with severe obesity. Thus, this study aimed to develop and validate new predictive equations for REE, based on data from the indirect calorimetry, in Italian older adults with severe obesity.MethodsA retrospective study was as conducted with 764 Caucasian older adults with severe obesity (age range: 60-74 years and BMI ≥ 35 kg/m/²). Four models were used to test the accuracy of anthropometry and body composition variables in multivariable prediction of REE. All models were derived by stepwise multiple regression analysis using a calibration group of 382 subjects [295 females and 87 males] and the equations were cross-validated in the remaining 382 subjects [295 females and 87 males] as validation group. The new prediction equations and the other published equations were tested using the Bland-Altman method. Prediction accuracy was defined as the percentage of subjects whose REE was predicted within ± 10% of measured REE.ResultsAll the equations analyzed predicted higher energy requirements for males than females, and most of them underestimated the energy requirement values of our sample. The highest accuracy values were observed in the new equations, with 62% in the anthropometric model and 63% in the body composition model.ConclusionAlthough the accuracy of our equations was slightly higher in comparison with the other taken into consideration, they cannot be considered completely satisfactory for predicting REE in Italians older adults with severe obesity. When predicting equations cannot guarantee precise or acceptable values of REE, the use of indirect calorimetry (if available) should be always recommended, especially in clinical practice.

BackgroundMycoplasma genitalium (MG) is one of the most warning emerging sexually transmitted pathogens also due to its ability in developing resistance to antibiotics. MG causes different conditions ranging from asymptomatic infections to acute mucous inflammation. Resistance-guided therapy has demonstrated the best cure rates and macrolide resistance testing is recommended in many international guidelines. However, diagnostic and resistance testing can only be based on molecular methods, and the gap between genotypic resistance and microbiological clearance has not been fully evaluated yet. This study aims at finding mutations associated with MG antibiotic resistance and investigating the relationship with microbiological clearance amongst MSM.MethodsFrom 2017 to 2021, genital (urine) and extragenital (pharyngeal and anorectal swabs) biological specimens were provided by men-who-have-sex-with-men (MSM) attending the STI clinic of the Infectious Disease Unit at the Verona University Hospital, Verona, Italy. A total of 1040 MSM were evaluated and 107 samples from 96 subjects resulted positive for MG. Among the MG-positive samples, all those available for further analysis (n=47) were considered for detection of mutations known to be associated with macrolide and quinolone resistance. 23S rRNA, gyrA and parC genes were analyzed by Sanger sequencing and Allplex™ MG and AziR Assay (Seegene).ResultsA total of 96/1040 (9.2%) subjects tested positive for MG in at least one anatomical site. MG was detected in 107 specimens: 33 urine samples, 72 rectal swabs and 2 pharyngeal swabs. Among them, 47 samples from 42 MSM were available for investigating the presence of mutations associated with macrolide and quinolone resistance: 30/47 (63.8%) showed mutations in 23S rRNA while 10/47 (21.3%) in parC or gyrA genes. All patients with positive Test of Cure (ToC) after first-line treatment with azithromycin (n=15) were infected with 23S rRNA-mutated MG strains. All patients undergoing second-line moxifloxacin treatment (n=13) resulted negative at ToC, even those carrying MG strains with mutations in parC gene (n=6).ConclusionOur observations confirm that mutations in 23S rRNA gene are associated with azithromycin treatment failure and that mutations in parC gene alone are not always associated with phenotypic resistance to moxifloxacin. This reinforces the importance of macrolide resistance testing to guide the treatment and reduce antibiotic pressure on MG strains.

BackgroundThe present investigation aimed at testing the psychometrics and diagnostics of the Italian version of the Caregiver Behavioral Questionnaire (CBQ) from the ALS Cognitive Behavioral Screen (ALS-CBS™), as well as its case–control discrimination, in a cohort of non-demented patients with ALS.MethodsThe caregivers of N = 265 non-demented patients with ALS and N = 99 healthy controls (HCs) were administered the CBQ and the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). For N = 98 patients, an in-depth behavioural/psychopathological assessment via the Frontal Behavioural Inventory (FBI), the Dimensional Apathy Scale (DAS), the State and Trait Anxiety Inventory-Form Y (STAI-Y), and the Beck Depression Inventory (BDI) was also available. Factorial and construct validity, internal reliability, and diagnostics against an abnormal ECAS-CI score were tested in patients. Case–control discrimination was explored through logistic regression.ResultsThe CBQ was internally reliable (McDonald’s ω = 0.90) and underpinned by a simple, unidimensional structure; it converged with ECAS-CI, FBI, and DAS scores and diverged from STAI-Y and BDI ones. A cutoff of ≤ 33 accurately detected abnormal ECAS-CI scores (AUC = 0.85), yielding optimal error- and information-based diagnostics. The CBQ was independent of demographic and disease-related variables and discriminated patients from HCs (p < 0.001).DiscussionThe Italian version of the CBQ from the ALS-CBS™ is a valid, reliable, diagnostically sound, and feasible screener for detecting frontotemporal-like behavioural changes in non-demented patients with ALS. Its adoption is thus recommended within clinical practice and research in the view of providing preliminary information on whether the administration of more extensive behavioural instruments is needed.

BackgroundThe semiology and determinants of apathy are largely unknown across amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Huntington’s disease (HD), due to both motor and non-motor confounders. This study thus aimed at (1) profiling apathy in ALS, PD, and HD and (2) exploring its clinical determinants.MaterialsConsecutive ALS (N = 99), PD (N = 73), and HD (N = 25) patients underwent a motor-free assessment of apathy (Dimensional Apathy Scale, DAS), global cognition, anxiety and depression. Function was assessed through disease-specific scales. The DAS was also completed by N = 101 healthy controls (HCs). Between-group comparisons on DAS scores were implemented by covarying for all applicable confounders. Predictive models on DAS scores were built through multiple, stepwise regressions.ResultsParkinson’s disease and HD, but not ALS, patients were more apathetic than HCs—with HD patients also selectively showing lower initiation and poorer goal-directed planning than HCs. Higher apathetic features were detected in PD and HD as compared to ALS. Education was a protective factor against apathy in ALS. Anxiety was a risk factor for global apathy in ALS, HD, and to a lesser extent, in PD, whereas, protective only toward affective disintegration in PD and ALS. Cognitive inefficiency was a risk factor toward apathy in both PD and ALS. Depression was a risk factor for executive-related apathy in PD.DiscussionThis study provides unprecedented insights into the heterogeneous semiology and determinants of apathy across ALS, PD, and HD via the DAS, in turn informing clinical practice and research.

BackgroundThe aim of this study was to explore the construct validity and diagnostic properties of the Reading the Mind in the Eyes Test (RMET) in non-demented patients with amyotrophic lateral sclerosis (ALS).MaterialsA total of 61 consecutive patients and 50 healthy controls (HCs) were administered the 36-item RMET. Additionally, patients underwent a comprehensive assessment of social cognition via the Story-Based Empathy Task (SET), which encompasses three subtests targeting Causal Inference, Emotion Attribution (SET-EA), and Intention Attribution (SET-IA), as well as global cognitive [the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and behavioral screening [the Frontal Behavioral Inventory (FBI); the Dimensional Apathy Scale (DAS); the Beck Depression Inventory (BDI); and the State and Trait Anxiety Inventory-Y]. The construct validity of the RMET was tested by regressing it within a stepwise model that encompassed as predictors the abovementioned cognitive and behavioral measures, covarying for demographic and motor confounders. Receiver-operating characteristics (ROC) analyses allowed exploring intrinsic and post-test properties of the RMET both in discriminating patients from HCs and in identifying patients with a defective SET-EA performance.ResultsThe RMET was solely predicted by the SET-EA (p = 0.003) and SET-IA (p = 0.005). RMET scores showed high accuracy both in discriminating patients from HCs (AUC = 0.81) and in identifying patients with a defective SET-EA score (AUC = 0.82), with adequate-to-optimal both intrinsic and post-test properties.DiscussionThe RMET is a convergently and divergently valid measure of affective social cognition in non-demented ALS patients, also featuring optimal intrinsic and post-test diagnostic properties in both case-control and case-finding scenarios.

BackgroundThis study aimed at assessing the diagnostic properties of the Frontal Assessment Battery (FAB) as to its capability to (1) discriminate healthy controls (HCs) from patients with Huntington’s disease (HD) and (2) identify cognitive impairment in this population.MaterialsThirty-eight consecutive HD patients were compared to 73 HCs on the FAB. Patients further underwent the Montreal Cognitive Assessment (MoCA) and the Unified Huntington’s Disease Rating Scale (UHDRS). Receiver-operating characteristics (ROC) analyses were run to assess both intrinsic—i.e., sensitivity (Se) and specificity (Sp), and post-test diagnostics, positive and negative predictive values (PPV; NPV) and likelihood ratios (LR+; LR–), of the FAB both in a case–control setting and to identify, within the patient cohort, cognitive impairment (operationalized as a below-cut-off MoCA score). In patients, its diagnostic accuracy was also compared to that of the cognitive section of the UHDRS (UHDRS-II).ResultsThe FAB and UHDRS-II were completed by 100 and 89.5% of patients, respectively. The FAB showed optimal case–control discrimination accuracy (AUC = 0.86–0.88) and diagnostic properties (Se = 0.68–0.74; Sp = 0.88–0.9; PPV = 0.74–0.8; NPV = 0.84–0.87; LR+ = 5.6–7.68; LR– = 0.36–0.29), performing even better (AUC = 0.9–0.91) at identifying cognitive impairment among patients (Se = 0.73–1; Sp = 0.86–0.71; PPV = 0.79–0.71; NPV = 0.82–1; LR+ =5.13–3.5; LR– = 0.31–0) and comparably to the UHDRS-II (89% vs. 85% of accuracy, respectively; p = 0.46).DiscussionIn HD patients, the FAB is highly feasible for cognitive screening aims, being also featured by optimal intrinsic/post-test diagnostics within both case-control and case-finding settings.

BackgroundThis study aimed at testing the ability of the frontal assessment battery (FAB) to differentiate between patients with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease (AD), as well as comparing its discriminative power to that of the Mini-Mental State Examination (MMSE).MethodsThe present retrospective cohort included N = 107 Aβ-positive patients diagnosed with either MCI due to AD (N = 40) or probable AD dementia (ADD; N = 67). A two-step multiple logistic regression (MLR) was run to predict an MCI vs. ADD diagnosis based on FAB scores. Within the baseline step, demographics, disease duration, MMSE scores, and information on cognitive phenotypes were entered, with the FAB being added within the second step. Receiver-operating characteristics analyses were also run to derive intrinsic and post-test diagnostics.ResultsWithin the baseline MLR step, only lower MMSE scores predicted the occurrence of ADD; by adding the FAB, which likewise was able to discriminate between MCI and ADD (p = 0.016), a significant increase in model fit was detected (p = 0.007). The diagnostic efficiency of the FAB (AUC = 0.85) was comparable (p = 0.583) to that of the MMSE (AUC = 0.82), also yielding good intrinsic and post-test diagnostics, which were comparable to those of the MMSE.DiscussionThe FAB is a diagnostically sound screener to discriminate between MCI and ADD, independently of patients’ overall cognitive profile. In doing so, the FAB is comparable to the MMSE, and the complementation of the latter with the former is advisable in order to increase the accuracy in differentiating between MCI and ADD within screening sessions.

Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%–5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers’ germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.

BackgroundThe present study aimed at (1) assessing the diagnostic properties of the Montreal Cognitive Assessment (MoCA) in non-demented ALS patients and at (2) exploring the MoCA administrability according to motor-functional status.MaterialsN = 348 patients were administered the MoCA and Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Administrability rates and prevalence of defective MoCA scores were compared across King’s and Milano-Torino clinical stages. Regression models were run to test whether the non-administrability of the MoCA and a defective score on it were predicted, net of the ECAS-Total, by disease duration, ALS Functional Rating Scale-Revised (ALSFRS-R) and progression rate, computed as (48: ALSFRS-R)/disease duration. Intrinsic and post-test diagnostics were tested against a below-cut-off ECAS-total score.ResultsThe 79.9% of patients successfully underwent the MoCA, whose administrability rates decreased with advanced clinical stages, at variance with its defective score prevalence. The probability of the FAB not being administrable was predicted only by lower ALSFRS-R-bulbar and-upper-limb scores; no motor features, but the ECAS-Total, predicted a defective MoCA performance. The MoCA showed high accuracy (AUC = 0.82) and good intrinsic and post-test properties—being slightly more specific than sensitive.DiscussionIn non-demented ALS patients, the MoCA is featured by optimal diagnostics as a screener for cognitive impairment, especially for ruling-out its occurrence, as long as patients are in the early stages of the disease and have sufficiently spared bulbar and upper-limb functions.

BackgroundThis study aims at reviewing, within the framework of motor neuron disease-frontotemporal degeneration (MND-FTD)-spectrum disorders, evidence on the co-occurrence between primary progressive aphasia (PPA) and MND in order to profile such a complex at pathological, genetic and clinical levels.MethodsThis review was pre-registered (osf.io/ds8m4) and performed in accordance with the 2020 PRISMA guidelines. Case reports/series and group studies were included if addressing (1) progressive non-fluent aphasia (PNFA) or semantic dementia (SD) with MND or (2) MND patients with co-morbid PNFA/SD.ResultsOut of 546 initial records, 56 studies were included. As to case reports/series (N = 35), which included 61 PPA-MND patients, the following findings yielded: (1) PNFA is more frequent than SD in PPA-MND; (2) in PPA-MND, the most prevalent motor phenotypes are amyotrophic lateral sclerosis and predominant-upper MND, with bulbar involvement being ubiquitous; (3) extrapyramidal features are moderately frequent in PPA-MND; (4) PPA-MND patients usually display frontotemporal, left-greater-than-right involvement; (5) TDP-43-B is the typical pathological substrate of PPA-MND; (6) TBK1 mutations represent the most frequent genetic risk factors for PPA-MND.As to group studies, including 121 patients, proportional meta-analytic procedures revealed that: (1) the lifetime prevalence of MND in PPA is 6%; (2) PPA occurs in 19% of patients with co-morbid MND and FTD; (3) MND is more frequent in PNFA (10%) than in SD patients (3%).DiscussionInsights herewith delivered into the clinical, neuropathological and genetic features of PPA-MND patients prompt further investigations aimed at improving clinical practice within the MND-FTD spectrum.

This study aims to evaluate the erythrocyte sedimentation rate (ESR) in Leishmania infantum-seropositive dogs compared with healthy dogs and to assess the existence of a correlation between ESR and clinical form of Canine leishmaniosis (CanL) as well as acute phase proteins (APPs). From October 2021 to January 2022, dogs were recruited in this study if L. infantum-seropositive by enzyme-linked immunoassay and classified as exposed or affected by a CanL active form based on physical examination, clinical score, and laboratory results [i.e., complete blood count, biochemical panel such as C-reactive protein (CRP) and serum ferritin, serum protein electrophoresis, and fibrinogen concentration measurement]. To evaluate the ESR of the dogs, a point-of-care device was used with a reference interval of 0–10 mm/h. Moreover, the ESR evaluation has been also performed in clinically healthy dogs, as control group. Thirty-six L. infantum-seropositive dogs [i.e., exposed (n = 10) and affected by CanL active form (n = 26)] were included in the study. Twenty-two healthy dogs were also enrolled. The mean value of ESR in dogs affected by a CanL active form was significantly higher than in exposed and healthy dogs (p < 0.0001). The ESR level was increased in 92% of dogs with CanL active form while positive APPs such as CRP, fibrinogen, and serum ferritin were increased only in 46, 48, and 58% of the animals, respectively. In exposed dogs, the ESR level was increased in 40% of cases. In dogs with active form, a significant positive correlation between ESR and total proteins, globulins, CRP, and fibrinogen, as well as a significant negative correlation between ESR and hematocrit, hemoglobin, and albumin/globulin ratio were detected. This study provides for the first-time data on ESR in L. infantum-seropositive dogs demonstrating dogs affected by a CanL active form have the highest ESR level and the majority of these dogs presented an increased ESR compared with exposed and healthy dogs. The evaluation of ESR by a point-of-care device proved to be a simple, inexpensive, and ready-to-use benchtop tool and ESR can be considered a helpful and timely inflammatory biomarker for the diagnosis of a CanL active form.

Isolated complex I deficiency represents the most common mitochondrial respiratory chain defect involved in mitochondrial disorders. Among these, the mitochondrial DNA (mtDNA) m.13513G>A pathogenic variant in the NADH dehydrogenase 5 subunit gene (MT-ND5) has been associated with heterogenous manifestations, including phenotypic overlaps of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, Leigh syndrome, and Leber’s hereditary optic neuropathy (LHON). Interestingly, this specific mutation has been recently described in patients with adult-onset nephropathy. We, here, report the unique combination of LHON, nephropathy, sensorineural deafness, and subcortical and cerebellar atrophy in association with the m.13513G>A variant.

Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis.

In the Medicago genus, triterpene saponins are a group of bioactive compounds extensively studied for their different biological and pharmaceutical properties. In this work, the CRISPR/Cas9-based approach with two single-site guide RNAs was used in Medicago truncatula (barrel medic) to knock-out the CYP93E2 and CYP72A61 genes, which are responsible for the biosynthesis of soyasapogenol B, the most abundant soyasapogenol in Medicago spp. No transgenic plants carrying mutations in the target CYP72A61 gene were recovered while fifty-two putative CYP93E2 mutant plant lines were obtained following Agrobacterium tumefaciens-mediated transformation. Among these, the fifty-one sequenced plant lines give an editing efficiency of 84%. Sequencing revealed that these lines had various mutation patterns at the target sites. Four T0 mutant plant lines were further selected and examined for their sapogenin content and plant growth performance under greenhouse conditions. The results showed that all tested CYP93E2 knock-out mutants did not produce soyasapogenols in the leaves, stems and roots, and diverted the metabolic flux toward the production of valuable hemolytic sapogenins. No adverse influence was observed on the plant morphological features of CYP93E2 mutants under greenhouse conditions. In addition, differential expression of saponin pathway genes was observed in CYP93E2 mutants in comparison to the control. Our results provide new and interesting insights into the application of CRISPR/Cas9 for metabolic engineering of high-value compounds of plant origin and will be useful to investigate the physiological functions of saponins in planta.

Several challenges to guarantee medical care have been exposed during the current COVID-19 pandemic. Although the literature has shown some robotics applications to overcome the potential hazards and risks in hospital environments, the implementation of those developments is limited, and few studies measure the perception and the acceptance of clinicians. This work presents the design and implementation of several perception questionnaires to assess healthcare provider's level of acceptance and education toward robotics for COVID-19 control in clinic scenarios. Specifically, 41 healthcare professionals satisfactorily accomplished the surveys, exhibiting a low level of knowledge about robotics applications in this scenario. Likewise, the surveys revealed that the fear of being replaced by robots remains in the medical community. In the Colombian context, 82.9% of participants indicated a positive perception concerning the development and implementation of robotics in clinic environments. Finally, in general terms, the participants exhibited a positive attitude toward using robots and recommended them to be used in the current panorama.

More than 30 years after discovering Leber's hereditary optic neuropathy (LHON) as the first maternally inherited disease associated with homoplasmic mtDNA mutations, we still struggle to achieve effective therapies. LHON is characterized by selective degeneration of retinal ganglion cells (RGCs) and is the most frequent mitochondrial disease, which leads young people to blindness, in particular males. Despite that causative mutations are present in all tissues, only a specific cell type is affected. Our deep understanding of the pathogenic mechanisms in LHON is hampered by the lack of appropriate models since investigations have been traditionally performed in non-neuronal cells. Effective in-vitro models of LHON are now emerging, casting promise to speed our understanding of pathophysiology and test therapeutic strategies to accelerate translation into clinic. We here review the potentials of these new models and their impact on the future of LHON patients.

Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.

In the year 2000, the discovery of OPA1 mutations as causative for dominant optic atrophy (DOA) was pivotal to rapidly expand the field of mitochondrial dynamics and describe the complex machinery governing this pathway, with a multitude of other genes and encoded proteins involved in neurodegenerative disorders of the optic nerve. OPA1 turned out to be a much more complex protein than initially envisaged, connecting multiple pathways beyond its strict role in mitochondrial fusion, such as sensing of OXPHOS needs and mitochondrial DNA maintenance. As a consequence, an increasing need to investigate OPA1 functions at multiple levels has imposed the development of multiple tools and models that are here reviewed. Translational mitochondrial medicine, with the ultimate objective of translating basic science necessary to understand pathogenic mechanisms into therapeutic strategies, requires disease modeling at multiple levels: from the simplest, like in yeast, to cell models, including the increasing use of reprogrammed stem cells (iPSCs) from patients, to animal models. In the present review, we thoroughly examine and provide the state of the art of all these approaches.

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

A major aim of the present study was to examine the relationship between time perspective, i.e., habitual ways of relating to the past, present, and future, and sleep quality. A second aim was to test a model by which the expected negative relationship between deviation from a balanced time perspective (DBTP), a measure taking temporal biases across all three time frames into account, and life satisfaction was mediated by poor sleep quality. To these ends, a sample of young adults (N = 386) completed a version of the Zimbardo Time Perspective Inventory (S-ZTPI), Pittsburg Sleep Quality Index (PSQI), and the Satisfaction with Life Scale (SWLS). A measure of chronotype was in addition included for control purposes. Bivariate analyses revealed that the S-ZTPI subscales Past Negative, Future Negative and Present Fatalistic were associated with poorer sleep quality (higher PSQI scores), with significant associations in the opposite direction for Past Positive and Future Positive. However, DBTP was the strongest predictor of (poorer) sleep quality, suggesting that time perspective biases have an additive effect on sleep quality. Regression analyses with PSQI as the dependent variable and all six ZTPI subscales as the predictors indicated that time perspective accounted for about 20% of the variance in sleep quality (17% beyond chronotype), with Past Negative, Past Positive, and Future Negative as the unique predictors. The results additionally confirmed a strong relationship between DBTP and life satisfaction. Finally, data were consistent with the hypothesis that the association of DBTP and life satisfaction is mediated, in part, by sleep quality. Taken together, the results confirmed a substantial link between time perspective sleep-related problems, factors that may have a negative impact on life satisfaction.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease causing severe bilateral visual loss, typically in young adults. The disorder is commonly caused by one of three primary point mutations in mitochondrial DNA, but a number of other rare mutations causing or associated with the clinical syndrome of LHON have been reported. The mutations in LHON are almost exclusively located in genes encoding subunits of complex I in the mitochondrial respiratory chain. Here we report two patients, a mother and her son, with the typical LHON phenotype. Genetic investigations for the three common mutations were negative, instead we found a new and previously unreported mutation in mitochondrial DNA. This homoplasmic mutation, m.13345G>A, is located in the MT-ND5 gene, encoding a core subunit in complex I in the mitochondrial respiratory chain. Investigation of the patients mitochondrial respiratory chain in muscle found a mild defect in the combined activity of complex I+III. In the literature six other mutations in the MT-ND5 gene have been associated with LHON and by this report a new putative mutation in the MT-ND5 can be added.

Recent experimental results on spike avalanches measured in the urethane-anesthetized rat cortex have revealed scaling relations that indicate a phase transition at a specific level of cortical firing rate variability. The scaling relations point to critical exponents whose values differ from those of a branching process, which has been the canonical model employed to understand brain criticality. This suggested that a different model, with a different phase transition, might be required to explain the data. Here we show that this is not necessarily the case. By employing two different models belonging to the same universality class as the branching process (mean-field directed percolation) and treating the simulation data exactly like experimental data, we reproduce most of the experimental results. We find that subsampling the model and adjusting the time bin used to define avalanches (as done with experimental data) are sufficient ingredients to change the apparent exponents of the critical point. Moreover, experimental data is only reproduced within a very narrow range in parameter space around the phase transition.

Purpose: The photopic negative response (PhNR) is an electrophysiological method that provides retinal ganglion cell function assessment using full-field stimulation that does not require clear optics or refractive correction. The purpose of this study was to assess ganglion cell function by PhNR in affected and asymptomatic carriers from Brazilian families with LHON.Methods: Individuals either under suspicion or previously diagnosed with LHON and their family members were invited to participate in this cross-sectional study. Screening for the most frequent LHON mtDNA mutations was performed. Visual acuity, color discrimination, visual fields, pattern-reversal visual evoked potentials (PRVEP), full-field electroretinography and PhNR were tested. A control group of healthy subjects was included. Full-field ERG PhNR were recorded using red (640 nm) flashes at 1 cd.s/m2, on blue (470 nm) rod saturating background. PhNR amplitude (μV) was measured using baseline-to-trough (BT). Optical coherence tomography scans of both the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were measured. PhNR amplitudes among affected, carriers and controls were compared by Kruskal-Wallis test followed by post-hoc Dunn test. The associations between PhNR amplitude and OCT parameters were analyzed by Spearman rank correlation.Results: Participants were 24 LHON affected patients (23 males, mean age=30.5 ± 11.4 yrs) from 19 families with the following genotype: m.11778G>A [N = 15 (62%), 14 males]; m.14484T>C [N = 5 (21%), all males] and m.3460G>A [N = 4 (17%), all males] and 14 carriers [13 females, mean age: 43.2 ± 13.3 yrs; m.11778G>A (N = 11); m.3460G>A (N = 2) and m.14484T>C (N = 1)]. Controls were eight females and seven males (mean age: 32.6 ± 11.5 yrs). PhNR amplitudes were significantly reduced (p = 0.0001) in LHON affected (−5.96 ± 3.37 μV) compared to carriers (−16.53 ± 3.40 μV) and controls (−23.91 ± 4.83; p < 0.0001) and in carriers compared to controls (p = 0.01). A significant negative correlation was found between PhNR amplitude and total macular ganglion cell thickness (r = −0.62, p < 0.05). Severe abnormalities in color discrimination, visual fields and PRVEPs were found in affected and subclinical abnormalities in carriers.Conclusions: In this cohort of Brazilian families with LHON the photopic negative response was severely reduced in affected patients and mildly reduced in asymptomatic carriers suggesting possible subclinical abnormalities in the latter. These findings were similar among pathogenic mutations.

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

Biallelic TYMP variants result in the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a juvenile-onset disorder with progressive course and fatal outcome. Milder late-onset (>40 years) form has been rarely described. Gene panel sequencing in a cohort of 60 patients featuring muscle accumulation of mitochondrial DNA (mtDNA) deletions detected TYMP defects in three subjects (5%), two of them with symptom onset in the fifth decade. One of the patients only displayed ptosis and ophthalmoparesis. Biochemical and molecular studies supported the diagnosis. Screening of TYMP is recommended in adult patients with muscle mtDNA instability, even in the absence of cardinal MNGIE features.

Alexander disease (AxD) is a rare, autosomal dominant neurological disorder. Three clinical subtypes are distinguished based on age at onset: infantile (0–2 years), juvenile (2–13 years), and adult (>13 years). The three forms differ in symptoms and prognosis. Rapid neurological decline with a fatal course characterizes the early-onset forms, while symptoms are milder and survival is longer in the adult forms. Currently, the sole known cause of AxD is mutations in the GFAP gene, which encodes a type III intermediate filament protein that is predominantly expressed in astrocytes. A wide spectrum of GFAP mutations comprising point mutations, small insertions, and deletions is associated with the disease. The genotype-phenotype correlation remains unclear. The considerable heterogeneity in severity of disease among individuals carrying identical mutations suggests that other genetic or environmental factors probably modify age at onset or progression of AxD. Describing new cases is therefore important for establishing reliable genotype-phenotype correlations and revealing environmental factors able to modify age at onset or progression of AxD. We report the case of a 54-year-old Caucasian woman, previously diagnosed with ovarian cancer and treated with surgery and chemotherapy, who developed dysarthria, ataxia, and spastic tetraparesis involving mainly the left side. Cerebral and spinal magnetic resonance imaging (MRI) revealed a peculiar tadpole-like atrophy of the brainstem. Genetic analysis of the GFAP gene detected a heterozygous mutation in exon 1 (c.219G>C), resulting in an amino acid exchange from methionine to isoleucine at codon 73 (p.M73I). The expression of this mutant in vitro affected the formation of the intermediate filament network. Thus, we have identified a new GFAP mutation in a patient with an adult form of AxD.

ObjectiveA complex relationship between neuropsychiatric symptoms, personality traits and neurochemical changes in patients with Parkinson’s disease (PD) has been highlighted in the past several decades. In particular, a specific Parkinson personality with obsessive traits has been described. However, despite the great amount of anecdotal evidence, this aspect, together with its neurobiological, psychological and clinical correlates, are still not clearly defined. Therefore, we performed a case-control study in order to investigate the presence and rate of obsessive personality traits in PD patients within the theoretical framework of cognitive-constructivist model. Moreover, the relationship between PD personality and clinical, psychological and quality of life (QoL) aspects in PD were investigated.MethodsFifty-one non-demented patients with probable or possible PD (not demented) were recruited at the inpatient-outpatient San Luca Hospital, IRCCS Istituto Auxologico Italiano. Control group was composed by forty-eight age- and education-matched healthy volunteers. Patients underwent a neurological investigation including Unified PD Rating Scale (UPDRS), Modified Hoehn and Yahr and Schwab and England staging scales. The following psychological questionnaires were administered to the overall sample: Personal Meaning Questionnaire (PMQ), State-Trait Anxiety Inventory-Form Y (STAI-Y), Beck Depression Inventory (BDI), Symptom Check List-90 (SCL-90), Short-Form Health Survey-36 (SF-36).ResultsNo significant differences in personality styles were observed in PD patients and controls, with a prevalence of phobic personal meaning organization (PMO) in both groups. However, PD patients showed more anxiety, depression and obsessive-compulsive (OC) symptoms than controls at the psychological questionnaires, as well as poorer QoL levels. The intensity of personality traits, and in particular for the obsessive personality style, were negatively associated with QoL and positively with disease severity. No significant relationships were observed between personality and other clinical aspects, such as side of onset and disease duration.ConclusionParkinson’s disease patients did not show a different personality profile according to the cognitive-constructivist model with respect to controls. However, in this population, a general enhancement in the tendency to codify experience by means of specific cognitive and emotional patterns was associated to disease progression and to a poorer QoL.

Prior research indicates that time perspective (TP; views of past, present, and future) is related to decision-making style. By contrast, no prior study considered relations between TP and decision-making competence. We therefore investigated associations between dimensions of the Swedish Zimbardo Time Perspective Inventory (S-ZTPI) and performance on the Adult Decision-Making Competence (A-DMC) battery in a sample of older adults (60–90 years, N = 346). A structural equation model involving four A-DMC components as indicators of a general DMC factor and the six TP dimensions as the predictors revealed a significant negative association between the Present Fatalistic dimension and DMC. Given that age-related differences were apparent in DMC and that Present Fatalistic orientation increased with age, we tested a model by which the age-related differences in DMC were mediated by age-related differences in Present Fatalistic attitudes and in working memory. The results were consistent with full mediation of the age effects, with Present Fatalistic and working memory jointly accounting for a substantial amount of the variance in DMC (51%). The finding that DMC among older adults, in particular more cognitively demanding aspects such as applying decision rules, can be undermined by increased present fatalistic attitudes and declines in working memory is discussed in terms of theoretical frameworks highlighting the contribution of both motivational and cognitive factors to effective decision making.

Synchronization is one of the brain mechanisms allowing the coordination of neuronal activity required in many cognitive tasks. Anticipated Synchronization (AS) is a specific type of out-of-phase synchronization that occurs when two systems are unidirectionally coupled and, consequently, the information is transmitted from the sender to the receiver, but the receiver leads the sender in time. It has been shown that the primate cortex could operate in a regime of AS as part of normal neurocognitive function. However it is still unclear what is the mechanism that gives rise to anticipated synchronization in neuronal motifs. Here, we investigate the synchronization properties of cortical motifs on multiple scales and show that the internal dynamics of the receiver, which is related to its free running frequency in the uncoupled situation, is the main ingredient for AS to occur. For biologically plausible parameters, including excitation/inhibition balance, we found that the phase difference between the sender and the receiver decreases when the free running frequency of the receiver increases. As a consequence, the system switches from the usual delayed synchronization (DS) regime to an AS regime. We show that at three different scales, neuronal microcircuits, spiking neuronal populations and neural mass models, both the inhibitory loop and the external current acting on the receiver mediate the DS-AS transition for the sender-receiver configuration by changing the free running frequency of the receiver. Therefore, we propose that a faster internal dynamics of the receiver system is the main mechanism underlying anticipated synchronization in brain circuits.

Background: Osteoarthritis of the knee (kOA) is a chronic, progressive, degenerative health condition that contributes to the imbalance between the synthesis and destruction of articular cartilage. Recently, whole body vibration (WBV) training has been recommended as an effective alternative for strength training in elderly people, and various physiological effects are obtained in response to exercise performed on a vibratory platform, such as an increase in muscle activation and improved muscle performance. However, the effects of WBV particularly on the strength of the quadriceps muscle and neuronal plasticity are unknown.Objective: The aim of this study was to evaluate the effects of adding WBV to squat training on the isometric quadriceps muscle strength (IQMS) and the plasma levels of brain-derived neurotrophic factor (BDNF) in elderly woman with kOA.Methods: Fifteen elderly women ≥65 years of age with kOA were randomized into two interventions: (1) the vibration group (VG), in which participants performed squat exercise training in association with WBV or (2) the exercise group (EG), in which participants performed squat exercise training without vibration, for 12 weeks 3×/week.Results: Compared to the EG group, the VG group demonstrated a significantly greater delta (Δ) in IQMS values (IC95% 0.43–7.06; p ≤ 0.05) and in Δ BDNF plasma levels (IC95% −32.51 to 4.217; p ≤ 0.05) after the intervention period. There was an association between increase of Δ BDNF plasma levels and increase of Δ IQMS (β = 0.57; R2 = 0.32; p = 0.03).Conclusion: The addition of WBV to squat exercise training improves lower limb muscle performance in elderly women with kOA. These findings suggest that the improvement in muscle performance is related to neuromuscular adaptations induced by WBV.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03918291.

Hidden auditory neuropathy is characterized by reduced performances in challenging auditory tasks with the preservation of hearing thresholds, resulting from diffuse loss of cochlear inner hair cell (IHC) synapses following primary degeneration of unmyelinated terminals of auditory fibers. We report the audiological and electrophysiological findings collected from 10 members (4 males, 6 females) of a large Italian family affected by dominant optic atrophy, associated with the OPA8 locus, who complained of difficulties in understanding speech in the presence of noise. The patients were pooled into two groups, one consisting of 4 young adults (19–50 years) with normal hearing thresholds, and the other made up of 6 patients of an older age (55–72 years) showing mild hearing loss. Speech perception scores were normal in the first group and decreased in the second. Otoacoustic emissions (OAEs) and cochlear microphonics (CMs) recordings were consistent with preservation of outer hair cell (OHC) function in all patients, whereas auditory brainstem responses (ABRs) showed attenuated amplitudes in the first group and severe abnormalities in the second. Middle ear acoustic reflexes had delayed peak latencies in all patients in comparison with normally hearing individuals. Transtympanic electrocochleography (ECochG) recordings in response to 0.1 ms clicks at intensities from 120 to 60 dB peak equivalent SPL showed a reduction in amplitude of both summating potential (SP) and compound action potential (CAP) together with delayed CAP peak latencies and prolonged CAP duration in all patients in comparison with a control group of 20 normally hearing individuals. These findings indicate that underlying the hearing impairment in OPA8 patients is hidden AN resulting from diffuse loss of IHCs synapses. At an early stage the functional alterations only consist of abnormalities of ABR and ECochG potentials with increased latencies of acoustic reflexes, whereas reduction in speech perception scores become apparent with progression of the disease. Central mechanisms increasing the cortical gain are likely to compensate for the reduction of cochlear input.

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive RGCs that mediate many relevant non-image forming functions of the eye, including the pupillary light reflex, through the projections to the olivary pretectal nucleus. In particular, the post-illumination pupil response (PIPR), as evaluated by chromatic pupillometry, can be used as a reliable marker of mRGC function in vivo. In the last years, pupillometry has become a promising tool to assess mRGC dysfunction in various neurological and neuro-ophthalmological conditions. In this review we will present the most relevant findings of pupillometric studies in glaucoma, hereditary optic neuropathies, ischemic optic neuropathies, idiopathic intracranial hypertension, multiple sclerosis, Parkinson's disease, and mood disorders. The use of PIPR as a marker for mRGC function is also proposed for other neurodegenerative disorders in which circadian dysfunction is documented.

This study examined the extent to which individual differences in time perspective, i.e., habitual way of relating to the personal past, present, and future, are associated with sleep quality and daytime sleepiness in a sample of older adults. The participants (N = 437, 60–90 years) completed the Karolinska Sleep Questionnaire (KSQ), a the Swedish version of the Zimbardo Time Perspective Inventory (S-ZTPI), and two ratings of subjective well-being (SWB) (life satisfaction, happiness). Based on established relationships between dimension of time perspective and other variables (e.g., depression) and relations between negative retrospection (rumination) and negative prospection (worry) in prior studies, we expected higher scores on Past Negative and Future Negative to be linked to poor sleep quality and (indirectly) increased daytime sleepiness. Moreover, we examined the possibility that variations in perceived sleep and sleepiness during the day mediates the expected association between an aggregate measure of deviations from a so called balanced time perspective (DBTP) and SWB. In regression analyses controlling for demographic factors (age, sex, and work status), higher scores on Past Negative and Future Negative predicted poorer sleep quality and higher levels of daytime sleepiness. Additionally, most of the association between time perspective and daytime sleepiness was accounted for by individual differences in sleep quality. Finally, structural equation modeling yielded results consistent with the hypothesis that variations in sleep mediate part of the negative relationship between DBTP and SWB. Given that good sleep is essential to multiple aspects of health, future studies evaluating relationships between time perspective and adverse health outcomes should consider sleep quality as a potentially contributing factor.

Introduction: The observed association between depressive symptoms and cognitive performances has not been previously clarified in patients with amyotrophic lateral sclerosis (pALS). In fact, the use of cognitive measures often not accommodating for motor disability has led to heterogeneous and not conclusive findings about this issue. The aim of the present study was to evaluate the relationship between cognitive and depressive/anxiety symptoms by means of the recently developed Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a brief assessment specifically designed for pALS.Methods: Sample included 168 pALS (114 males, 54 females); they were administered two standard cognitive screening tools (FAB; MoCA) and the ECAS, assessing different cognitive domains, including ALS-specific (executive functions, verbal fluency, and language tests) and ALS non-specific subtests (memory and visuospatial tests). Two psychological questionnaires for depression and anxiety (BDI; STAI/Y) were also administered to patients. Pearson’s correlation coefficient was used to assess the degree of association between cognitive and psychological measures.Results: Depression assessment negatively correlated with the ECAS, more significantly with regard to the executive functions subdomain. In particular, Sentence Completion and Social Cognition subscores were negatively associated with depression levels measured by BDI total score and Somatic-Performance symptoms subscore. Conversely, no significant correlations were observed between depression level and cognitive functions as measured by traditional screening tools for frontal abilities (FAB) and global cognition (MoCA) assessment. Finally, no significant correlations were observed between state/trait anxiety and the ECAS.Discussion and conclusion: This represents the first study focusing on the relationship between cognitive and psychological components in pALS by means of the ECAS, the current gold standard for ALS cognitive-behavioral assessment. If confirmed by further investigations, the observed association between depression and executive functions suggests the need for a careful screening and treatment of depression, to avoid overestimation of cognitive involvement and possibly improve cognitive performances in ALS.

This study examined the relation between perceived stress and time perspective (views of past, present, future) in a population-based sample of older adults (65–90 years, N = 340). The Perceived Questionnaire (PSQ index) was used to measure stress and the Swedish version of the Zimbardo Time Perspective Inventory (S-ZTPI) was used to operationalize time perspective. Unlike the original inventory, S-ZTPI separates positive and negative aspects of a future time perspective and we hypothesized that the Future Negative (FN) scale would be important to account for variations in stress. Additionally, associations with Catechol-O-methyltransferase (COMT) Val158Met polymorphism were examined, motivated by prior associations of this single nucleotide polymorphism (SNP) with stress (or “anxiety”) related personality traits. In line with the hypotheses, FN was the strongest predictor of PSQ index scores in multiple regression analyses. In a related vein, the dichotomization of the unitary Future scale increased the association between PSQ scores and a measure of deviations from a balanced time perspective, i.e., the difference between a proposed optimal and observed ZTPI profile. Finally, higher levels of stress as well as higher scores on FN were observed in COMT Val/Val carriers, at least among men. This suggests a shared dopaminergic genetic influence on these variables. Collectively, the results demonstrate that perceived stress is closely linked to time perspective and highlight the need to take negative aspects of a future temporal orientation into account to understand this relation.

Many neurodegenerative disorders, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), are characterized by loss of retinal ganglion cells (RGCs) as part of the neurodegenerative process. Optical coherence tomography (OCT) studies demonstrated variable degree of optic atrophy in these diseases. However, the pattern of degenerative changes affecting the optic nerve (ON) can be different. In particular, neurodegeneration is more evident for magnocellular RGCs in AD and multiple system atrophy with a pattern resembling glaucoma. Conversely, in PD and Huntington’s disease, the parvocellular RGCs are more vulnerable. This latter pattern closely resembles that of mitochondrial optic neuropathies, possibly pointing to similar pathogenic mechanisms. In this review, the currently available evidences on OCT findings in these neurodegenerative disorders are summarized with particular emphasis on the different pattern of RGC loss. The ON degeneration could become a validated biomarker of the disease, which may turn useful to follow natural history and possibly assess therapeutic efficacy.

Many studies support the existence of an association between type 2 diabetes (T2DM) and Alzheimer’s disease (AD). In AD, in addition to brain, a number of peripheral tissues and cells are affected, including red blood cell (RBC) and because there are currently no reliable diagnostic biomarkers of AD in the blood, a gradually increasing attention has been given to the study of RBC’s alterations. Recently it has been evidenced in diabetes, RBC alterations superimposable to the ones occurring in AD RBC. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of RBC’s alterations and vice versa. Once again this represents a further evidence of a shared pathway between AD and T2DM. The present review summarizes the two disorders, highlighting the role of RBC in the postulated common biochemical links, and suggests RBC as a possible target for clinical trials.

There is increasing awareness on the role played by circadian rhythm abnormalities in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The characterization of the circadian dysfunction parallels the mounting evidence that the hallmarks of neurodegeneration also affect the retina and frequently lead to loss of retinal ganglion cells (RGCs) and to different degrees of optic neuropathy. In the RGC population, there is the subgroup of cells intrinsically photosensitive and expressing the photopigment melanopsin [melanopsin-containing retinal ganglion cells (mRGCs)], which are now well known to drive the entrainment of circadian rhythms to the light–dark cycles. Thus, the correlation between the pathological changes affecting the retina and mRGCs with the circadian imbalance in these neurodegenerative diseases is now clearly emerging, pointing to the possibility that these patients might be amenable to and benefit from light therapy. Currently, this connection is better established for AD and PD, but the same scenario may apply to other neurodegenerative disorders, such as Huntington’s disease. This review highlights similarities and differences in the retinal/circadian rhythm axis in these neurodegenerative diseases posing a working frame for future studies.