MITOCHONDRIAL MEMORY AT SKELETAL MUSCLE LEVEL

Mitochondria are key components of skeletal muscles as they provide the energy required for almost all cellular activities. Different forms of exercise training have been associated with mitochondrial adaptations, such as increased mitochondrial content and function, and enhanced mitochondrial biogenesis, as well as improved endurance performance. High-intensity interval training and sprint interval training have been demonstrated to be the most effective training modalities to induce mitochondrial adaptations. However, surprisingly, greater changes in mitochondrial content and biogenesis were also observed after repeated resistance training interventions separated by prolonged detraining. This mechanism, defined muscle memory, has been well established for hypertrophy and skeletal muscle growth in response to resistance training and it has been related to the retention of acquired myonuclei or epigenetic modifications. Thereby, even mitochondrial adaptations might be influenced by muscle memory, but it remains to be explored whether repeated endurance training interventions can rely on the same mechanism. Therefore, the overarching aim of the present thesis was to investigate the potential presence of mitochondrial memory in response to repeated high- intensity endurance training interventions. An experimental design composed of two periods of 8 weeks of interval training interspersed by 3 months of detraining was conducted on murine model and humans. In mice, maximal running velocity (Vmax) by graded exercise test (GXT) on a rodent treadmill. In addition, biomarkers of mitochondrial biogenesis and content, and fusion-fission mitochondrial key factors were analyzed on gastrocnemius muscle by western Blot. Results revealed that endurance performance improved to a greater extent after retraining than training. This functional adaptation was supported by a larger mitochondrial content resulting from a more pronounced mitochondrial biogenesis response after retraining. Mitochondrial dynamics were shifted mainly towards fusion, suggesting larger and more elongated mitochondria and finally, the retraining period elicited increased mitophagic flux, which, associated with a smaller increment in the amount of respiratory chain complexes, suggests an improvement in clearance of damaged mitochondria in order to ensure healthier mitochondria and more efficient respiratory function. In humans, maximal aerobic capacity and peak power output were measured and muscle sample from vastus lateralis was used for mitochondrial respiration and epigenetic analysis. Mitochondrial function resulted in a greater improvement after high intensity aerobic stimulus when previous exposure to an identical stimulus has been occurred separated by long-term period of stimulus cessation. The underlying mechanism could reside in epigenetic modifications induced by interval training which led to DNA hypomethylation. Two memory profiles were highlighted at epigenetic level characterized by retention of hypomethylation even during the prolonged detraining period and involving differentially methylated regions related with genes implicated in skeletal muscle metabolic pathways. Overall, these studies provided evidence for a skeletal muscle memory mechanism, specifically at mitochondrial level, elicited by high-intensity aerobic training that affects muscle aerobic phenotype initiating at the epigenetic level and extends upstream to affect mitochondrial function and endurance performance

Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features

Because of its involvement in the progression of several malignant tumors, the histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target in modern medicinal chemistry research. We report on the discovery of two classes of noncovalent inhibitors displaying unique structural features. The antibiotics polymyxins bind at the entrance of the substrate cleft, where their highly charged cyclic moiety interacts with a cluster of positively charged amino acids. The same site is occupied by quinazoline-based compounds, which were found to inhibit the enzyme through a most peculiar mode because they form a pile of five to seven molecules that obstruct access to the active center. These data significantly indicate unpredictable strategies for the development of epigenetic inhibitors

CSF alpha-synuclein aggregates by seed amplification and clinical presentation of AD

Introduction: Accumulating evidence suggests that α-synuclein (αSyn) can modulate Alzheimer's disease (AD) pathology. The aim of this study was to evaluate the prevalence and clinical features associated with cerebrospinal fluid (CSF) αSyn detected by seed amplification assay (SAA) in AD. Methods: Eighty AD patients with CSF AT(N) biomarker positivity (mean age 70.3 ± 7.3 years) and 28 non-AD age-matched controls were included. All subjects underwent standardized clinical assessment; CSF αSyn aggregates were detected by SAA. Results: CSF was αSyn-SAA positive (αSyn+) in 36/80 AD patients (45%) and in 2/28 controls (7.1%). AD αSyn+ and αSyn- patients were comparable for age, disease severity, comorbidity profile, and CSF core biomarkers. AD αSyn+ presented a higher prevalence of atypical phenotypes and symptoms. Conclusions: Our findings demonstrate that concomitant CSF αSyn pathology is present in a significant proportion of AD patients starting in the early stages and can affect clinical presentation. Longitudinal studies are warranted to evaluate the significance for the disease course

Metabolic connectivity of resting-state networks in alpha synucleinopathies, from prodromal to dementia phase

Previous evidence suggests that the derangement of large-scale brain networks reflects structural, molecular, and functional mechanisms underlying neurodegenerative diseases. Although the alterations of multiple large-scale brain networks in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are reported, a comprehensive study on connectivity reconfiguration starting from the preclinical phase is still lacking. We aimed to investigate shared and disease-specific changes in the large-scale networks across the Lewy Bodies (LB) disorders spectrum using a brain metabolic connectivity approach. We included 30 patients with isolated REM sleep behavior disorder (iRBD), 28 with stable PD, 30 with DLB, and 30 healthy controls for comparison. We applied seed-based interregional correlation analyses (IRCA) to evaluate the metabolic connectivity in the large-scale resting-state networks, as assessed by [18F]FDG-PET, in each clinical group compared to controls. We assessed metabolic connectivity changes by applying the IRCA and specific connectivity metrics, such as the weighted and unweighted Dice similarity coefficients (DC), for the topographical similarities. All the investigated large-scale brain resting-state networks showed metabolic connectivity alterations, supporting the widespread involvement of brain connectivity within the alpha-synuclein spectrum. Connectivity alterations were already evident in iRBD, severely affecting the posterior default mode, attentive and limbic networks. Strong similarities emerged in iRBD and DLB that showed comparable connectivity alterations in most large-scale networks, particularly in the posterior default mode and attentive networks. Contrarily, PD showed the main connectivity alterations limited to motor and somatosensory networks. The present findings reveal that metabolic connectivity alterations in the large-scale networks are already present in the early iRBD phase, resembling the DLB metabolic connectivity changes. This suggests and confirms iRBD as a risk condition for progression to the severe LB disease phenotype. Of note, the neurobiology of stable PD supports its more benign phenotype

Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria

Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction since birth has led to normal cognitive development. However, PKU patients can still develop cognitive or behavioral abnormalities and subtle neurological deficits. Despite the increasing evidence in the field, the assessment of neurocognitive, psychopathological, and neurological follow-up of PKU patients at different ages is still debated. The high interindividual variability in the cognitive outcome of PKU patients makes the specificity of the neurocognitive and behavioral assessment extremely challenging. In the present paper, a multidisciplinary panel of Italian PKU experts discussed different tools available for cognitive, psychopathological, and neurological assessment at different ages based on the existing literature and daily clinical practice. This study aims to provide evidence and a real-life-based framework for a specific clinical assessment of pediatric, adolescent, and adult patients affected by PKU

Unsupervised but not supervised gait parameters are related to fatigue in Parkinson’s disease: a pilot study

IntroductionFatigue is a common and disabling symptom in Parkinson’s disease (PD), also affecting gait. Detection of fatigue-associated changes of gait using mobile health technologies (MHT) could become increasingly effective.MethodsCognitively unimpaired PD patients without fluctuations (UPDRS IV < 1) underwent a standard neurological assessment including the PD-Fatigue scale (PFS-16). PD patients with (PD-F) and without fatigue (PD-N) were matched for age, sex, cognitive function and disease severity. Each participant underwent MHT gait assessment under supervised condition (SC) and unsupervised condition (UC).ResultsGait parameters of 21 PD-F and 21 PD-N did not significantly differ under SC. Under UC, PD-F showed higher step time, step time variability and asymmetry index compared to PD-N and the PFS-16 correlated with step time.ConclusionThis is the first MHT-based study with PD patients showing a correlation between fatigue and gait parameters. In addition, the data collected suggest that UC is clearly superior to SC in addressing this question

Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient

Background: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood–cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. Methods: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40–60 and 9.0 over 60 years. Results: 1209 subjects were included in the study. 718 females and 491 males (age: 15–88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease sub- groups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivari- able linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. Conclusions: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach

Effects of dopaminergic treatment on inhibitory control differ across Hoehn and Yahr stages of Parkinson's disease

: Motor inhibitory control, a core component of cognitive control, is impaired in Parkinson's disease, dramatically impacting patients' abilities to implement goal-oriented adaptive strategies. A progressive loss of the midbrain's dopamine neurons characterizes Parkinson's disease and causes motor features responsive to dopaminergic treatments. Although such treatments restore motor symptoms, their impact on response inhibition is controversial. Most studies failed to show any effect of dopaminergic medicaments, although three studies found that these drugs selectively improved inhibitory control in early-stage patients. Importantly, all previous studies assessed only one domain of motor inhibition, i.e. reactive inhibition (the ability to react to a stop signal). The other domain, i.e. proactive inhibition (the ability to modulate reactive inhibition pre-emptively according to the current context), was utterly neglected. To re-examine this issue, we recruited cognitively unimpaired Parkinson's patients under dopaminergic treatment in the early (Hoehn and Yahr, 1-1.5, n = 20), intermediate (Hoehn and Yahr 2, n = 20), and moderate/advanced (Hoehn and Yahr, 2.5-3, n = 20) stages of the disease. Using a cross-sectional study design, we compared their performance on a simple reaction-time task and a stop-signal task randomly performed twice on dopaminergic medication (ON) and after medication withdrawal (OFF). Normative data were collected on 30 healthy controls. Results suggest that medication effects are stage-dependent. In Hoehn and Yahr 1-1.5 patients, drugs selectively impair reactive inhibition, leaving proactive inhibition unaffected. In the ON state, Hoehn and Yahr two patients experienced impaired proactive inhibition, whereas reactive inhibition is no longer affected, as it deteriorates even during the OFF state. By contrast, Hoehn and Yahr 2.5-3 patients exhibited less efficient reactive and proactive inhibition in the OFF state, and medication slightly improved proactive inhibition. This evidence aligns with the dopamine overdose hypothesis, indicating that drug administration may overdose intact dopamine circuitry in the earliest stages, impairing associated cognitive functions. In later stages, the progressive degeneration of dopaminergic neurons prevents the overdose and can exert some beneficial effects. Thus, our findings suggest that inhibitory control assessment might help tailor pharmacological therapy across the disease stage to enhance Parkinson's disease patients' quality of life by minimizing the hampering of inhibitory control and maximizing the reduction of motor symptoms