Stage-dependent phosphoproteome remodeling of Parkinson's disease blood cells.

The complexity and heterogeneity of PD necessitate advanced diagnostic and prognostic tools to elucidate its molecular mechanisms accurately. In this study, we addressed this challenge by conducting a pilot phospho-proteomic analysis of peripheral blood mononuclear cells (PBMCs) from idiopathic PD patients at varying disease stages to delineate the functional alterations occurring in these cells throughout the disease course and identify key molecules and pathways contributing to PD progression. By integrating clinical data with phospho-proteomic profiles across various PD stages, we identify potential stage-specific molecular signatures indicative of disease progression. This integrative approach allows for the discernment of distinct disease states and enhances our understanding of PD heterogeneity.

Safinamide effect on sleep architecture of motor fluctuating Parkinson's disease patients: A polysomnographic rasagiline-controlled study.

INTRODUCTION: Sleep problems commonly occur in Parkinson's disease (PD) and significantly affect patients' quality of life. A possible effect on subjective sleep disturbances of monoamine oxidase-B inhibitors (MAOB-Is) has been described. METHODS: This prospective, observational, single-centre study involved 45 fluctuating PD patients complaining sleep problems as documented by the PD Sleep Scale -2nd version (PDSS-2 ≥18) starting rasagiline 1 mg/daily or safinamide 100 mg/daily, according to common clinical practice, and maintaining antiparkinsonian therapy unchanged. Polysomnography (PSG), sleep questionnaires (PDSS-2, Epworth Sleepiness Scale - ESS), and motor function were evaluated at baseline (T0) and after 4 months of treatment (T1). RESULTS: Safinamide was prescribed in thirty patients and rasagiline in fifteen patients. Both drugs induced a significant improvement in Movement Disorder Society Unified PD Rating Scale III scores. Patients treated with rasagiline showed a significant increase in stage 1 (N1) Non-REM sleep compared to T0, with no significant effects on sleep scales. Patients treated with safinamide showed a significant increase in stage 3 of Non-REM sleep and sleep efficiency and a reduction in the rate of periodic limb movements, matching a significant reduction in PDSS-2 and ESS scales compared to T0. CONCLUSION: This study showed that safinamide, in addition to having a significant effect on PD motor symptoms, like the other MAOB-Is, may exert a specific beneficial effect on subjective and objective sleep, probably driven by its dual mechanism of action, which involves both dopaminergic and glutamatergic neurotransmission.

Poor Adherence to the Mediterranean Diet and Sleep Disturbances Are Associated with Migraine Chronification and Disability among an Adult Population in the Lazio Region, Italy.

Lifestyle factors, such as diet and sleep quality, are receiving increasing interest as accessible therapeutic approaches to migraine. The Mediterranean diet (MD) has shown clear benefits in cardiovascular and metabolic diseases, as well as in sleep patterns. Here, our objective was to identify the impact of adherence to the MD and other lifestyle factors on the clinical burden of migraine. For this purpose, we enrolled 170 migraine patients and 100 controls, assessing the clinical disability of headache using standardized clinical scales (HIT-6 and MIDAS) in the migraineur cohort and lifestyle patterns in both groups through the PREDIMED score for MD adherence, the IPAQ scale for physical activity, and BMI. Subjects were also screened for sleep-wake disturbances based on the Pittsburgh Sleep Quality Index (PSQI). We found that migraine patients had lower adherence to the MD compared to the controls and that the HIT-6 scale had a significant negative relationship with MD adherence in patients with high-frequency episodic and chronic migraine. Additionally, in the same migraine patients, the presence of sleep-wake disturbances was correlated with greater migraine disability as assessed by the MIDAS score. In conclusion, this study found that among different lifestyle factors, poor adherence to the MD and the presence of sleep-wake disturbances were closely associated with migraine disability and chronification.

Contribution of testosterone and estradiol in sexual dimorphism of early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) occurs during the fertile life, when circulating neuroactive sex hormones might enhance the sexual dimorphism of the disease. Here, we aimed to examine how sex hormones can contribute to sex differences in EOPD patients. A cohort of 34 EOPD patients, 20 males and 14 females, underwent comprehensive clinical evaluation of motor and non-motor disturbances. Blood levels of estradiol, total testosterone, follicle-stimulating hormone, and luteinizing hormone were measured in all patients and correlated to clinical features. We found that female patients exhibited greater non-motor symptoms and a relatively higher rate of dystonia than males. In females, lower estradiol levels accounted for higher MDS-UPDRS-II and III scores and more frequent motor complications, while lower testosterone levels were associated with a major occurrence of dystonia. In male patients, no significant correlations emerged. In conclusion, this study highlighted the relevance of sex hormone levels in the sexual dimorphism and unique phenotype of EOPD.

Obstructive sleep apnea may induce sleep-wake cycle dysregulation: An actigraphic study.

Obstructive sleep apnea (OSA) causes sleep fragmentation and excessive daytime sleepiness (EDS). OSA has been hypothesised to impair the circadian sleep-wake rhythm, and this dysregulation may in turn exacerbate OSA-related diurnal symptoms. Hence, this study aimed to assess the sleep-wake rhythm through actigraphy, and its relationship with EDS in patients with untreated OSA. Patients with moderate-severe OSA (apnea-hypopnea index ≥15/h) and healthy controls (HC) underwent a 7-day actigraphic recording to evaluate the sleep-wake rhythm. Participants underwent a sleep medicine visit and completed the self-report questionnaires assessing EDS (Epworth sleepiness scale, ESS), sleep quality (Pittsburgh sleep quality index, PSQI), and chronotype (morningness-eveningness questionnaire, MEQ). This study included 48 OSA patients (72.9% males; mean age 56.48 ± 9.53 years), and 22 HC (45.5% males; mean age 53.73 ± 18.20 years). After controlling for MEQ scores, actigraphic recording showed that the OSA patients present a lower sleep time (p = 0.011) and sleep efficiency (p = 0.013), as well as a higher sleep latency (p = 0.047), and sleep fragmentation (p = 0.029) than the HC. Regarding the sleep-wake rhythm actigraphic parameters, the OSA patients showed a lower average activity during the most active 10-hour period (p = 0.036) and a lower day/night activity ratio (p = 0.007) than the HC. Patients with OSA also reported higher ESS (p = 0.005) and PSQI scores (p < 0.001), and a chronotype less of morning type (p = 0.027) than the HC. In conclusion, this study documented a reduced diurnal motor activity and lower day/night activity ratio in OSA patients than in controls. These findings suggest a dysregulation of the circadian sleep-wake rhythm in OSA, possibly related to both EDS and reduced daytime motor activity.

Early effect of onabotulinumtoxinA on EEG-based functional connectivity in patients with chronic migraine: A pilot study.

OBJECTIVE: In this pilot prospective cohort study, we aimed to evaluate, using high-density electroencephalography (HD-EEG), the longitudinal changes in functional connectivity (FC) in patients with chronic migraine (CM) treated with onabotulinumtoxinA (OBTA). BACKGROUND: OBTA is a treatment for CM. Several studies have shown the modulatory action of OBTA on the central nervous system; however, research on migraine is limited. METHODS: This study was conducted at the Neurology Unit of "Policlinico Tor Vergata," Rome, Italy, and included 12 adult patients with CM treated with OBTA and 15 healthy controls (HC). Patients underwent clinical scales at enrollment (T0) and 3 months (T1) from the start of treatment. HD-EEG was recorded using a 64-channel system in patients with CM at T0 and T1. A source reconstruction method was used to identify brain activity. FC in δ-θ-α-ß-low-γ bands was analyzed using the weighted phase-lag index. FC changes between HCs and CM at T0 and T1 were assessed using cross-validation methods to estimate the results' reliability. RESULTS: Compared to HCs at T0, patients with CM showed hyperconnected networks in δ (p = 0.046, area under the receiver operating characteristic curve [AUC: 0.76-0.98], Cohen's κ [0.65-0.93]) and ß (p = 0.031, AUC [0.68-0.95], Cohen's κ [0.51-0.84]), mainly involving orbitofrontal, occipital, temporal pole and orbitofrontal, superior temporal, occipital, cingulate areas, and hypoconnected networks in α band (p = 0.029, AUC [0.80-0.99], Cohen's κ [0.42-0.77]), predominantly involving cingulate, temporal pole, and precuneus. Patients with CM at T1, compared to T0, showed hypoconnected networks in δ band (p = 0.032, AUC [0.73-0.99], Cohen's κ [0.53-0.90]) and hyperconnected networks in α band (p = 0.048, AUC [0.58-0.93], Cohen's κ [0.37-0.78]), involving the sensorimotor, orbitofrontal, cingulate, and temporal cortex. CONCLUSION: These preliminary results showed that patients with CM presented disrupted EEG-FC compared to controls restored by a single session of OBTA treatment, suggesting a primary central modulatory action of OBTA.

Effectiveness of Highly Purified Cannabidiol in Refractory and Super-Refractory Status Epilepticus: A Case Series.

INTRODUCTION: Refractory and super-refractory status epilepticus are medical emergencies that must be promptly treated in consideration of their high mortality and morbidity rate. Nevertheless, the available evidence of effective treatment of these conditions is scarce. Among novel antiseizure medications (ASMs), highly purified cannabidiol (hpCBD) has shown noteworthy efficacy in reducing seizures in Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). CASE PRESENTATION: Here, we present two cases of effective use of hpCBD in both refractory and super- refractory status epilepticus. The administration of the nasogastric tube permitted the resolution of status epilepticus without adverse events. At 6-month follow-up, both patients were on hpCBD treatment, which continued to be efficacious for treating seizures. CONCLUSION: According to our experience, hpCBD should be taken into consideration as an add-on therapy of RSE and SRSE while also considering the possibility of maintaining this treatment during the follow-up of patients. However, more studies and real-world experiences are needed to better understand its effectiveness in this setting and the interaction with other ASMs.

Astrocytic-derived vascular remodeling factors are independently associated with blood brain barrier permeability in Alzheimer's disease.

Astrocytes in Alzheimer's disease (AD) exert a pivotal role in the maintenance of blood-brain barrier (BBB) integrity essentially through structural support and release of soluble factors. This study provides new insights into the vascular remodeling processes occurring in AD, and reveals, in vivo, a pathological profile of astrocytic secretion involving Vascular Endothelial Growth Factor (VEGF), Matrix Metalloproteinases (MMP)-9, MMP-2 and Endothelin-1 (ET-1). Cerebrospinal fluid (CSF) levels of VEGF, MMP-2/-9 were lower in patients belonging to the AD continuum, compared to aged-matched controls. CSF levels of VEGF and ET-1 positively correlated with MMP-9 but negatively with MMP-2, suggesting a complex vascular remodeling process occurring in AD. Only MMP-2 levels were significantly associated with CSF AD biomarkers. Conversely, higher MMP-2 (ß = 0.411, p < 0.001), ET-1 levels (ß = 0.344, p < 0.001) and VEGF (ß = 0.221, p = 0.022), were associated with higher BBB permeability. Astrocytic-derived vascular remodeling factors are altered in AD, disclosing the failure of important protective mechanisms which proceed independently alongside AD pathology.

Constitutive NOS Production Is Modulated by Alzheimer's Disease Pathology Depending on APOE Genotype.

Both the endothelial (eNOS) and the neuronal (nNOS) isoforms of constitutive Nitric Oxide Synthase have been implicated in vascular dysfunctions in Alzheimer's disease (AD). We aimed to explore the relationship between amyloid pathology and NO dynamics by comparing the cerebrospinal fluid (CSF) levels of nNOS and eNOS of 8 healthy controls (HC) and 27 patients with a clinical diagnosis of Alzheimer's disease and isolated CSF amyloid changes, stratified according to APOE ε genotype (APOE ε3 = 13, APOE ε4 = 14). Moreover, we explored the associations between NOS isoforms, CSF AD biomarkers, age, sex, cognitive decline, and blood-brain barrier permeability. In our cohort, both eNOS and nNOS levels were increased in APOE ε3 with respect to HC and APOE ε4. CSF eNOS inversely correlated with CSF Amyloid-ß42 selectively in carriers of APOE ε3; CSF nNOS was negatively associated with age and CSF p-tau only in the APOE ε4 subgroup. Increased eNOS could represent compensative vasodilation to face progressive Aß-induced vasoconstriction in APOE ε3, while nNOS could represent the activation of NO-mediated plasticity strategies in the same group. Our results confirm previous findings that the APOE genotype is linked with different vascular responses to AD pathology.

Alteration of circadian sleep-wake rhythm and salivary melatonin secretion in idiopathic/isolated REM sleep behavior disorder: Preliminary evidence.

OBJECTIVE/BACKGROUND: Idiopathic/isolated REM sleep behavior disorder (iRBD) is widely regarded as an early sign of neurodegeneration leading to synucleinopathies. While circadian rhythm alterations in iRBD have been preliminarily demonstrated, evidence on melatonin secretion patterns in this clinical condition is limited. To address this knowledge gap, this exploratory study aimed to integrate salivary melatonin measurement with actigraphic monitoring in individuals with iRBD and age-matched healthy controls (HC) under real-life conditions. METHODS: Participants diagnosed with iRBD and HC underwent clinical evaluation and wore an actigraph for seven days and nights. Salivary melatonin concentrations were measured at five time points during the last night of recording. Comparative analyses were conducted on clinical data, actigraphic parameters, and melatonin levels between the two groups. RESULTS: iRBD participants (n = 18) showed greater motor (p < 0.01) and non-motor symptoms (p < 0.001), alongside disruptions in circadian sleep-wake rhythm compared to HC (n = 10). Specifically, actigraphy revealed a delayed central phase measurement (p < 0.05), reduced activity during the most active hours (p < 0.001), and decreased relative amplitude (p < 0.05). Total salivary melatonin concentration was significantly lower in iRBD (p < 0.05), with a slight but non-significant phase delay in dim light melatonin onset. CONCLUSIONS: This exploratory study highlights a dysregulation of circadian sleep-wake rhythm coupled with reduced melatonin secretion in iRBD. Future research could add to these preliminary findings to evaluate novel treatment approaches to regulate the sleep-wake cycle and elucidate the implications of circadian dysregulation in the conversion from iRBD to neurodegeneration.

Hearing dysfunction heralds an increase in non-motor burden and a worse quality of life in Parkinson's disease: new insights from non-motor spectrum.

BACKGROUND: Sensorial non-motor symptoms (NMSs) in Parkinson's disease (PD) still lack appropriate investigation in clinical practice. This study aimed to assess if and to what extent auditory dysfunction is associated with other NMSs in PD and its impact on patient's quality of life (QoL). METHODS: We selected patients with idiopathic PD, without other concomitant neurological diseases, dementia, or diagnosis of any audiological/vestibular disease. Demographic and clinical data were collected. Patients underwent otoscopic examination, audiological testing with pure tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAEs) and completed Non-Motor Symptoms Scale (NMSS) and Parkinson's Disease Questionnaires-39 (PDQ-39). ANCOVA and partial correlation analysis have been used for statistical analysis. RESULTS: 60 patients were enrolled and completed PTA and DPOAEs. 32 patients with hearing impairment (HI), assessed by PTA, (hearing threshold ≥ 25 dB) showed similar disease duration, motor impairment, and staging, compared to patients without HI, but higher scores both in NMSS and in PDQ-39, except for cardiovascular (CV), gastrointestinal (GI), urogenital (U) and sexual function (SF) of NMSS. In addition, DPOAEs showed a significant correlation with higher scores both in NMSS and PDQ-39, except for CV, SF, GI, U and perceptual problem subdomains of NMSS. CONCLUSION: This study demonstrated that PD patients with HI have a greater burden of NMS and lower related QoL and functioning. Our results highlight the importance to reconsider HI as a NMS, in parallel with the others. HI evaluation, even in asymptomatic patients, may reveal a wider pathology with a worse QoL.

Long-Term Treatment with the Calcitonin Gene-Related Peptide Receptor Antagonist Erenumab in CADASIL: Two Case Reports.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of cerebral small vessel disease, caused by a mutation in the NOTCH3 gene on chromosome 19. The main clinical features include migraine (often with aura), early onset, recurrent subcortical ischemic strokes, mood disturbances, and cognitive impairment, frequently leading to dementia and disability with a reduction in life expectancy. Cerebral chronic global hypoperfusion, due to impaired cerebrovascular reactivity, seems to play a primary role in CADASIL. Migraine is the most common early feature of the disease, and to date, there are no consensus guidelines for treatment. Given the vasomodulatory influence of many antimigraine drugs, there is concern about their use in this disease. In particular, the calcitonin gene-related peptide (CGRP) system serves as a vasodilatory protective mechanism during cerebral and cardiac ischemia. Blocking this system could exacerbate ischemic events. Herein, we describe two CADASIL patients who were treated with the calcitonin gene-related peptide (CGRP) receptor antagonist erenumab for chronic migraine, reporting a significant reduction in the frequency of attacks and intensity of pain, and an improvement in quality of life without adverse effects.

Post-COVID-19 Hyposmia Does Not Exhibit Main Neurodegeneration Markers in the Olfactory Pathway.

The biological substrate of persistent post-COVID-19 hyposmia is still unclear. However, as many neurodegenerative diseases present with smell impairment at onset, it may theoretically reflect degeneration within the central olfactory circuits. However, no data still exist regarding the post-COVID-19 patients. As the olfactory neurons (ONs) mirror pathological changes in the brain, allowing for tracking the underlying molecular events, here, we performed a broad analysis of ONs from patients with persistent post-COVID-19 OD to identify traces of potential neurodegeneration. ONs were collected through the non-invasive brushing of the olfactory mucosa from ten patients with persistent post-COVID-19 hyposmia (lasting > 6 months after infection) and ten age/sex-matched controls. Immunofluorescence staining for protein quantification and RT-PCR for gene expression levels were combined to measure ONs markers of α-synuclein, amyloid-ß, and tau pathology, axonal injury, and mitochondrial network. Patients and controls had similar ONs levels of oligomeric α-synuclein, amyloid-ß peptide, tau protein, neurofilament light chain (NfL), cytochrome C oxidase subunit 3 (COX3), and the heat shock protein 60 (HSP60). Our findings thus did not provide evidence for synucleinopathy and amyloid-ß mismetabolism or gross traces of neuronal injury and mitochondrial dysfunction within the olfactory system in the early phase of persistent post-COVID-19 hyposmia.

Sex differences in Parkinson's disease-related non motor symptoms: a focus on sleep problems.

Parkinson's disease (PD) symptomatology differs between females and males, yet the contribution of sex on sleep problems needs further analysis. Here, we aimed to investigate sex-specific patterns in the relationship between sleep problems, assessed using the Parkinson's disease sleep scale (PDSS-2), non motor symptoms (NMS), measured by the NMS scale (NMSS), and health-related quality of life (HR-QoL), evaluated by the Parkinson's disease questionnaire (PDQ-39), in a large cohort of PD patients. One-hundred-fifty-four PD patients were included in the study. Female PD patients (n = 62) exhibited a higher prevalence of sleep problems than males (n = 92), with nocturnal motor-related sleep issues being the most frequent. Sleep disturbances differently correlated with a range of NMS between the two sexes. In females, sleep problems mostly correlated with pain; on the other hand, sleep disturbances were linked to a frailer phenotype characterized by global dysautonomia, perception disturbances, and impaired cognitive function in males. Whether female PD patients experienced a lower HR-QoL than males, sleep disturbances were associated with a worse HR-QoL in both sexes. In conclusion, sleep problems in PD differently burden the two sexes, suggesting possible different etiopathogenesis, diagnostic investigations, and possibly tailored approaches.

A biological characterization of patients with postmenopausal Parkinson's disease.

Menopause increases the risk for Parkinson's disease (PD), although the underlying biological mechanisms have not been established in patients. Here, we aimed to understand the basis of menopause-related vulnerability to PD. Main motor and non-motor scores, blood levels of estradiol, testosterone, follicle-stimulating hormone, and luteinizing hormone, CSF levels of total α-synuclein, amyloid-ß-42, amyloid-ß-40, total tau, and phosphorylated-181-tau were examined in 45 women with postmenopausal-onset PD and 40 age-matched controls. PD patients had higher testosterone and lower estradiol levels than controls, and the residual estradiol production was associated with milder motor disturbances and lower dopaminergic requirements. In PD but not in controls, follicle-stimulating hormone levels correlated with worse cognitive scores and CSF markers of amyloidopathy and neuronal loss. In conclusion, menopause-related hormonal changes might differentially contribute to clinical-pathological trajectories of PD, accounting for the peculiar vulnerability to the disease.

Correlation between endometriosis and migraine features: Results from a prospective case-control study.

BACKGROUND: Endometriosis and migraine frequently coexist, but only a limited number of studies have focused on their mutual association. The aim of our study was to investigate, in untreated women with comorbid endometriosis/adenomyosis and migraine, the correlation between headache features and endometriotic subtypes and their possible relationship with pain severity and disease disability. METHODS: Fifty women affected by endometriosis/adenomyosis and migraine matched (1:2) with 100 patients with endometriosis alone and 100 patients with only migraine were recruited and underwent pelvic ultrasound imaging and neurological examination. RESULTS: Severe adenomyosis, posterior and anterior deep infiltrating endometriosis (p = 0.027, p = 0.0031 and p = 0.029, respectively) occurred more frequently in women with migraine. Dysmenorrhea was the most commonly reported symptom in women with endometriosis and migraine and the mean VAS scores of all typical endometriotic symptoms were significantly higher in the presence of comorbidity. Women with both migraine and endometriosis reported significant higher pain intensity (p = 0.004), higher monthly migraine days (p = 0.042) and increased HIT 6-scores (p = 0.01), compared with those without endometriosis. CONCLUSIONS: Our results demonstrated that the co-occurrence of migraine in untreated women with endometriosis is associated with more severe gynecological infiltrations and correlated with increased pain intensity and disease disability.Trial Registration: Protocol number 119/21.

Assessment of Psychometric Characteristics of Parkinson's Disease Sleep Scale 2 and Analysis of a Cut-Off Score for Detecting Insomnia in Italian Patients with Parkinson's Disease: A Validation Study.

INTRODUCTION: Sleep disorders are frequent non-motor symptoms affecting patients with Parkinson's disease (PD). Insomnia represents the most common sleep disorder. Parkinson's disease Sleep Scale 2 (PDSS-2) is a specific tool to investigate sleep problems in PD. The General Sleep Disturbances Scale (GSDS) was a general scale validated for the Italian population. Our goal was to assess the psychometric characteristics of PDSS-2 and the GSDS in this population, calculating a cut-off score for insomnia symptoms by using subitems of PDSS-2. METHODS: Patients admitted at the PD Unit of the Hospital of Rome Tor Vergata outpatient clinic and those afferent to PD associations were asked to complete PDSS-2 and GSDS to be correlated to identify a cut-off for insomnia symptoms. Items 1,2,3,8,13 of PDSS-2 were used to detect insomnia. An ROC curve to assess a cut-off score for insomnia was determined. A cross-cultural analysis of PD population characteristics was performed. RESULTS: In total, 350 PD patients were recruited. Cronbach's alpha was high for the total score (0.828 for PDSS-2 and 0.832 for GSDS). A cross-cultural analysis did not show any significant p-value. The ROC curve yielded an AUC of 0.79 (CI: 0.75-0.84). The cut-off value for insomnia disorder based on items 1,2,3,8,13 of PDSS-2 was >10, demonstrating a sensitivity of 76% and a specificity of 69% in determining the presence of subjective insomnia symptoms in PD. DISCUSSION: PDSS-2 is demonstrated to be a valid, specific tool to address sleep disturbances in PD patients. A cut-off score of 10 for items 1,2,3,8,13 was identified for detecting insomnia symptoms in PD patients.

Trimetazidine Improves Mitochondrial Dysfunction in SOD1G93A Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation.

Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1G93A-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1G93A, with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.

The VEGFs/VEGFRs system in Alzheimer's and Parkinson's diseases: Pathophysiological roles and therapeutic implications.

The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer's (AD) and Parkinson's (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.

Parkinson's disease motor progression in relation to the timing of REM sleep behavior disorder presentation: an exploratory retrospective study.

REM sleep behavior disorder (RBD) is a frequent non-motor symptom of Parkinson's disease (PD), and the timing of its presentation might have a role in the underlying neurodegenerative process. Here, we aimed to define the potential impact of probable RBD (pRBD) on PD motor progression.We conducted a longitudinal retrospective study on 66 PD patients followed up at the University Hospital of Rome Tor Vergata. Patients were divided into three groups: with post-motor pRBD (pRBDpost, n = 25), without pRBD (pRBDwo, n = 20), and with pre-motor pRBD (pRBDpre, n = 21). Hoehn and Yahr (H&Y) scores, Unified PD Rating Scale (UPDRS) motor scores, and levodopa equivalent daily dose were collected at two follow-up visits conducted in a 5-year interval (T0 and T1). pRBDpost patients had a greater rate of motor progression in terms of the H&Y scale compared to pRBDpre and pRBDwo patients, without the influence of anti-parkinsonian treatment.These preliminary findings suggest that the post-motor occurrence of pRBD can be associated with an acceleration in PD motor progression.