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.

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.

Line-field confocal optical coherence tomography for the differential diagnosis of porokeratosis from clinical simulators: a preliminary study.

Porokeratosis variants are relatively rare and can be clinically misdiagnosed with several common papulo-keratosic simulators. Line-field confocal optical coherence tomography (LC-OCT) is a new technology able to explore the skin in vivo up to 500µm depth. In this preliminary study we aimed to investigate the role of LC-OCT in the diagnosis of many porokeratosis variants. A total of 54 patients (28 was affected by one among 13 porokeratosis variants, 26 had a simulator condition) were examined at lesional and perilesional sites in vertical and horizontal view. We found an almost perfect interobserver agreement in LC-OCT images interpretation and a perfect correspondence with histologic slides. In addition, a series of morphologic in vivo and 3D features related to the cornoid lamella were detected by LC-OCT, not visible under histology. This device can be proposed for rapid bed-side non-invasive differentiation of porokeratosis variants from their simulators, possibly sparing incisional biopsy in doubtful cases.

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.

Multidisciplinary care use in neurodegenerative complex diseases: The example of progressive supranuclear palsy and advanced Parkinson's disease in real-life.

BACKGROUND: In spite of being considered the gold-standard of care, little is known about the real-life use of in-home and multidisciplinary care in atypical parkinsonism. OBJECTIVE: Primary: Examine real-life multidisciplinary care use for Progressive Supranuclear Palsy (PSP). Secondary: a) Compare PSP care to advanced Parkinson's disease (APD) care; (b) Explore demographic and clinical variables associated with care needs in both groups. METHODS: A cross-sectional multicenter observational study enrolled 129 PSP patients and 65 APD patients (Hoehn and Yahr ≥3), matched for sex and age. Univariate and multivariate regression analysis were performed. RESULTS: Over the previous year, 40 % of PSP patients did not encounter a physical therapist, while only one-third met a speech and language therapist and 5 % an occupational therapist. More than 20 % received in-home care and 32 % needed home structural changes. Compared to APD, PSP patients required more day-time, night-time and home structural changes. When considering both PSP and APD in multivariate analysis, reduced functional autonomy and living without a family caregiver were both related to day-time home assistance and to the need of at least one home care service. A PSP diagnosis compared to APD was a risk factor for having at least four multidisciplinary visits in a year. Finally, PSP diagnosis and being from the Northern Italy were significantly related with home structural changes. CONCLUSIONS: There's a significant gap in providing multidisciplinary care for PSP patients. Our findings emphasize the need for a shared, integrated care plan at a national level for patients with atypical parkinsonism.

Insular and limbic abnormal functional connectivity in early-stage Parkinson's disease patients with autonomic dysfunction.

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-ß-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.

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.

Successful Use of Dupilumab in the Treatment of Acquired Perforating Dermatosis Associated with Atopic Dermatitis.

Acquired reactive perforating collagenosis is a rare cutaneous disorder characterised by the extrusion of abnormal connective tissue trough epidermidis and/or follicular units. Reactive perforating collagenosis is often associated with systemic diseases in which pruritus is a common symptom (e.g., diabetes and chronic kidney disease). Less commonly, it has been associated with chronic inflammatory dermatoses, including atopic dermatitis, as in this case. In this report, we describe the exceptional case of a 35-year-old man affected by acquired reactive perforating collagenosis associated with atopic dermatitis who was resistant to conventional topical and systemic treatment and experienced complete resolution of clinical signs and symptoms after 12 weeks of treatment with dupilumab. In our patient, the severe pruritus induced by atopic dermatitis likely contributed to the development of acquired perforating collagenosis lesions, which are thought to be a reactive response to chronic scratching and repetitive injury to the skin. Chronic pruritus in atopic dermatitis is known to be driven by type 2 cytokines, including IL-4 and IL-13, and dupilumab, a monoclonal antibody inhibiting IL-4 and IL-13 signalling, has been shown to be effective in the treatment of moderate to severe atopic dermatitis as well as other type 2-driven pruritic dermatological conditions. This case supports the potential use of dupilumab for the treatment of reactive perforating dermatosis.

Rare association between spinocerebellar ataxia and amyotrophic lateral sclerosis: a case series.

INTRODUCTION: In this work, we describe a new case of association between SCA2 and MND. CASE REPORT: A 58-year-old man who was diagnosed with spinocerebellar ataxia type 2 presented dysphagia and a significant decline in his ability to walk, with a reduction in autonomy and the need to use a wheelchair. We performed electromyography and electroneurography of the four limbs and of the cranial district and motor-evoked potentials to study upper and lower motor neurons. Referring to the revised El Escorial criteria of 2015, ALS diagnosis was made. DISCUSSION: Considering different cases described in literature over the years, SCA2 could represent an important risk factor for developing ALS. In particular, the presence of alleles of ATXN2 with 27 and 28 CAG repeats seems to slightly decrease the risk of developing the disease, which would instead be progressively increased by the presence of alleles with 29, 30, 31, 32, and 33 repeats. The exact physiopathological mechanism by which the mutation increases the risk of developing the disease is currently unknown. Transcriptomic studies on mouse models have demonstrated the involvement of several pathways, including the innate immunity regulation by STING and the biosynthesis of fatty acid and cholesterol by SREBP. CONCLUSION: CAG repeat expansions in the ATXN2 gene have been associated with variable neurological presentations, which include SCA2, ALS, Parkinsonism, or a combination of them. Further research is needed to understand the relationship between SCA2 and ALS better and explore molecular underlying mechanisms.

Quality of life impact in patients with cutaneous toxicities caused by EGFR inhibitors and immunotherapy.

BACKGROUND: novel oncologic therapies, including epidermal growth factor receptor inhibitors (EGFR-Is) and immune checkpoint inhibitors (ICIs), are associated with a new spectrum of adverse reactions, with prominent cutaneous toxicities. The impact of cutaneous adverse events (cAEs) on patients' quality of life (QoL) represents an unmet clinical need. OBJECTIVES: 1) to assess whether cutaneous toxicities directed therapies are effective in reducing the QoL burden via the submission of two patient reported outcome measures (PROMs); 2) to investigate whether class of oncologic therapy, type of cAE and toxicity severity differently impact on patients' QoL. METHODS: a prospective observational study was conducted at the Dermatology department of the Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, from October 2018 to October 2019. Patients aged ≥ 18 years, under therapy with EGFR-Is or ICIs and experiencing a treatment-related cAE were eligible for the study. Dermatology Life Quality Index (DLQI) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30 version 3.0 (EORTC QLQ-C30) were administered to patients at first clinical visit (T0), at 1-month (T1), and at 3-month (T2) dermatological follow-up. RESULTS: Sixty cAEs of 51 patients have been recorded. A significant difference in the mean score for both DLQI and EORTC QLQ-C30 was found along the 3-months dermatological follow-up (p <0.0001). A similar QoL improvement was reported for PROMs stratified by class of therapy and toxicity severity (p <0.0001). No difference was reported for patients with pyogenic granuloma-like lesions and psoriasiform eruption as per DLQI. Class of therapy and toxicity severity did not differently impact on patients' QoL at selected timepoints; we reported a higher EORTC QLQ-C30 score at T2 for patients developing psoriasiform eruption compared to other types of cAEs. CONCLUSIONS: Early patients' referral to dermatologists and tailored management could result in better QoL.

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.

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.

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.

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.

The Role of Postoperative Radiotherapy in the Management of Dermatofibrosarcoma Protuberans: A Multidisciplinary Systematic Review.

Background: Dermatofibrosarcoma protuberans (DFSP) is a superficial soft tissue sarcoma, and surgical excision is the first-line treatment. The aim of this systematic review is to provide an update about the current indications and clinical results regarding the use of postoperative radiotherapy in DSFP, considering both adjuvant and salvage setting. Methods: We conducted a systematic literature review using the main scientific database, including Cochrane library, Scopus, and PubMed, for any relevant article about the topic, and we considered all available papers without any time restriction. Results: Twenty-two papers, published between 1989 and 2023, were retrieved and considered eligible for inclusion in this review. Regarding the fractionation schedules, most authors reported using standard fractionation (2 Gy/die) with a wide total dose ranging from 50 to 70 Gy. The local control after postoperative radiotherapy was excellent (75-100%), with a median follow-up time of 69 months. Conclusions: After the primary surgical management of DFSP, postoperative radiotherapy may either be considered as adjuvant treatment (presence of risk factors, i.e., close margins, recurrent tumours, aggressive histological subtypes) or as salvage treatment (positive margins) and should be assessed within the frame of multidisciplinary evaluation.

Confocal Assessment of Pigmented-Mucosal Lesions: A Monocentric, Retrospective Evaluation of Lip and Genital Area.

INTRODUCTION: Pigmentation of lip and/or genitalia is mainly due to the development of benign melanotic macules, with a less occurrence of melanocytic and other non-melanocytic lesions. Mucosal melanoma has worse prognosis compared with cutaneous counterpart, hence identification of atypical features for an early diagnosis is crucial. OBJECTIVES: The aim of this study was to report further data of confocal features characterizing pigmented mucosal lesions of genital area and of the lips and test the diagnostic role of the reflectance confocal microscopy (RCM)lip score. METHODS: Clinical, dermoscopic and RCM images of histologically proven pigmented lesions, involving the genital area (vulva or glans penis) and lip, were retrospectively reviewed. RCM images were evaluated for malignant criteria, and statistical analysis was conducted for categorical variables. RESULTS: Seventy pigmented lesions were included in the study and divided into two groups based on the body area location: lip (17) and genital area (53). Architectural disarray (P = 0.002), dendritic (P = 0.031) and roundish cells in epidermis (P < 0.0001), interpapillary dendritic cells (P = 0.039) and junctional atypical cells (P = 0.002) were associated to genital melanoma. Melanoma involving the lip was characterized by roundish cells in epidermis, a criterion found in one labial benign lesion, only (P = 0.005). Main limitations of the study are the inclusion of low melanomas and the presence of epidermal dendritic cells in melanosis and melanoma, as a confusing factor in imaging. CONCLUSIONS: Dermatologists should consider confocal microscopy as an adjunctive tool to dermoscopy in the differential diagnosis of pigmented mucosal lesions, especially in presence of clinical and dermoscopic findings suspicious for malignancy.