Evaluating the Diagnostic Potential of Combined Salivary and Skin Biomarkers in Parkinson's Disease.

Oligomeric alpha-synuclein (α-syn) in saliva and phosphorylated α-syn deposits in the skin have emerged as promising diagnostic biomarkers for Parkinson's disease (PD). This study aimed to assess and compare the diagnostic value of these biomarkers in discriminating between 38 PD patients and 24 healthy subjects (HSs) using easily accessible biological samples. Additionally, the study sought to determine the diagnostic potential of combining these biomarkers and to explore their correlations with clinical features. Salivary oligomeric α-syn levels were quantified using competitive ELISA, while skin biopsies were analyzed through immunofluorescence to detect phosphorylated α-syn at Ser129 (p-S129). Both biomarkers individually were accurate in discriminating PD patients from HSs, with a modest agreement between them. The combined positivity of salivary α-syn oligomers and skin p-S129 aggregates differentiated PD patients from HSs with an excellent discriminative ability with an AUC of 0.9095. The modest agreement observed between salivary and skin biomarkers individually suggests that they may reflect different aspects of PD pathology, thus providing complementary information when combined. This study's results highlight the potential of utilizing a multimodal biomarker approach to enhance diagnostic accuracy in PD.

A systematic review of salivary biomarkers in Parkinson's disease.

The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-ß1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.

Psychometric properties of the Parkinson's disease Questionnaire-39 and its short form Parkinson's disease Questionnaire-8: A systematic review and meta-analysis.

Parkinson's disease (PD) affects Quality of Life (QoL), since it is responsible for cognitive impairment, non-motor, and motor symptoms. Outcome measures are fundamental for evaluating treatment's effect on QoL over time. This systematic review aimed to identify the psychometric properties of PDQ-39 and PDQ-8 in the different populations in which they were validated. The electronic databases systematically searched are MEDLINE (via PubMed), CINAHL, SCOPUS, and Web of Science; the research was conducted in July 2023. The psychometric properties considered were those of the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist. Risk of bias was assessed using the COSMIN checklist. The search identified 1306 articles. 398 duplicates were eliminated; 908 articles were analyzed reading title and abstract; 799 were finally excluded because used PDQ-39 and PDQ-8 as outcome measures or were not dealing with psychometric properties; 66 articles were excluded after reading the full text. 43 articles were included in the review; meta-analysis showed all the Cronbach's alpha values were statistically significant for all the subscales of PDQ-39 and PDQ-8. PDQ-39 demonstrated to be a specific HRQoL questionnaire that is correlated with generic HRQoL questionnaires, in fact in many studies included in the review, correlations with SF-36 were found. In the last studies about psychometric properties of PDQ-8 emerged that it is a practical and informative instrument that can be easily used in clinical settings, especially in busy ones, but also in large-scale studies in which a brief instrument would be preferred.

Oromandibular dystonia: from onset to spread a multicenter italian study.

BACKGROUND: Detailed information about the epidemiological and phenomenological differences among the aetiological subtypes of oromandibular dystonia (OMD) is lacking. Moreover, the OMD tendency to spread to other body sites has never been investigated. AIM: To compare the main demographic and clinical features of OMD in different aetiological groups and assess the risk of spread. MATERIALS AND METHODS: We retrospectively analysed data from patients contained in the Italian Dystonia Registry. The risk of spread was assessed by Kaplan Meyer curves and Cox regression analysis. RESULTS: The study included 273 patients (175 women) aged 55.7 years (SD 12.7) at OMD onset. Female predominance was observed. Idiopathic dystonia was diagnosed in 241 patients, acquired dystonia in 22. In 50/273 patients, dystonia started in the oromandibular region (focal OMD onset); in 96/273 patients the onset involved the oromandibular region and a neighbouring body site (segmental/multifocal OMD onset); and in 127/273 patients OMD was a site of spread from another body region. Sensory trick (ST) and positive family history predominated in the idiopathic group. No dystonia spread was detected in the acquired group, whereas spread mostly occurred within the first five years of history in 34% of the focal OMD onset idiopathic patients. Cox regression analysis revealed ST as a significant predictor of spread (HR, 12.1; 95% CI, 2.5 - 18.8; P = 0.002). CONCLUSION: This large study provides novel information about the clinical phenomenology of idiopathic and acquired OMD. We pointed out a possible role of oestrogens in favouring dystonia development. Moreover, we described for the first time the association between ST and dystonia spread, revealing possible common pathophysiological mechanisms. Our findings may be suggested as a referral point for future pathophysiological and therapeutic studies on OMD.

Progressive supranuclear palsy phenotype as an atypical clinical presentation of Creutzfeldt-Jakob disease: A case report and review of the literature.

Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive neurodegenerative disorder, characterized by the accumulation of abnormal prion proteins in the brain. While CJD has some typical clinical features, its presentation can be quite heterogeneous, particularly in the early stages of the disease, posing challenges in diagnosis. Atypical manifestations of CJD can mimic various neurodegenerative disorders, including atypical parkinsonisms. In this case report, we present an 81-year-old man who exhibited an atypical clinical presentation of sporadic CJD, initially resembling progressive supranuclear palsy (PSP). The patient presented with symmetric parkinsonism, postural instability, and ocular motor dysfunction, accompanied by rapid clinical deterioration. Alongside the case report, we also provide a review of the literature on atypical presentations of CJD as PSP, highlighting the importance of recognizing these manifestations in clinical practice.

Does sex influence the natural history of idiopathic adult-onset dystonia?

BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

Objective assessment of the effects of opicapone in Parkinson's disease through kinematic analysis.

BACKGROUND: Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson's disease (PD) patients. OBJECTIVES: In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements. METHODS: We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3). RESULTS: Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0-T3 was significantly lower in the L-DOPA + OPC than L-DOPA session. CONCLUSIONS: This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.

Effective connectivity abnormalities in Lewy body disease with visual hallucinations.

OBJECTIVE: To assess the changes in effective connectivity of important regions of the visual network (VIS) and dorsal attention network (DAN) underlying visual hallucinations (VHs) in Dementia with Lewy Bodies (DLB), Parkinson's Disease (PD) and Parkinson's Disease Dementia (PDD), as measured by a transcranial magnetic stimulation-electroencephalographic technique (TMS-EEG). METHODS: We stimulated the right visual cortex (V1/V2), the right intraparietal sulcus and the right frontal eye fields, two key regions of the DAN, and measured TMS-evoked cortical activation within the VIS and the DAN. We compared 11 patients with VHs and 15 patients without VHs. RESULTS: Patients with VHs showed lower TMS-evoked cortical activation within the DAN following intraparietal sulcus and frontal eye fields stimulation than patients without VHs. No difference was found between patients with and without cognitive impairment. Also, when considering only patients with cognitive impairment, VHs were associated with lower TMS-evoked cortical activation following intraparietal sulcus stimulation. CONCLUSIONS: DLB, PD, and PDD patients with VHs had less effective connectivity of the right intraparietal sulcus within the DAN than patients without VHs. SIGNIFICANCE: We provided the first evidence that VHs are associated with specific intraparietal sulcus dysfunction within the DAN in patients with PDD, PD, and DLB.

Postural Instability and Risk of Falls in Patients with Parkinson's Disease Treated with Deep Brain Stimulation: A Stabilometric Platform Study.

Postural instability (PI) in Parkinson's disease (PD) exposes patients to an increased risk of falls (RF). While dopaminergic therapy and deep brain stimulation (DBS) improve motor performance in advanced PD patients, their effects on PI and RF remain elusive. PI and RF were assessed using a stabilometric platform in six advanced PD patients. Patients were evaluated in OFF and ON dopaminergic medication and under four DBS settings: with DBS off, DBS bilateral, and unilateral DBS of the more- or less-affected side. Our findings indicate that dopaminergic medication by itself exacerbated PI and RF, and DBS alone led to a decline in RF. No combination of medication and DBS yielded a superior improvement in postural control compared to the baseline combination of OFF medication and the DBS-off condition. Yet, for ON medication, DBS significantly improved both PI and RF. Among DBS conditions, DBS bilateral provided the most favorable outcomes, improving PI and RF in the ON medication state and presenting the smallest setbacks in the OFF state. Conversely, the more-affected side DBS was less beneficial. These preliminary results could inform therapeutic strategies for advanced PD patients experiencing postural disorders.

Do cerebrovascular risk factors impact the clinical expression of idiopathic isolated adult-onset dystonia?

BACKGROUND: Although acquired dystonia may develop following ischaemic/haemorrhagic stroke, the relationship between cerebrovascular disease and idiopathic dystonia has been poorly investigated. This cross sectional study aimed at evaluating the impact of cerebrovascular risk factors on the clinical expression of idiopathic adult onset dystonia (IAOD), with reference to dystonia localization and dystonia-associated features. METHODS: Data were obtained from the Italian Dystonia Registry. Patients with IAOD were stratified into two groups according to the presence of diabetes mellitus and/or arterial hypertension and/or dyslipidemia and/or heart disease. The two groups were compared for demographic features, dystonia phenotype, and dystonia-associated features (sensory trick, tremor, eye symptoms in blepharospasm, and neck pain in cervical dystonia). RESULTS: A total of 1108 patients participated into the study. Patients who reported one cerebrovascular factor or more (n = 555) had higher age and longer disease duration than patients who did not. On multivariable logistic regression analysis, blepharospasm was the only localization, and sensory trick was the only dystonia-associated feature that was significantly associated with cerebrovascular risk factors. Linear regression analysis showed that the strength of the association between cerebrovascular factors and blepharospasm/sensory trick increased with increasing the number of cerebrovascular factors per patient. CONCLUSIONS: Results of the present study showed that cerebrovascular risk factors may be associated with specific features of IAOD that is development of blepharospasm and sensory trick. Further studies are needed to better understand the meaning and the mechanisms underlying this association.

Distal Upper Limb Tremor during Walking in Parkinson's Disease.

Background: Distal upper limb tremor during walking (TW) is frequently observed in Parkinson's disease (PD) but its clinical features are unknown. Objective: To characterize the occurrence and the clinical features of TW in comparison to the other types of tremors in PD. Methods: Fifty-one PD patients with rest tremor were evaluated off- and on-treatment. Occurrence, body distribution, severity and latency of TW and of other tremor types were assessed. Results: TW was present in 78% of the PD patients examined. TW body distribution and severity were similar to those of rest and re-emergent tremor but different from the postural tremor presented by the same patients. TW latency, observed in 85% of patients, was on average 5.8 s. Dopaminergic treatment significantly improved TW, rest, and re-emergent tremor severity but left TW latency unaffected. Conclusions: TW is a frequent motor sign in PD and is likely a clinical variant of rest tremor.

Phenotypic Variability in Acquired and Idiopathic Dystonia.

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias. Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias. Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia. Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor. Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories.

Risk and protective factors in Parkinson's disease: a simultaneous and prospective study with classical statistical and novel machine learning models.

BACKGROUND: Several environmental/lifestyle factors have been individually investigated in previous Parkinson's disease (PD) studies with controversial results. No study has prospectively and simultaneously investigated potential risk/protective factors of PD using both classical statistical and novel machine learning analyses. The latter may reveal more complex associations and new factors that are undetected by merely linear models. To fill this gap, we simultaneously investigated potential risk/protective factors involved in PD in a large prospective population study using both approaches. METHODS: Participants in the Moli-sani study were enrolled between 2005 and 2010 and followed up until December 2018. Incident PD cases were identified by individual-level record linkage to regional hospital discharge forms, the Italian death registry, and the regional prescription register. Exposure to potential risk/protective factors was assessed at baseline. Multivariable Cox Proportional Hazards (PH) regression models and survival random forests (SRF) were built to identify the most influential factors. RESULTS: We identified 213 incident PD cases out of 23,901 subjects. Cox PH models revealed that age, sex, dysthyroidism and diabetes were associated with an increased risk of PD. Both hyper and hypothyroidism were independently associated with PD risk. SRF showed that age was the most influential factor in PD risk, followed by coffee intake, daily physical activity, and hypertension. CONCLUSION: This study sheds light on the role of dysthyroidism, diabetes and hypertension in PD onset, characterized to date by an uncertain relationship with PD, and also confirms the relevance of most factors (age, sex, coffee intake, daily physical activity) reportedly shown be associated with PD. Further methodological developments in SRF models will allow to untangle the nature of the potential non-linear relationships identified.

Motor Cortical Correlates of Paired Associative Stimulation Induced Plasticity: A TMS-EEG Study.

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique that modulates synaptic plasticity in the human motor cortex (M1). Since previous studies have primarily used motor-evoked potentials (MEPs) as outcome measure, cortical correlates of PAS-induced plasticity remain unknown. Therefore, the aim of this observational study was to investigate cortical correlates of a standard PAS induced plasticity in the primary motor cortex by using a combined TMS-EEG approach in a cohort of eighteen healthy subjects. In addition to the expected long-lasting facilitatory modulation of MEPs amplitude, PAS intervention also induced a significant increase in transcranial magnetic stimulation-evoked potentials (TEPs) P30 and P60 amplitude. No significant correlation between the magnitude of PAS-induced changes in TEP components and MEP amplitude were observed. However, the linear regression analysis revealed that the combined changes in P30 and P60 component amplitudes significantly predicted the MEP facilitation after PAS. The findings of our study offer novel insight into the neurophysiological changes associated with PAS-induced plasticity at M1 cortical level and suggest a complex relationship between TEPs and MEPs changes following PAS.

Assessment of the psychometric properties of the Italian version of the New Freezing of Gait Questionnaire (NFOG-Q-IT) in people with Parkinson disease: a validity and reliability study.

INTRODUCTION: Freezing of gait (FOG) in Parkinson's disease (PD) is a challenging clinical symptom to assess, due to its episodic nature. A valid and reliable tool is the New FOG Questionnaire (NFOG-Q) used worldwide to measure FOG symptoms in PD. OBJECTIVE: The aim of this study was to translate, to culturally adapt, and to test the psychometric characteristics of the Italian version of the NFOG-Q (NFOG-Q-It). METHODS: The translation and cultural adaptation was based on ISPOR TCA guidelines to finalize the 9-item NFOG-Q-It. Internal consistency was assessed in 181 Italian PD native speakers who experienced FOG using Cronbach's alpha. Cross-cultural analysis was tested using the Spearman's correlation between the NFOG-Q-It and the Modified Hoehn-Yahr Scale (M-H&Y). To assess construct validity, correlations among NFOG-Q-It, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Falls Efficacy Scale-International (FES-I), the 6-min Walking Test (6MWT), the Mini Balance Evaluation System Test (Mini-BESTest) and the Short Physical Performance Battery (SPPB) were investigated. RESULTS: The Italian N-FOGQ had high internal consistency (Cronbach's α = 0.859). Validity analysis showed significant correlations between NFOG-Q-IT total score and M-H&Y scores (r = 0.281 p < 0.001), MDS-UPDRS (r = 0.359 p < 0.001), FES-I (r = 0.230 p = 0.002), Mini BESTest (r = -0.256 p = 0.001) and 6MWT (r = -0.166 p = 0.026). No significant correlations were found with SPPB, MOCA and MMSE. CONCLUSION: The NFOG-It is a valuable and reliable tool for assessing FOG symptoms, duration and frequency in PD subjects. Results provide the validity of NFOG-Q-It by reproducing and enlarging previous psychometric data.

Short-term plasticity of the motor cortex compensates for bradykinesia in Parkinson's disease.

Patients with Parkinson's disease (PD) show impaired short-term potentiation (STP) mechanisms in the primary motor cortex (M1). However, the role played by this neurophysiological abnormality in bradykinesia pathophysiology is unknown. In this study, we used a multimodal neuromodulation approach to test whether defective STP contributes to bradykinesia. We evaluated STP by measuring motor-evoked potential facilitation during 5 Hz-repetitive transcranial magnetic stimulation (rTMS) and assessed repetitive finger tapping movements through kinematic techniques. Also, we used transcranial alternating current stimulation (tACS) to drive M1 oscillations and experimentally modulate bradykinesia. STP was assessed during tACS delivered at beta (ß) and gamma (γ) frequency, and during sham-tACS. Data were compared to those recorded in a group of healthy subjects. In PD, we found that STP was impaired during sham- and γ-tACS, while it was restored during ß-tACS. Importantly, the degree of STP impairment was associated with the severity of movement slowness and amplitude reduction. Moreover, ß-tACS-related improvements in STP were linked to changes in movement slowness and intracortical GABA-A-ergic inhibition during stimulation, as assessed by short-interval intracortical inhibition (SICI). Patients with prominent STP amelioration had greater SICI reduction (cortical disinhibition) and less slowness worsening during ß-tACS. Dopaminergic medications did not modify ß-tACS effects. These data demonstrate that abnormal STP processes are involved in bradykinesia pathophysiology and return to normal levels when ß oscillations increase. STP changes are likely mediated by modifications in GABA-A-ergic intracortical circuits and may represent a compensatory mechanism against ß-induced bradykinesia in PD.