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.

Secondary neurodegeneration following Stroke: what can blood biomarkers tell us?

Stroke is one of the leading causes of death and the primary source of disability in adults, resulting in neuronal necrosis of ischemic areas, and in possible secondary degeneration of regions surrounding or distant to the initial damaged area. Secondary neurodegeneration (SNDG) following stroke has been shown to have different pathogenetic origins including inflammation, neurovascular response and cytotoxicity, but can be associated also to regenerative processes. Aside from focal neuronal loss, ipsilateral and contralateral effects distal to the lesion site, disruptions of global functional connectivity and a transcallosal diaschisis have been reported in the chronic stages after stroke. Furthermore, SNDG can be observed in different areas not directly connected to the primary lesion, such as thalamus, hippocampus, amygdala, substantia nigra, corpus callosum, bilateral inferior fronto-occipital fasciculus and superior longitudinal fasciculus, which can be highlighted by neuroimaging techniques. Although the clinical relevance of SNDG following stroke has not been well understood, the identification of specific biomarkers that reflect the brain response to the damage, is of paramount importance to investigate in vivo the different phases of stroke. Actually, brain-derived markers, particularly neurofilament light chain, tau protein, S100b, in post-stroke patients have yielded promising results. This review focuses on cerebral morphological modifications occurring after a stroke, on associated cellular and molecular changes and on state-of-the-art of biomarkers in acute and chronic phase. Finally, we discuss new perspectives regarding the implementation of blood-based biomarkers in clinical practice to improve the rehabilitation approaches and post stroke recovery.

Blood-Brain Barrier Dysfunction and Aß42/40 Ratio Dose-Dependent Modulation with the ApoE Genotype within the ATN Framework.

The definition of Alzheimer's disease (AD) now considers the presence of the markers of amyloid (A), tau deposition (T), and neurodegeneration (N) essential for diagnosis. AD patients have been reported to have increased blood-brain barrier (BBB) dysfunction, but that has not been tested within the ATN framework so far. As the field is moving towards the use of blood-based biomarkers, the relationship between BBB disruption and AD-specific biomarkers requires considerable attention. Moreover, other factors have been previously implicated in modulating BBB permeability, including age, gender, and ApoE status. A total of 172 cognitively impaired individuals underwent cerebrospinal fluid (CSF) analysis for AD biomarkers, and data on BBB dysfunction, demographics, and ApoE status were collected. Our data showed that there was no difference in BBB dysfunction across different ATN subtypes, and that BBB damage was not correlated with cognitive impairment. However, patients with BBB disruption, if measured with a high Qalb, had low Aß40 levels. ApoE status did not affect BBB function but had a dose-dependent effect on the Aß42/40 ratio. These results might highlight the importance of understanding dynamic changes across the BBB in future studies in patients with AD.

Clinical and neurochemical correlates of the APOE genotype in early-stage Parkinson's disease.

Emerging evidence indicates that apolipoprotein E (APOE) genotype may influence Parkinson's disease (PD) course, although clinical and neurochemical correlates have not been completely established. This study aimed to determine the associations of APOE genotypes (ε4 vs. non-ε4) with cerebrospinal fluid (CSF) neurodegeneration biomarkers and clinical parameters in early-stage PD patients. One hundred and seventy-five PD patients and 89 non-neurodegenerative controls grouped in APOE-ε4 carriers (28 PD; 12 controls) and non-APOE-ε4 carriers (147 PD; 78 controls) were enrolled. CSF levels of amyloid-ß-42, amyloid-ß-40, total and 181-phosphorylated tau, and clinical scores were compared among groups adjusting for main covariates. APOE genotypes prevalence was similar in PD and controls. PD APOE-ε4 carriers had lower amyloid-ß-42 CSF levels than PD non-APOE-ε4 carriers and controls, independently from age. PD APOE-ε4 carriers also had higher total and "item 5" (attention and memory) non-motor symptoms scale scores than PD non-APOE-ε4 carriers, independently from confounding factors. APOE-ε4 genotype might thus account for a more vulnerable PD subtype characterized by prominent amyloidopathy and a greater burden of non-motor symptoms in the early disease stages. DATA AVAILABILITY: Data are available upon reasonable request.

Neutrophil-to-lymphocyte ratio and lymphocyte count reflect alterations in central neurodegeneration-associated proteins and clinical severity in Parkinson Disease patients.

INTRODUCTION: Peripheral inflammation has been recently associated to Parkinson disease (PD). However, how the peripheral inflammatory immune response could affect the clinical-pathological features of the disease is not fully understood. In this study, we assessed the peripheral immune profile of a well-characterized PD cohort, examining several correlations with CSF biomarkers of neurodegeneration and the main clinical parameters, aimed at better elucidating the complex dynamics of the brain-periphery interactions in PD. METHODS: The leukocyte populations counts (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and the neutrophil-to-lymphocyte ratio (NLR) were collected and compared in 61 PD patients and 60 sex/age matched controls (CTRLs). Immune parameters were correlated with CSF levels of total α-synuclein, amyloid-ß-42, total and phosphorylated-tau and main motor and non-motor scores. RESULTS: PD patients had lower lymphocyte and higher NLR counts compared to CTRLs. In PD patients, the lymphocyte count directly correlated with CSF α-synuclein levels, whereas NLR displayed an inverse correlation with the CSF amyloid-ß42 levels. The lymphocyte count also negatively correlated with HY stage, while NLR positively with the disease duration. CONCLUSIONS: This study provided in vivo evidence that, in PD, changes in leukocytes in the periphery, assessed as relative lymphopenia and NLR increase, reflect in central neurodegeneration-associated proteins modifications, especially in α-synuclein and amyloid-ß pathways, and greater clinical burden.

Sex hormones differentially contribute to Parkinson disease in males: A multimodal biomarker study.

BACKGROUND AND PURPOSE: Parkinson disease (PD) presents relevant sex-related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human-based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinical-pathological features in male PD patients. METHODS: A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α-synuclein, amyloid-ß-42, amyloid-ß-40, total tau, and phosphorylated-181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3-T magnetic resonance imaging for further correlations. A control group of 56 age-matched individuals was enrolled for comparative analyses. RESULTS: Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF α-synuclein and right globus pallidus volume. FSH and LH had age-dependent correlations with cognitive impairment and CSF amyloid-ß-42/amyloid-ß-40 ratio. CONCLUSIONS: The study suggested that sex hormones could differentially contribute to clinical-pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age-dependent phenomena of amyloidopathy and cognitive decline.

Constipation distinguishes different clinical-biochemical patterns in de novo Parkinson's disease.

INTRODUCTION: Prodromal constipation (PC) at Parkinson's disease (PD) onset may mark a distinct neurodegenerative trajectory; accordingly, presenting phenotype, biochemical signature, and progression of PD patients with PC (PD + PC) might differ from those without (PDwoPC). We compared the clinical-biochemical profile of de novo PD patients with and without PC, and the respective mid-term progression, to establish the grouping effect of PC. METHODS: Motor and non-motor scores were collected at diagnosis in n = 57 PD + PC patients and n = 73 PDwoPC. Paired CSF biomarkers (α-synuclein, amyloid and tau peptides, lactate, CSF/serum albumin ratio or AR) were assessed into a smaller sample and n = 46 controls. Clinical progression was estimated as Hoehn and Yahr stage (HY) and levodopa equivalent daily dose (LEDD) change 2.06 ± 1.35 years after diagnosis. RESULTS: At onset, PD + PC patients had higher HY and MDS-UPDRS-part III scores, and higher CSF AR. PDwoPC had higher Non-Motor Symptoms Scale domain-2 score, and lower CSF α-synuclein level. At follow-up, PD + PC had greater LEDD. CONCLUSIONS: PC identifies a group of de novo patients with more severe motor impairment, possible blood brain barrier disruption, and greater dopaminergic requirement at mid-term; conversely, de novo PDwoPC patients had prominent fatigue, and pronounced central synucleinopathy.

Tau and Amyloid-ß Peptides in Serum of Patients With Parkinson's Disease: Correlations With CSF Levels and Clinical Parameters.

Relevance of blood-based biomarkers is increasing into the neurodegenerative diseases field, but data on Parkinson's disease (PD) remain still scarce. In this study, we used the SiMoA technique to measure serum content of total tau protein and amyloid-ß peptides (Aß-42, Aß-40) in 22 PD patients and ten control subjects. Serum levels of each biomarker were correlated with the respective CSF levels in both the groups; in PD patients, also the correlations between serum biomarkers and main clinical parameters were tested (motor, non-motor, cognitive scores and levodopa equivalent daily dose). Serum biomarkers did not exhibit quantitative differences between patients and controls; however, only PD patients had inter-fluids (serum-CSF) associations in tau and amyloid-ß-42 levels. Moreover, serum content of tau protein was inversely correlated with cognitive performances (MoCA score). These findings, albeit preliminary, indicate that brain-derived peptides may change in parallel in both peripheral blood and CSF of PD patients, eventually even in association with some clinical features. Further studies are now needed to validate the use of blood-based biomarkers in PD.

Biofluids profile of α-Klotho in patients with Parkinson's disease.

We measured α-Klotho in CSF and serum of PD patients at early stage of the disease, finding two distinct pools, the first increased, the second reduced. CSF α-Klotho was inversely associated with CSF α-synuclein levels. Our preliminary results suggest α-Klotho as potential biomarker or therapeutic target in PD.

Effects of head trauma and sport participation in young-onset Parkinson's disease.

Head trauma (HT) is emerging as an event anticipating onset of neurodegenerative disorders. However, the potential contribution of HT in young-onset cases (YOPD, age at onset < 50) of Parkinson's disease (PD) has not been examined yet. Here, we systematically assessed HT history in PD patients to estimate the risk associated, especially in terms of age of onset, and define the correlations with the clinical-biochemical profile. The Brain Injury Screening Questionnaire (BISQ) was administered to 94 PD patients (31 with YOPD, known monogenic forms excluded) and 70 controls. HT history was correlated with motor and non-motor scores in all patients, and to CSF biomarkers of neurodegeneration (α-synuclein, amyloid-ß42, total and phosporiled-181 tau, lactate, CSF/serum albumin) into a subgroup. HT increased the risk for both PD and YOPD. In PD patients, but not in those with YOPD, the number of HTs directly correlated with CSF total-tau levels. No other correlations resulted between HT and clinical parameters. Sport-related HT was a specific risk factor for YOPD; conversely, the prolonged sporting life represented a protective factor. HTs can favor PD onset, even as YOPD. Sport-related HT resulted a risk factor for YOPD, although the longer sporting practice delayed PD onset, protecting from YOPD. Tauopathy may underlie the overall association between HT and PD. Additional mechanisms could be instead implicated in HT contribution to YOPD onset.

How Comorbidity Reflects on Cerebrospinal Fluid Biomarkers of Neurodegeneration in Aging.

Systemic comorbidity precipitates the risk for dementia. To comprehend the underlying mechanisms into a therapeutic perspective, we analyzed how comorbidity affects neurodegeneration-related cerebrospinal fluid (CSF) biomarkers of 55 cognitively intact subjects. The Charson Comorbidity Index (CCI) was correlated with CSF amyloid-ß42 (Aß42), amyloid-ß40, total-tau, 181-phosphorylated-tau (p-tau), the Aß42/p-tau ratio, neurogranin, and lactate. The age-related brain lesions at imaging were also considered. CCI had a raw association with Aß42/p-tau and p-tau, and a stronger, age-independent correlation with lactate. These preliminary findings suggested that, in normal subjects, systemic comorbidity might increase CNS oxidative stress and, together with aging, contribute to develop an Alzheimer's disease-like biochemical profile.

Amyloid-ß42/Neurogranin Ratio as a Potential Index for Cognitive Impairment in Parkinson's Disease.

BACKGROUND: Synaptopathy is critical in pathophysiology of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-ß42 (Aß42) are considered markers of synaptic dysfunction in neurodegenerative diseases. OBJECTIVE: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aß42/NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. METHODS: Levels of NG, Aß42, amyloid-ß40, total and phosphorylated tau, and Aß42/NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was determined. RESULTS: NG and Aß42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aß42/NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. CONCLUSIONS: The novel Aß42/NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD.

Young-onset and late-onset Parkinson's disease exhibit a different profile of fluid biomarkers and clinical features.

Young-onset Parkinson's disease (YOPD) is a relevant condition whose neurobiology is questioned if different from those of typical late-onset Parkinson's disease (LOPD). Here, we explored whether the clinical-biochemical profile of Parkinson's disease (PD) could be affected by the age-of-onset (AO), as a possible result of a distinct neurodegenerative process. A panel of fluid biomarkers (CSF lactate, 42-amyloid-ß peptide, total and 181-phosphorylated tau; serum uric acid) and the standard scores for motor and nonmotor signs were assessed in 76 idiopathic PD patients (genetic cases excluded; YOPD, AO ≤ 50, n = 44; LOPD, AO > 50, n = 32) and 75 sex/age-matched controls, adjusting the models for the main confounding factors. In PD, AO directly correlated to either CSF lactate and tau proteins or the nonmotor symptoms scale score. Specifically, a younger AO was associated with lower levels of biomarkers and minor burden of nonmotor symptoms. Our findings indicate that clinical-biochemical features of idiopathic PD may vary depending on the AO, accounting for different profiles in YOPD and LOPD whose recognition is fundamental for further pathophysiological implications and clinical applications.

Sleep-Wake Cycle in Alzheimer's Disease Is Associated with Tau Pathology and Orexin Dysregulation.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease. OBJECTIVE: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations. METHODS: Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls. RESULTS: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation. CONCLUSION: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

Phospho-S129 Alpha-Synuclein Is Present in Human Plasma but Not in Cerebrospinal Fluid as Determined by an Ultrasensitive Immunoassay.

Accumulation and aggregation of misfolded alpha-synuclein is believed to be a cause of Parkinson's disease (PD). Phosphorylation of alpha-synuclein at S129 is known to be associated with the pathological misfolding process, but efforts to investigate the relevance of this post-translational modification for pathology have been frustrated by difficulties in detecting and quantifying it in relevant samples. We report novel, ultrasensitive immunoassays based on single-molecule counting technology, useful for detecting alpha-synuclein and its S129 phosphorylated form in clinical samples in the low pg/ml range. Using human CSF and plasma samples, we find levels of alpha-synuclein comparable to those previously reported. However, while alpha-synuclein phosphorylated on S129 could easily be detected in human plasma, where its detection is extremely sensitive to protein phosphatases, its levels in CSF were undetectable, with a possible influence of a matrix effect. In plasma samples from a small test cohort comprising 5 PD individuals and five age-matched control individuals we find that pS129 alpha-synuclein levels are increased in PD plasma samples, in line with previous reports. We conclude that pS129 alpha-synuclein is not detectable in CSF and recommend the addition of phosphatase inhibitors to plasma samples at the time of collection. Moreover, the findings obtained on the small cohort of clinical plasma samples point to plasma pS129 alpha-synuclein levels as a candidate diagnostic biomarker in PD.

Aggregation States of Aß1-40, Aß1-42 and Aßp3-42 Amyloid Beta Peptides: A SANS Study.

Aggregation states of amyloid beta peptides for amyloid beta A ß 1 - 40 to A ß 1 - 42 and A ß p 3 - 42 are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are of key importance for the comprehension of neurodegenerative diseases (e.g., Alzheimer's disease). The SANS technique allows to study the size and fractal nature of the monomers, oligomers and fibrils of the three different peptides. Results show that all the investigated peptides have monomers with a radius of gyration of the order of 10 Å, while the oligomers and fibrils display differences in size and aggregation ability, with A ß p 3 - 42 showing larger oligomers. These properties are strictly related to the toxicity of the corresponding amyloid peptide and indeed to the development of the associated disease.

Neuropsychiatric symptoms differently affect mild cognitive impairment and Alzheimer's disease patients: a retrospective observational study.

Alzheimer's disease (AD) is the most common form of dementia characterized by the prevalent memory impairment. Mild cognitive impairment (MCI) may represent the early stage of AD, in particular when MCI patients show biomarkers consistent with AD pathology (MCI due to AD). Neuropsychiatric symptoms (NPS) frequently affect both MCI and AD patients. Cerebrospinal-fluid (CSF) tau and ß-amyloid42 (Aß42) levels are actually considered the most sensitive and specific biomarkers for AD neurodegeneration. In the present retrospective observational study, we evaluated CSF biomarkers and neuropsychological data (also including NPS measured by the neuropsychiatric inventory-NPI) in a population of patients affected by MCI due to AD compared with mild to moderate AD patients. We documented higher NPI scores in MCI compared with AD patients. In particular, sub-items related to sleep, appetite, irritability, depression, and anxiety were higher in MCI than AD. We also found the significant correlation between NPS and CSF AD biomarkers in the whole population of MCI and AD patients. Consistently, t-tau/Aß42 ratio correlated with NPS in all the MCI and AD patients. These results suggest the more prevalent occurrence of NPS in MCI patients showing AD pathology and converting to dementia than AD patients. Moreover, a more significant degree of AD neurodegeneration, featured by high t-tau/Aß42 ratio, correlated with more severe NPS, thus supposing that in MCI and AD patients a more extensive AD neurodegeneration is related to more severe behavioral disturbances.

Association between physical activity and dementia's risk factors in patients with Parkinson's disease.

Evidence suggests that physical activity (PA) exerts beneficial effects on neurodegenerative processes, either as symptomatic relief or disease-modifying strategy. Actually, it may represent a viable neuroprotective intervention in Parkinson's disease dementia (PDD), a severe, frequent, and untreatable complication of Parkinson's disease (PD). According to such hypothesis, this cross-sectional study tested, in PD patients, the association between levels of PA and well-known risk factors for PDD, such as mood disorders and amyloid-ß42 CSF content. Amount of PA was measured by the International Physical Activity Questionnaires-Short Form (IPAQ-SF) in 128 cognitively intact PD patients and correlated with the Hamilton-Depression (HAM-D) and the Hamilton-Anxiety (HAM-A) scores; in a homogenous subgroup of 40 patients, it was further correlated with a panel of CSF biomarkers, including amyloid-ß42, total α-synuclein, total, and phosphorylated tau. The statistical model was corrected for the main potential confounding factors (motor impairment, dopaminergic treatment, disease duration, age, and sex). Both the HAM-A and HAM-D scores, as well as the Aß42 CSF content, improved in parallel with the increase of the total week amount of PA. Although with several limitations, we preliminarily demonstrated that a high level of PA is associated with a more favourable profile of PDD risk factors, in terms of both mood disturbances and CSF markers of neurodegeneration. However, confirmative studies are necessary to validate the efficacy of PA as protective intervention for PDD.

CSF Biomarkers for Early Diagnosis of Synucleinopathies: Focus on Idiopathic RBD.

PURPOSE OF REVIEW: Idiopathic REM sleep behavior disorder (iRBD) is one of the most significant prodromal manifestations of synucleinopathies. Different predictive biomarkers for iRBD conversion have been investigated, but scarce data are present in literature about the predictive role of cerebrospinal fluid (CSF) biomarkers. In this review, we focus on CSF biomarkers in patients with both iRBD and RBD associated with synucleinopathies to explore their potential predictive power. RECENT FINDINGS: Recent studies revealed that CSF α-synuclein levels are higher in Parkinson's disease (PD) patients with RBD compared to those without RBD, even if α-synuclein does not seem to predict conversion of iRBD into PD. In the Parkinson Progression Marker Initiative (PPMI) cohort, early PD patients with RBD show lower CSF Aß42 levels, which predict faster cognitive decline. CSF prion protein and inflammatory biomarkers have been also investigated in RBD and synucleinopathies with controversial results. A variety of CSF biomarkers are promising candidate for predicting iRBD conversion into synucleinopathies. Further studies are needed in iRBD patients followed for several years in order to observe the phenoconversion in synucleinopathies and to elucidate the possible role of CSF biomarkers as predictive biomarkers of conversion.

CSF α-synuclein inversely correlates with non-motor symptoms in a cohort of PD patients.

INTRODUCTION: Although non-motor symptoms are early and disabling features of PD, reliable predictors and effective therapies are not yet available. Measurement of CSF proteins mirroring brain pathology is currently utilized for diagnostic and prognostic clustering of patients with neurodegenerative diseases but the association with non-motor symptoms in PD has not been evaluated. Here we performed a cross-sectional correlation study, aimed at identifying potential fluid biomarkers for non-motor symptoms in PD. METHODS: CSF levels of 42-amyloid-ß, total and phosphorylated tau, α-synuclein and reciprocal ratios were measured in a group of 46 PD patients compared to 37 gender/age-matched controls and correlated with standard clinical scores for motor and non-motor features. RESULTS: We observed that α-synuclein levels were reduced in PD (p < 0.05, AUC = 0.8; p < 0.05) and inversely correlated with non-motor symptoms scale total score and items 3 and 9, even independently from age, disease duration, motor impairment severity and dopaminergic treatment (T = -2,9, p < 0.014; T = -3.6, p < 0.05; item 9: T = -2.1, p < 0.05, respectively). CONCLUSIONS: Our findings suggest that the reduction of CSF α-synuclein may parallel degeneration of non-dopaminergic systems. Although confirmatory studies are necessary, CSF α-synuclein reduction might represent a potential biomarker to monitor non-motor symptoms burden.