Cerebrospinal Fluid Α-syn Research Articles

Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study.

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease. A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between amyloid and α-syn and their association with disease progression. Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Biofluid Markers and Tissue Biopsies Analyses for the Prodromal and Earliest Phase of Parkinson's Disease.

The recent development of new methods to detect misfolded α-synuclein (αSyn) aggregates in biofluids and tissue biopsies in the earliest Parkinson's disease (PD) phases is dramatically challenging the biological definition of PD. The αSyn seed amplification methods in cerebrospinal fluid (CSF) showed high sensitivity and specificity for early diagnosis of PD and Lewy bodies disorders. Several studies in isolated REM sleep behavior disorders and other at-risk populations also demonstrated a high prevalence of CSF αSyn positivity and its potential value in predicting the phenoconversion to clinically manifested diseases. Growing evidence exists for αSyn aggregates in olfactory mucosa, skin, and other tissues in subjects with PD or at-risk subjects. DOPA decarboxylase and numerous other candidates have been additionally proposed for either diagnostic or prognostic purposes in earliest PD phases. The newly described αSyn detection in blood, through its quantification in neuronally-derived exosome vesicles, represents a technical challenge that could open a new scenario for the biological diagnosis of PD. Despite this growing evidence in the field, most of method of αSyn detection and markers still need to be validated in ongoing longitudinal studies through an accurate assessment of different prodromal disease subtypes and scenarios before being definitively implemented in clinical settings.

Clinical, neuropathological, and molecular characteristics of rapidly progressive dementia with Lewy bodies: a distinct clinicopathological entity?

BackgroundThe term rapidly progressive dementia (RPD) with Lewy bodies (rpDLB) is used for DLB patients who develop a rapidly progressive neurological syndrome and have reduced survival. Here, we characterise the clinical, neuropathological, and molecular characteristics of a large rpDLB neuropathological series.MethodsWe included all RPD patients with a disease duration < 4 years submitted to our prion disease referral centre between 2003 and 2022 who showed Lewy body pathology (LBP) in limbic or neocortical stages as primary neuropathological diagnosis, had no systemic condition justifying the rapid deterioration and were previously neurologically unimpaired. Clinical features were retrieved and compared with Creutzfeldt-Jakob disease (CJD) and rapidly progressive Alzheimer’s disease (rpAD) cohorts. Neuropathological and genetic (whole exome sequencing, APOE genotyping, and C9orf72 repeat expansion analysis) characteristics of rpDLB patients were systematically investigated. We scored semi-quantitatively the LBP load and performed a α-synuclein (αSyn) RT-QuIC seeding amplification assay (SAA) on cerebrospinal fluid (CSF) and tenfold serially diluted brain homogenates from different brain areas in rpDLB patients and typical long-lasting Lewy body disease (LBD) with dementia patients as control group.ResultsRpDLB patients were older (p = 0.047) and presented more cognitive fluctuations (p = 0.005), visual hallucinations (p = 0.020), neuropsychiatric symptoms (p = 0.006) and seizures (p = 0.032), and fewer cerebellar (p < 0.001) and visual (p = 0.004) signs than CJD ones. Delirium onset was more common than in both CJD (p < 0.001) and rpAD (p = 0.008). Atypical LBD signs (pyramidal, myoclonus, akinetic mutism) were common. All tested patients were positive by CSF αSyn SAA. Concomitant pathologies were common, with only four cases showing relatively “pure” LBP. LBP load and αSyn seeding activity measured through αSyn RT-QuIC SAA were not significantly different between rpDLB patients and typical LBD. We found a likely pathogenic variant in GBA in one patient.ConclusionsOur results indicate that: 1) rpDLB exhibits a distinct clinical signature (2) CSF αSyn SAA is a reliable diagnostic test; 3) rpDLB is a heterogeneous neuropathological entity that can be underlain by both widespread pure LBP, or multiple copathologies 4) rpDLB is likely not sustained by distinct αSyn conformational strains; 5) genetic defects may, at least occasionally, contribute to the poor prognosis in these patients.

Intracerebroventricular injection of α-synuclein preformed fibrils do not induce motor and olfactory impairment in C57BL/6 mice

IntroductionAlpha-synuclein (αSyn) is believed to play a central role in the pathogenesis of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) total αSyn were significantly lower in PD patients, whereas the aggregates were higher, and this phenomenon was further exacerbated with longer disease duration. However, whether CSF αSyn can be the cause and/or a consequence in PD is not fully elucidated. MethodWe administered 2 ng or 200 ng αSyn preformed fibrils (PFFs) by intracerebroventricular injection for consecutive 7 days in C57BL/6 mice. The olfactory function was assessed by the olfactory discrimination test and buried food-seeking test. The locomotor function was assessed by the rotarod test, pole test, open field test and CatWalk gait analysis. Phosphorylated αSyn at serine 129 was detected by the immunohistochemistry staining. Iron levels was determined by Perl’s-diaminobenzidine iron staining and synchrotron-based X-ray fluorescence. ResultsThe mice did not exhibit any diffuse synucleinopathy in the brain for up to 30 weeks, although αSyn PFFs induced aggregation in SH-SY5Y cells and in the substantia nigra and striatum of mice with stereotactic injection. No impairment of motor behaviors or olfactory functions were observed, although there was a temporary motor enhancement at 1 week. We then demonstrated iron levels were comparable in certain brain regions, suggesting there was no iron deposition/redistribution occurred. ConclusionThe intraventricular injection of αSyn PFFs does not induce synucleinopathy or behavioral symptoms. These findings have implications that CSF αSyn aggregates may not necessarily contribute to the onset or progression in PD.

Contribution of alpha-synuclein pathology to cerebral glucose metabolism in patients with amnestic MCI.

The in vivo detection of mixed Alzheimer's disease (AD) and α-synuclein (αSyn) pathology is important for clinical management and prognostic stratification. We investigated the contribution of αSyn pathology, detected by cerebrospinal fluid (CSF) seed amplification assay (αSyn SAA), on [18F]-fluorodeoxyglucose positron emission tomography (FDG PET) pattern in subjects with amnestic mild cognitive impairment (aMCI). We included 562 aMCI participants and 204 cognitively normalcontrols (CN) with available αSyn SAA and cerebral metabolic rate for glucose utilization (rCMRgl) data. 24% of aMCI cases were positive (+) for CSF αSyn SAA. Compared to CN, both αSyn+ and negative (-) aMCI participants showed reductions in rCMRgl within AD typical regions. αSyn+ aMCI had lower rCMRgl within AD and dementia with Lewy bodies (DLB) typical regions compared to αSyn- aMCI, even after stratification according to the CSF AT(N) system. αSyn pathology contributes to a distinct FDG PET pattern in aMCI. αSyn pathology can be detected in vivo by CSF αSyn SAA. We investigated the FDG PET pattern in aMCI patients with CSF αSyn SAA positivity. αSyn+ aMCI showed a marked brain hypometabolism in AD and DLB typical regions.

Predicting Cerebrospinal Fluid Alpha-Synuclein Seed Amplification Assay Status from Demographics and Clinical Data.

To develop and externally validate models to predict probabilities of alpha-synuclein (a-syn) positive or negative status in vivo in a mixture of people with and without Parkinson's disease (PD) using easily accessible clinical predictors. Uni- and multi-variable logistic regression models were developed in a cohort of participants from the Parkinson Progression Marker Initiative (PPMI) study to predict cerebrospinal fluid (CSF) a-syn status as measured by seeding amplification assay (SAA). Models were externally validated in a cohort of participants from the Systemic Synuclein Sampling Study (S4) that had also measured CSF a-syn status using SAA. The PPMI model training/testing cohort consisted of 1260 participants, of which 76% had manifest PD with a mean (± standard deviation) disease duration of 1.2 (±1.6) years. Overall, 68.7% of the overall PPMI cohort (and 88.0% with PD of those with manifest PD) had positive CSF a-syn SAA status results. Variables from the full multivariable model to predict CSF a-syn SAA status included age- and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) percentile values, sex, self-reported presence of constipation problems, leucine-rich repeat kinase 2 (LRRK2) genetic status and pathogenic variant, and GBA status. Internal performance of the model on PPMI data to predict CSF a-syn SAA status had an area under the receiver operating characteristic curve (AUROC) of 0.920, and sensitivity/specificity of 0.881/0.845. When this model was applied to the external S4 cohort, which included 71 participants (70.4% with manifest PD for a mean 5.1 (±4.8) years), it performed well, achieving an AUROC of 0.976, and sensitivity/specificity of 0.958/0.870. Models using only UPSIT percentile performed similarly well upon internal and external testing. Data-driven models using non-invasive clinical features can accurately predict CSF a-syn SAA positive and negative status in cohorts enriched for people living with PD. Scores from the UPSIT were highly significant in predicting a-syn SAA status.

A dual target molecular magnetic resonance imaging probe for noninvasive profiling of pathologic alpha-synuclein and microgliosis in a mouse model of Parkinson's disease.

The pathogenesis of Parkinson's disease (PD) is characterized by progressive deposition of alpha-synuclein (α-syn) aggregates in dopaminergic neurons and neuroinflammation. Noninvasive in vivo imaging of α-syn aggregate accumulation and neuroinflammation can elicit the underlying mechanisms involved in disease progression and facilitate the development of effective treatment as well as disease diagnosis and prognosis. Here we present a novel approach to simultaneously profile α-syn aggregation and reactive microgliosis in vivo, by targeting oligomeric α-syn in cerebrospinal fluid with nanoparticle bearing a magnetic resonance imaging (MRI), contrast payload. In this proof-of-concept report we demonstrate, in vitro, that microglia and neuroblastoma cell lines internalize agglomerates formed by cross-linking the nanoparticles with oligomeric α-syn. Delayed in vivo MRI scans following intravenous administration of the nanoparticles in the M83 α-syn transgenic mouse line show statistically significant MR signal enhancement in test mice versus controls. The in vivo data were validated by ex-vivo immunohistochemical analysis which show strong correlation between in vivo MRI signal enhancement, Lewy pathology distribution, and microglia activity in the treated brain tissue. Furthermore, neuronal and microglial cells in brain tissue from treated mice display strong cytosolic signal originating from the nanoparticles, attributed to in vivo cell uptake of nanoparticle/oligomeric α-syn agglomerates.

Biomarkers of Parkinson's disease in perspective of early diagnosis and translation of neurotrophic therapies.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopamine neurons and aberrant deposits of alpha-synuclein (α-syn) in the brain. The symptomatic treatment is started after the onset of motor manifestations in a late stage of the disease. Preclinical studies with neurotrophic factors (NTFs) show promising results of disease-modifying neuroprotective or even neurorestorative effects. Four NTFs have entered phase I-II clinical trials with inconclusive outcomes. This is not surprising because the preclinical evidence is from acute early-stage disease models, but the clinical trials included advanced PD patients. To conclude the value of NTF therapies, clinical studies should be performed in early-stage patients with prodromal symptoms, that is, before motor manifestations. In this review, we summarize currently available diagnostic and prognostic biomarkers that could help identify at-risk patients benefiting from NTF therapies. Focus is on biochemical and imaging biomarkers, but also other modalities are discussed. Neuroimaging is the most important diagnostic tool today, but α-syn imaging is not yet viable. Modern techniques allow measuring various forms of α-syn in cerebrospinal fluid, blood, saliva, and skin. Digital biomarkers and artificial intelligence offer new means for early diagnosis and longitudinal follow-up of degenerative brain diseases.

Highly sensitive biosensor based on IGZO thin-film transistors for detection of Parkinson's disease

α-Synuclein (α-Syn) is a major biomarker of Parkinson's disease (PD). Concentration detection of α-Syn in cerebrospinal fluid and plasma of patients are used as a clue for early PD detection. Herein, we propose a thin-film transistor (TFT) biosensor based on an indium gallium zinc oxide (IGZO) thin film fabricated by the sol-gel method. The IGZO TFT biosensor is used for the early detection of PD after surface functionalization for α-Syn. The surface functionalization worked on the surface of the extended gate indium tin oxide sensing platform instead of the channel layer of TFT. Depending on concentrations of α-Syn in human cerebrospinal fluid and plasma, we diluted six different concentrations of α-Syn for detection, ranging from 1 pg ml−1 to 100 ng ml−1. The result shows that the biosensor exhibits high sensitivity and selectivity for α-Syn, a reliable sensing performance with a sensitivity of 189.9 mV dec−1, and a coefficient of determination R2 of 99.7% between 10 pg ml−1 and 100 ng ml−1.

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

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

Effects of soluble TREM2 on motor progression in Parkinson’s disease

ObjectivesTo determine whether sTREM2 is changed during the pathogenesis of PD and reflect motor decline in PD individuals. MethodsThe cerebrospinal fluid (CSF) from PD and healthy individuals were obtained to measure the expression of sTREM2 and further to evaluate the motor function at baseline and after four years of follow-up using the Parkinson’s Progression Markers Initiative (PPMI) database. The relationship between motor disease progression at baseline and longitudinal CSF sTREM2 was evaluated by linear mixed-effects (LME) and multiple linear regression (MLR) models. The change rates of the motor symptoms and sTREM2 level in CSF were further rigorously analyzed using the LME model. Cox proportional-hazards regression models were used to evaluate the predictive values of sTREM2 in CSF for motor progression. The regulatory role of CSF α-syn and Tau between sTREM2 and motor assessments was evaluated by Mediating effect analysis. ResultsWe found no significant difference in CSF sTREM2 levels between the PD and HC groups (p = 0.155). However, late-onset PD patients had higher CSF sTREM2 levels than early-onset PD patients (p = 0.044). The basal levels of sTREM2 could predict motor progression over the four years of follow-up. The change rate of CSF sTREM2 was correlated with the progressive deterioration of motor function in PD individuals. Our observations also showed that CSF Tau was a significant mediator of the association between CSF sTREM2 and total UPDRS scores and UPDRS III and tremor at baseline with 26.5% and 33.5%, and 28.7% mediation, respectively. ConclusionOur results indicated that CSF sTREM2 was associated with the prognosis of PD motor symptoms. Besides, CSF Tau could effectively mediate the association of sTREM2 with motor progression.

Cerebrospinal fluid glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in Alzheimer’s Disease and Related Dementias (ADRD)

AbstractBackgroundDiscerning Dementia with Lewy Bodies (DLB) from Alzheimer's disease (AD) can be a challenge for the clinician and represents a critical unmet medical need. Diagnosis of DLB is especially challenging in early stages due to variable core features and coexistent pathologies such as AD. A variable immune response has been implicated in AD/ADRD. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a myeloid cell activity marker, has been genetically linked to AD risk and glial fibrillary acidic protein (GFAP), an astrocyte activity marker, is liked to astrogliosis in a number of neurologic disorders. Our objective was to explore differences in cerebrospinal fluid (CSF) values of both sTREM2 and GFAP in AD/ADRD. This included individuals clinically diagnosed with AD, DLB, mild‐cognitive impairment (MCI), Parkinson’s Disease (PD), and cognitively normal controls (CN).MethodCohorts included participants from the Cleveland Clinic‐based Dementia with Lewy Body Consortium (DLBC), the Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease biobank (LRCBH‐biobank) and the Cleveland Alzheimer's Disease Research Center (CADRC). Patients were clinically characterized based on CSF biomarkers, clinical symptoms, and consensus review. Analytes measured included: CSF GFAP, CSF sTREM2, CSF a‐synuclein (aSyn) and plasma neurofilament light chain (NfL) using multiple platforms such as the Luminex/Millipore and Meso Scale Discovery systems.ResultIn this AD/ADRD cohort, CSF aSyn was higher in MCI than both PD and DLB, while lower in DLB than CN and AD. CSF sTREM2 was higher in MCI, AD and DLB than CN. GFAP was higher in MCI than either CN or DLB, while AD was higher than DLB. sTREM2/GFAP ratio was higher in DLB than CN, MCI, AD and PD.ConclusionThese findings suggest that inflammatory factors, CSF sTREM2 and GFAP are altered in both AD and DLB. Future study of the relationship between CSF amyloid or tau and the immune response will help tease apart the potential influence of co‐existent AD‐related pathology on inflammatory factors in DLB. The findings will help inform possible immunotherapeutic strategies that seek to target the immune response in AD/ADRD.

The associations of cerebrospinal fluid biomarkers with cognition, and rapid eye movement sleep behavior disorder in early Parkinson's disease.

In Parkinson's disease (PD), levels of cerebrospinal fluid (CSF) biomarkers and progression of non-motor symptoms are associated, but the specifics are not yet clear. The aim of this study was to investigate the associations of non-motor symptoms with CSF biomarkers in PD. We assessed 487 individuals from the Parkinson's Progression Markers Initiative (PPMI), consisting of 155 healthy controls (HCs) and 332 individuals with PD. Patients with PD were grouped according to non-motor symptoms and compared CSF α-synuclein (α-syn), amyloid-beta 1-42 (Aβ1-42), and total tau (t-tau) levels. Multiple linear regressions were used in baseline analysis and linear mixed-effects models in longitudinal analysis. Analyses of mediating effects between cognition and CSF biomarkers were also performed. At baseline, PD patients with cognitive impairment (PDCI) exhibited significantly lower CSF α-syn (β = -0.1244; P = 0.0469), Aβ (β = -0.1302; P = 0.0447), and t-tau (β = -0.1260; P = 0.0131) levels than PD patients without cognitive impairment (PDCU). Moreover, a faster decline of α-syn (β = -0.2152; P = 0.0374) and Aβ (β = -0.3114; P = 0.0023) and a faster rise of t-tau (β = -0.1534; P = 0.0274) have been found in longitudinal analysis. The Aβ positive group showed an earlier decline in cognitive performance (β = -0.5341; P = 0.0180) compared with the negative Aβ group in both analyses. In addition, we found that PD patients with probable rapid eye movement sleep behavior disorder (pRBD) showed decreased CSF α-syn (β = -0.1343; P = 0.0033) levels. Finally, mediation analysis demonstrated that olfactory function partially mediated the relationship between cognition and CSF biomarkers levels. Our study shows that CSF biomarkers are associated with cognition at baseline and longitudinally. Cognitive impairment is more severe in patients with a heavier Aβ burden. CSF α-syn decreased in PD patients with pRBD. This study suggests that early recognition of the increased risk of non-motor symptoms is important for disease surveillance and may be associated with the pathological progression of CSF markers.

Potential value of cerebrospinal fluid α-synuclein in the identification of postoperative delirium undergoing knee/hip arthroplasty: The perioperative neurocognitive disorder and biomarker lifestyle study.

Postoperative delirium (POD) is a common postoperative complication, which may be associated with α-synuclein (α-syn). The purpose of this study was to explore the association between the expression level of α-syn in cerebrospinal fluid (CSF) and POD. We conducted a prospective observational cohort study, which involved in 740 participants (mean age of 61.86 years, range 40-90 years; 40% female) from the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE) study in the final analysis. POD was diagnosed using the Confusion Assessment Scale (CAM), and its severity was measured using the Memorial Delirium Assessment Scale (MDAS). Enzyme-linked immune-sorbent assay (ELISA) was used to detect the concentrations of α-syn, Aβ40, Aβ42, T-tau, and P-tau in CSF. The incidence of POD was 11.22% (83/740). The logistic regression analysis showed that the increased concentrations of CSF α-syn (OR = 1.005, 95%CI 1.004-1.006, P < 0.001), P-tau (OR = 1.093, 95%CI 1.071-1.115, P < 0.001), and T-tau (OR = 1.008, 95%CI 1.006-1.009, P < 0.001) were risk factors of POD. Linear regression showed that CSF α-syn had positive correlations with P-tau (β = 0.480, P < 0.001), T-tau (β = 0.334, P < 0.001), while negative correlations with Aβ40 (β = -0.378 P < 0.001), Aβ42 (β = -0.800, P = 0.001) in POD patients. Mediation analyses showed the association between α-syn and POD was partially mediated by tau pathologies (proportion: 16-17%). CSF α-syn is one of the preoperative risk factors for POD, which may be mediated through tau pathologies. [www.ClinicalTrials.gov], identifier [ChiCTR20 00033439].

Neurofilament light as a biomarker for motor decline in Parkinson’s disease

ObjectivesThe aim of this study was to determine whether neurofifilament light (NfL) could reflect motor decline and compare the predictive values of cerebrospinal fluid (CSF) and serum NfL in individuals with PD.MethodsCSF/serum samples were collected from patients with PD and healthy controls (HCs) with motor assessments at baseline and after three years of follow-up from the Parkinson’s Progression Markers Initiative (PPMI). Multiple linear regression models and linear mixed-effects models were used to investigate the associations of motor assessments with baseline and longitudinal CSF/serum NfL. Associations between the change rates of motor assessments and CSF/serum NfL were further investigated via multiple linear regression models. Mediating effect analysis was used to research whether CSF alpha-synuclein (α-syn) acts as the mediator between NfL and motor assessments.ResultsWe found patients with PD had higher baseline CSF/serum NfL levels than HCs. Both baseline CSF/serum NfLs and their change rates predicted measurable motor decline in PD assessed by different motor scores. Baseline serum NfL and its rate of change were strongly associated with CSF NfL levels in patients with PD (P < 0.001). Besides, there were also significant differences in CSF/serum NfL levels and predicted values of motor decline between men and women with PD. Mediating effect analysis showed CSF α-syn mediated the effect of CSF NfL on total Unified Parkinson’s Disease Rating Scale (UPDRS) scores and UPDRSIII with 30.6 and 20.2% mediation, respectively.ConclusionOur results indicated that NfL, especially serum NfL concentration, could serve as an easily accessible biomarker to monitor the severity and progression of motor decline in individuals with PD, especially in men with PD. Besides, CSF α-syn acts as a mediator between NfL and motor progression.

Clinical correlations of cerebrospinal fluid biomarkers including neuron-glia 2 and neurofilament light chain in patients with multiple system atrophy

BackgroundMultiple system atrophy (MSA) is a progressive neurodegenerative disorder. The usefulness of biomarkers in diagnosing MSA has been recently reported, but few studies have investigated the correlations among cerebrospinal fluid (CSF) biomarkers or the relationship between CSF biomarkers and the clinical parameters of patients with MSA. Thus, this was the aim of our study. MethodsWe performed cross-sectional study of CSF biomarkers in 50 patients with MSA and 20 control subjects. Ten of the patients with MSA were longitudinally followed for a period of 2 ± 1 years (mean ± standard deviation) as a substudy. We quantified CSF biomarkers including α-synuclein (α-syn), β-amyloid42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau), neurofilament light chain (NfL), and neuron-glia2 (NG2), and assessed their relationship with clinical parameters (clinical subtypes, motor symptoms, nonmotor symptoms, and disease progression). ResultsThe levels of CSF α-syn, Aβ42, and p-tau were significantly lower, while those of NfL were higher in the patients with MSA than in the control subjects. Importantly, we found the significant elevation of soluble NG2 in the CSF of patients with MSA. CSF NfL showed the optimal diagnostic performance for MSA with levels at baseline significantly associated with longitudinal motor progression. With the exception of t-tau, there were no differences in the levels of CSF biomarkers between the MSA-parkinsonism and MSA-cerebellar subtypes. ConclusionsOur results suggest CSF levels of NG2 and NfL as possible diagnostic and prognostic biomarkers in MSA. Further study is necessary to validate these findings.

Evaluation of Alpha-Synuclein Cerebrospinal Fluid Levels in Several Neurological Disorders.

(1) Background: Alpha-synuclein (α-syn) is a presynaptic neuronal protein that regulates several neuronal functions. In recent decades, the role of α-syn as a biomarker of neurodegenerative diseases has been explored, especially in synucleinopathies. However, only a few studies have assessed its role as biomarker in other neurological disorders. The aim of the study was to evaluate cerebrospinal fluid (CSF) α-syn levels in several neurological disorders; (2) Methods: We measured CSF α-syn levels by a commercial ELISA kit in 158 patients classified in the following group: controls, Alzheimer’s Disease (AD), cerebrovascular diseases, inflammatory central nervous system diseases, other neurological diseases, Parkinson’s Disease (PD), and peripheral neuropathy; (3) Results: Patients with PD showed the lowest and patients with AD the highest levels of CSF α-syn (1372 vs. 2912 pg/mL, respectively, p < 0.001). In AD patients, α-syn levels were significantly associated with tau proteins; (4) Conclusions: α-syn could represent a biomarker of neurodegenerative diseases.

Combined CSF α-SYN RT-QuIC, CSF NFL and midbrain-pons planimetry in degenerative parkinsonisms: From bedside to bench, and back again

IntroductionDifferential diagnosis between Parkinson's disease (PD) and atypical parkinsonisms (APs: multiple system atrophy[MSA], progressive supranuclear palsy[PSP], corticobasal degeneration[CBD]) remains challenging. Lately, cerebrospinal fluid (CSF) studies of neurofilament light-chain (NFL) and RT-QuIC of alpha-synuclein (α-SYN) have shown promise, but data on their combination with MRI measures is lacking. Objective(1) to assess the combined diagnostic ability of CSF RT-QuIC α-SYN, CSF NFL and midbrain/pons MRI planimetry in degenerative parkinsonisms; (2) to evaluate if biomarker-signatures relate to clinical diagnoses and whether or not unexpected findings can guide diagnostic revision. MethodsWe collected demographic and clinical data and set up α-SYN RT-QuIC at our lab in a cross-sectional cohort of 112 participants: 19 control subjects (CSs), 20PD, 37MSA, 23PSP, and 13CBD cases. We also determined CSF NFL by ELISA and, in 74 participants (10CSs, 9PD, 26MSA, 19PSP, 10CBD), automatized planimetric midbrain/pons areas from 3T-MRI. ResultsSensitivity of α-SYN RT-QuIC for PD was 75% increasing to 81% after revisiting clinical diagnoses with aid of biomarkers. Sensitivity for MSA was 12% but decreased to 9% with diagnostic revision. Specificities were 100% against CSs, and 89% against tauopathies raising to 91% with diagnostic revision. CSF NFL was significantly higher in APs. The combination of biomarkers yielded high diagnostic accuracy (PD vs. non-PD AUC = 0.983; MSA vs. non-MSA AUC = 0.933; tauopathies vs. non-tauopathies AUC = 0.924). Biomarkers-signatures fitted in most cases with clinical classification. ConclusionsThe combination of CSF NFL, CSF RT-QuIC α-SYN and midbrain/pons MRI measures showed high discriminant ability across all groups. Results opposite to expected can assist diagnostic reclassification.

REM sleep behavior disorder and cerebrospinal fluid alpha-synuclein, amyloid beta, total tau and phosphorylated tau in Parkinson's disease: a cross-sectional and longitudinal study.

Proteinopathies as a consequence of cellular pathological pathways associated with Parkinson's disease (PD), leading to alteration of protein aggregation in cerebrospinal fluid (CSF). Rapid eye movement (REM) sleep behavior disorder (RBD is generally accepted as a prognostic factor predicting neurodegeneration, worse cognitive impairment, and the development of dementia PD. Here we aimed to investigate the difference and longitudinal alteration of the CSF level of α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in PD subjects with RBD and without RBD. We entered 413 early stage PD patients and 187 healthy controls (HCs) from PPMI. We compared the level of CSF biomarkers at baseline, 6months, 1year, and 2years visits. In addition, we used linear mixed models to assess longitudinal changes of CSF proteins over 6months, 1year, and 2years within groups. The level of CSF α-syn, Aβ1-42, t-tau, and p-tau was significantly higher in HCs compared to PD groups at any timepoint. In addition, there was a significantly lower CSF Aβ1-42 in PD-RBD subjects at 2years timepoint (p = 0.020). There was no difference in CSF Aβ1-42 at other timepoints. Furthermore, comparisons between PD subjects with RBD and without RBD did not show any significant difference in CSF α-syn, t-tau, and p-tau at timepoints. The longitudinal analysis demonstrated that there was only a significant change in CSF level of Aβ1-42 after 1year in PD patients with RBD (p = 0.031). In our study, baseline values and longitudinal changes in CSF α-syn, t-tau, and p-tau were not remarkable enough to distinguish PD patients with and without RBD. Both of these groups demonstrated a stable trend in the longitudinal changes of these biomarkers. However, CSF Aβ1-42 seems to decrease in short follow-up and represents a significant difference after a while in PD patients with and without RBD. These findings suggested that CSF Aβ1-42 could be a more sensitive biomarker for early neurodegeneration and cognitive impairment in PD patients. The stable trend in other CSF biomarkers such as α-syn, t-tau, and p-tau can be justified by the fact that severe neurodegeneration may not be predictable in the early stages of PD patients.

SNCA rs3910105 Is Associated With Development of Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease.

Background and PurposeRapid eye movement (REM) Rapid eye movement sleep behavior disorder (RBD) is a common non-motor symptom of PD. However, the association between the SNCA rs3910105 genotype and RBD in Parkinson’s disease (PD) remains unclear.MethodsThis study used Parkinson’s Progression Markers Initiative (PPMI) data and included 270 patients with newly diagnosed PD without RBD who were divided into SNCA rs3910105 C carriers (CC+CT; n = 187) and TT carriers (n = 83). They were followed up for 5 years to identify the development of RBD. To investigate the influence of cerebrospinal fluid (CSF) alpha-synuclein (α-syn) and β-amyloid 1–42 (Aβ42) in the association between rs3910105 and RBD, the patients were additionally classified into “high-level” and “low-level” groups using cutoff values for CSF α-syn and Aβ42 levels.ResultsAt baseline, the rs3910105 C allele group had lower CSF α-syn and Aβ42 levels than the TT group. During the 5.0-year follow-up, the rs3910105 C allele group had a higher incidence of RBD than the TT group. In the subgroup analyses, the effect of the rs3910105 C allele was not found in the “low-level” group. However, in the “high-level” group, the rs3910105 C allele independently increased the risk of RBD.ConclusionThe SNCA rs3910105 C allele might be a novel genetic risk factor for RBD development in PD, α-syn pathways might have a role in this association and more basic research would be needed to elucidate the mechanism in the future.