Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults.

BACKGROUND: The role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood. METHODS: A total of 331 non-demented individuals were included in the study from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition. RESULTS: Higher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1. CONCLUSIONS: These findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.

Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra.

OBJECTIVE: More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. METHODS: Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. RESULTS: Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2(3) = 13.87, p = 0.003). INTERPRETATION: Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

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.

Differential associations of clinical features with cerebrospinal fluid biomarkers in dementia with Lewy bodies and Alzheimer's disease.

AIM: To explore associations of cerebrospinal fluid biomarkers of neurodegeneration and amyloidosis with caregiver burden, cognition and functionality in dementia with Lewy bodies (DLB) paired with late-onset Alzheimer's disease (AD) and healthy older people. METHODS: Consecutive outpatients with DLB were matched with outpatients with AD according to sex, cognitive scores and dementia stage, and with cognitively healthy controls according to age and sex to investigate associations of cerebrospinal fluid amyloid-ß (Aß42,Aß40,Aß38), tau, phospho-tau Thr181, ubiquitin, α-synuclein and neurofilament light with caregiver burden, functionality, reverse digit span, a clock drawing test, Mini-Mental State Examination (MMSE) and Severe MMSE, adjusted for sex, age, education, dementia duration and APOE-ε4 alleles. RESULTS: Overall, 27 patients with DLB (78.98 ± 9.0 years-old; eleven APOE-ε4 +) were paired with 27 patients with AD (81.50 ± 5.8 years-old; twelve APOE-ε4 +) and 27 controls (78.98 ± 8.7 years-old; four APOE-ε4 +); two-thirds were women. In AD, Aß42/Aß38 and Aß42 were lower, while tau/Aß42 and phospho-tau Thr181/Aß42 were higher; α-synuclein/Aß42 was lower in DLB and higher in AD. The following corrected associations remained significant: in DLB, instrumental functionality was inversely associated with tau/phospho-tau Thr181 and tau/Aß42, and reverse digit span associated with α-synuclein; in AD, instrumental functionality was inversely associated with neurofilament light, clock drawing test scores inversely associated with phospho-tau Thr181/Aß42 and α-synuclein/Aß42, and Severe MMSE inversely associated with tau/Aß42 and tau/phospho-tau Thr181. CONCLUSIONS: Cerebrospinal fluid phospho-tau Thr181 in DLB was similar to AD, but not Aß42. In associations with test scores, biomarker ratios were superior to isolated biomarkers, while worse functionality was associated with axonal degeneration only in AD.

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.

The Mediating Role of Inflammation in the Relationship Between α-Synuclein and Cognitive Functioning.

Accumulating evidence suggests that α-synuclein plays a role in the pathophysiology of Alzheimer's disease (AD). This study examined whether α-synuclein level in cerebrospinal fluid (CSF) was associated with cognitive functioning among older adults. We also explored whether this relationship was mediated by proinflammatory cytokines TNF-α and IL-6, along with sIL-6R and vascular endothelial growth factor (VEGF). Using a cross-sectional Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 148) sample, we examined the relationship between α-synuclein and participants' performance on Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog 13) at baseline. Mediation analyses were utilized, adjusting for age, education, APOEe4, and Geriatric Depression Scale scores. All biological markers were measured in CSF. Participants in the current sample were 58.3% males, 41.7% females, and Caucasian (95.5%); their average education and age were 15.5 (standard deviation [SD] = 2.97) and 74.4 (SD = 7.51) years, respectively. Higher accumulation of α-synuclein was associated with poorer MMSE scores (ß = -0.41, standard error [SE] = 1.54, p < .001). This relationship appeared to be mediated by VEGF (ß = 0.27, SE = 2.15, p = .025) and IL-6r (ß = 0.22, SE = 1.66, p < .026). In addition, α-synuclein was associated with poorer performance on the ADAS-Cog 13 (ß = 0.34, p = .005) and mediated by VEGF (ß = -0.19, SE = 4.13, p = .025) after adjusting for age, education, APOEe4, and depressive symptoms. α-Synuclein may serve as an additional biomarker for determining poor cognitive functioning. VEGF and IL-6 soluble receptors were significant mediators of the relationship between α-synuclein and cognitive functioning. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD.

Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Pattern of Mitochondrial Respiration in Peripheral Blood Cells of Patients with Parkinson's Disease.

Mitochondria are central in the pathogenesis of Parkinson's disease (PD), as they are involved in oxidative stress, synaptopathy, and other immunometabolic pathways. Accordingly, they are emerging as a potential neuroprotection target, although further human-based evidence is needed for therapeutic advancements. This study aims to shape the pattern of mitochondrial respiration in the blood leukocytes of PD patients in relation to both clinical features and the profile of cerebrospinal fluid (CSF) biomarkers of neurodegeneration. Mitochondrial respirometry on the peripheral blood mononucleate cells (PBMCs) of 16 PD patients and 14 controls was conducted using Seahorse Bioscience technology. Bioenergetic parameters were correlated either with standard clinical scores for motor and non-motor disturbances or with CSF levels of α-synuclein, amyloid-ß peptides, and tau proteins. In PD, PBMC mitochondrial basal respiration was normal; maximal and spare respiratory capacities were both increased; and ATP production was higher, although not significantly. Maximal and spare respiratory capacity was directly correlated with disease duration, MDS-UPDRS part III and Hoehn and Yahr motor scores; spare respiratory capacity was correlated with the CSF amyloid-ß-42 to amyloid-ß-42/40 ratio. We provided preliminary evidence showing that mitochondrial respiratory activity increases in the PBMCs of PD patients, probably following the compensatory adaptations to disease progression, in contrast to the bases of the neuropathological substrate.

In Vivo Diagnosis of Synucleinopathies: A Comparative Study of Skin Biopsy and RT-QuIC.

OBJECTIVE: To determine whether (1) immunofluorescence is a reproducible technique in detecting misfolded α-synuclein in skin nerves and subsequently whether (2) immunofluorescence and real-time quaking-induced conversion (RT-QuIC) (both in skin and CSF) show a comparable in vivo diagnostic accuracy in distinguishing synucleinopathies from non-synucleinopathies in a large cohort of patients. METHODS: We prospectively recruited 90 patients fulfilling clinical and instrumental diagnostic criteria for all synucleinopathies variants and non-synucleinopathies (mainly including Alzheimer disease, tauopathies, and vascular parkinsonism or dementia). Twenty-four patients with mainly peripheral neuropathies were used as controls. Patients underwent skin biopsy for immunofluorescence and RT-QuIC; CSF was examined in patients who underwent lumbar puncture for diagnostic purposes. Immunofluorescence and RT-QuIC analysis were made blinded to the clinical diagnosis. RESULTS: Immunofluorescence showed reproducible results between 2 pairs of neighboring skin samples. Both immunofluorescence and RT-QuIC showed high sensitivity and specificity in discriminating synucleinopathies from non-synucleinopathies and controls but immunofluorescence presented higher diagnostic accuracy. Immunofluorescence presented a good level of agreement with RT-QuIC in both skin and CSF in synucleinopathies. CONCLUSIONS: Both immunofluorescence and RT-QuIC showed high diagnostic accuracy, although immunofluorescence displayed the better value as well as optimal reproducibility; they presented a good level of agreement in synucleinopathies, supporting the use of less invasive tests such as skin immunofluorescence or RT-QuIC instead of CSF RT-QuIC as a diagnostic tool for synucleinopathies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that immunofluorescence or RT-QuIC accurately distinguish synucleinopathies from non-synucleinopathies.

In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease.

OBJECTIVE: The Systemic Synuclein Sampling Study (S4) measured α-synuclein in multiple tissues and biofluids within the same patients with Parkinson disease (PD) vs healthy controls (HCs). METHODS: S4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and nonmotor measures and dopamine transporter SPECT were obtained. Biopsies of skin, colon, submandibular gland (SMG), CSF, saliva, and blood were collected. Tissue biopsy sections were stained with 5C12 monoclonal antibody against pathologic α-synuclein; digital images were interpreted by neuropathologists blinded to diagnosis. Biofluid total α-synuclein was quantified using ELISA. RESULTS: The final cohort included 59 patients with PD and 21 HCs. CSF α-synuclein was lower in patients with PD vs HCs; sensitivity/specificity of CSF α-synuclein for PD diagnosis was 87.0%/63.2%, respectively. Sensitivity of α-synuclein immunoreactivity for PD diagnosis was 56.1% for SMG and 24.1% for skin; specificity was 92.9% and 100%, respectively. There were no significant relationships between different measures of α-synuclein within participants. CONCLUSIONS: S4 confirms lower total α-synuclein levels in CSF in patients with PD compared to HCs, but specificity is low. In contrast, α-synuclein immunoreactivity in skin and SMG is specific for PD but sensitivity is low. Relationships within participants across different tissues and biofluids could not be demonstrated. Measures of pathologic forms of α-synuclein with higher accuracy are critically needed. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that total CSF α-synuclein does not accurately distinguish patients with PD from HCs, and that monoclonal antibody staining for SMG and skin total α-synuclein is specific but not sensitive for PD diagnosis.

CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers.

BACKGROUND: Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson's disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers. METHODS: We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aß-40), amyloid-beta-42 (Aß-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD. RESULTS: Discriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve > 0.80 was generated. CONCLUSIONS: The current study suggests that CSF t-, o-α-syn and TNF-α are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers' panel approach for an accurate and timely diagnosis of PD.

Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid.

α-Synuclein aggregates, a key hallmark of the pathogenesis of Parkinson's disease, can be amplified by using their seeding activity, and the evaluation of the seeding activity of cerebrospinal fluid (CSF) is reportedly useful for diagnosis. However, conventional shaking-based assays are time-consuming procedures, and the clinical significance of the diversity of seeding activity among patients remains to be clarified. Previously, we reported a high-throughput ultrasonication-induced amyloid fibrillation assay. Here, we adapted this assay to amplify and detect α-synuclein aggregates from CSF, and investigated the correlation between seeding activity and clinical indicators. We confirmed that this assay could detect α-synuclein aggregates prepared in vitro and also aggregates released from cultured cells. The seeding activity of CSF correlated with the levels of α-synuclein oligomers measured by an enzyme-linked immunosorbent assay. Moreover, the seeding activity of CSF from patients with Parkinson's disease was higher than that of control patients. Notably, the lag time of patients with Parkinson's disease was significantly correlated with the MIBG heart-to-mediastinum ratio. These findings showed that our ultrasonication-based assay can rapidly amplify misfolded α-synuclein and can evaluate the seeding activity of CSF.

A Genome-Wide Association Study of α-Synuclein Levels in Cerebrospinal Fluid.

α-Synuclein is a 140-amino acid protein produced predominantly by neurons in the brain which plays a role in the regulation of neurotransmitter release, synaptic function, and plasticity, thus making it the focus in understanding the etiology of a group of neurodegenerative diseases. We conducted genome-wide association studies (GWAS) of α-synuclein levels in cerebrospinal fluid (CSF) with 209 non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort using a linear regression model to identify novel variants associated with α-synuclein concentration. The minor allele (T) of rs7072338 in the long intergenic non-protein coding RNA 1515 (LINC01515) and the minor allele (T) of rs17794023 in clusterin-associated protein 1 (CLUAP1) were associated with higher CSF α-synuclein levels at genome-wide significance (P = 4.167 × 10-9 and 9.56 × 10-9, respectively). In addition, single nucleotide polymorphisms (SNPs) near amyloid beta precursor protein (APP) (rs1394839) (P = 2.31 × 10-7), Rap guanine nucleotide exchange factor 1 (RAPGEF1) (rs10901091) (P = 8.07 × 10-7), and two intergenic loci on chromosome 2 and 14 (rs11687064 P = 2.50 × 10-7and rs7147386 P = 4.05 × 10-7) were identified as suggestive loci associated with CSF α-synuclein levels. We have identified significantly associated SNPs for CSF α-synuclein. These associations have important implications for a better understanding of α-synuclein regulation and allow researchers to further explore the relationships between these SNPs and α-synuclein-related neurodegenerative disorders.

Identification of an Alternatively Spliced α-Synuclein Isoform That Generates a 41-Amino Acid N-Terminal Truncated Peptide, 41-syn: Role in Dopamine Homeostasis.

The presynaptic protein, α-synuclein (α-syn), has been shown to play a crucial role in multiple neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and dementia with Lewy bodies (DLB). The three major domains of α-syn protein were shown to govern its membrane interaction, protein fibrillation, and chaperone activity. So far, four different alternatively spliced isoforms of α-syn, which lack either exon 3 (syn-126) or exon 5 (syn-112) or both (syn-98) resulting in altered function of the proteins, have been identified. In the present study, we have identified the smallest isoform of α-syn due to the skipping of exons 3 and 4 generating a 238 bp transcript. Due to the presence of a premature stop codon, the 238 bp transcript generated a 41 aa N-terminal peptide instead of the 78 aa protein, which is secreted into the extracellular medium when overexpressed in cells. The presence of 41-syn was initially noticed in the substantia nigra of PD autopsy tissues, as well as in cells undergoing oxidative stress. In vitro studies inferred that 41-syn neither aggregates nor alters the aggregation propensity of either WT or 112-syn. Overexpression of 41-syn or treatment of cells with 41-syn peptide did not affect cell viability. However, PC-12 cells treated with 41-syn exhibited a time and dose dependent enhancement in the cellular uptake of dopamine. Based on the physiological role of the N-terminal region of α-syn in modulating membrane trafficking events, we believe that the identification of 41-syn may provide novel impetus in unraveling the physiological basis of alternative splicing events in governing PD pathophysiology.

Tau/α-synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study.

BACKGROUND: No CSF or plasma biomarker has been validated for diagnosis or progression of PD. OBJECTIVES: To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. METHODS: CSF levels of α-synuclein, amyloid-ß1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1ß, interleukin-2, interleukin, interferon-γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. RESULTS: CSF levels of α-synuclein, amyloid-ß1-42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α-synuclein, phosphorylated tau/α-synuclein, total tau/amyloid-ß1-42+α-synuclein, and phosphorylated tau/amyloid-ß1-42+α-synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α-synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut-off value of ≤ 0.71). Phosphorylated tau/α-synuclein and phosphorylated tau/amyloid-ß1-42+α-synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin-6 levels were positively correlated with UPDRS-I, -II, and -III scores. CONCLUSIONS: The CSF phosphorylated tau/α-synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin-6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society.

The Systemic Synuclein Sampling Study: toward a biomarker for Parkinson's disease.

The search for a biomarker for Parkinson's disease (PD) has led to a surge in literature describing peripheral α-synuclein (aSyn) in both biofluids and biopsy/autopsy tissues. Despite encouraging results, attempts to capitalize on this promise have fallen woefully short. The Systemic Synuclein Sampling Study (S4) is uniquely designed to identify a reproducible diagnostic and progression biomarker for PD. S4 will evaluate aSyn in multiple tissues and biofluids within the same subject and across the disease spectrum to identify the optimal biomarker source and provide vital information on the evolution of peripheral aSyn throughout the disease. Additionally, S4 will correlate the systemic aSyn profile with an objective measure of nigrostriatal dopaminergic function furthering our understanding of the pathophysiological progression of PD.

Glucocerebrosidase modulates cognitive and motor activities in murine models of Parkinson's disease.

Mutations in GBA1, the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. A higher prevalence and increased severity of motor and non-motor symptoms is observed in PD patients harboring mutant GBA1 alleles, suggesting a link between the gene or gene product and disease development. Interestingly, PD patients without mutations in GBA1 also exhibit lower levels of glucocerebrosidase activity in the central nervous system (CNS), implicating this lysosomal enzyme in disease pathogenesis. Here, we investigated whether modulation of glucocerebrosidase activity in murine models of synucleinopathy (expressing wild type Gba1) affected α-synuclein accumulation and behavioral phenotypes. Partial inhibition of glucocerebrosidase activity in PrP-A53T-SNCA mice using the covalent inhibitor conduritol-B-epoxide induced a profound increase in soluble α-synuclein in the CNS and exacerbated cognitive and motor deficits. Conversely, augmenting glucocerebrosidase activity in the Thy1-SNCA mouse model of PD delayed the progression of synucleinopathy. Adeno-associated virus-mediated expression of glucocerebrosidase in the Thy1-SNCA mouse striatum led to decrease in the levels of the proteinase K-resistant fraction of α-synuclein, amelioration of behavioral aberrations and protection from loss of striatal dopaminergic markers. These data indicate that increasing glucocerebrosidase activity can influence α-synuclein homeostasis, thereby reducing the progression of synucleinopathies. This study provides robust in vivo evidence that augmentation of CNS glucocerebrosidase activity is a potential therapeutic strategy for PD, regardless of the mutation status of GBA1.

Excessive Iron and α-Synuclein Oligomer in Brain are Relevant to Pure Apathy in Parkinson Disease.

OBJECTIVES: To investigate the demographic features, clinical features, and potential mechanism in patients with Parkinson disease (PD) with pure apathy. METHOD: A total of 145 patients with PD without depression and dementia and 30 age-matched controls were consecutively recruited. Patients with PD were evaluated by Apathy Scale (AS), scales for motor symptoms and quality of life. The levels of iron, oxidative and neuroinflammatory factors, α-synuclein oligomer, and dopamine in cerebrospinal fluid (CSF) from patients with PD and controls were detected by enzyme-linked immunosorbent assay, chemical colorimetric method, and high-performance liquid chromatography. Comparisons between PD with pure apathy and with no pure apathy groups and correlation between AS score and the levels of above factors were analyzed. RESULTS: There were 64 (44.14%) cases in PD-apathy group. The PD-apathy group had older age, (97.81 ± 10.82) years versus (61.86 ± 10.80) years, and severer quality of life (P < .05). The PD-apathy and PD without apathy groups presented no remarkable differences in motor symptoms (P > .05). The levels of iron, hydroxyl radical (·OH), hydrogen peroxide (H2O2), and α-synuclein oligomer in CSF in PD-apathy group were significantly higher than that in PD without the apathy group (P < .05). In patients with PD, the AS score was positively correlated with the levels of iron, ·OH, H2O2 and α-synuclein oligomer in CSF (r = 19.838, .063, 1.046, and 0.498, respectively, P < .05). In PD-apathy group, iron level was positively correlated with ·OH level (r = .011, P < .05), and H2O2 level was positively correlated with α-synuclein oligomer level in CSF (r = .045, P < .05). CONCLUSION: Patients with PD had high prevalence of pure apathy. Patients with PD having pure apathy had older age. Pure apathy reduced quality of life for patients without worsening motor function. Excessive iron and α-synuclein oligomer in brain commonly contributed to pure apathy of PD through potential mechanism of oxidative stress.

The role of biomarkers and imaging in Parkinson's disease.

The diagnosis of Parkinson's disease (PD) currently relies on the appearance of certain clinical features. However, these features appear only years after the loss of nigral dopaminergic neurons. The progression of PD may be measured using clinical rating scales that are subjective and that have a variable inter-rater consistency. There is a growing need for a biomarker that will allow for early detection of the disease as well as provide a measure of disease progression. In this article, we review different biomarkers, with a focus on functional imaging techniques, which while imperfect, currently provide the best approach to this problem. We also discuss the use of structural imaging and emerging progress in other biochemical and molecular markers. While there is no single biomarker that will satisfy all requirements, a combination is likely to be of great use in identifying those subjects most likely to benefit from neuroprotective therapies, as well as in monitoring the effects of any interventions.

Cerebrospinal fluid levels of IL-6 are decreased and correlate with cognitive status in DLB patients.

INTRODUCTION: Inflammatory processes have previously been shown to influence cognition and progression of dementia. An involvement of interleukin (IL)-6 has in particular been suggested as altered levels of IL-6 in cerebrospinal fluid (CSF) have been found in patients with Alzheimer's disease (AD). Also, an association between cognitive decline and levels of IL-6 in CSF have been reported. The aim of the present study was to investigate whether patients clinically diagnosed with dementia with Lewy bodies (DLB) display altered CSF IL-6 levels in comparison with patients with AD and control subjects without dementia and whether the IL-6 levels are correlated with cognitive status and biomarkers for AD and synucleinopathy. METHODS: To analyse CSF of patients with AD (n = 45), patients with DLB (n = 29) and control subjects without dementia (n = 36), we used immunoassays to measure levels of IL-6 (multiplex electrochemiluminescence); AD markers phosphorylated tau, total tau and amyloid-ß1-42 (enzyme-linked immunosorbent assay [ELISA]); and α-synuclein (ELISA). Cognitive status was evaluated using the Mini Mental State Examination (MMSE). RESULTS: Our analysis showed significantly lower levels of IL-6 in CSF from patients with DLB than in CSF from patients with AD and control subjects without dementia. The IL-6 levels were also negatively correlated with MMSE and positively correlated with α-synuclein CSF levels. CONCLUSIONS: Our findings support previous studies by demonstrating a link between inflammatory processes and dementia progression and further strengthen the hypothesis that IL-6 is involved in dementia pathology and cognitive decline.