alpha-synuclein and 2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane

The clinical diagnostic criteria for dementia with Lewy bodies (DLB) have a low sensitivity, and there are no generally accepted biomarkers to distinguish DLB from other dementias. Our aim was to identify biomarkers that may differentiate DLB from Alzheimer's disease (AD).. We performed a systematic literature search for studies of EEG, imaging techniques and genetic and CSF markers that provide sensitivity and specificity in the identification of DLB.. The best evidence was for scintigraphy of the striatal dopamine transporter system using FP-CIT SPECT. Several small scintigraphy studies of cardiovascular autonomic function using metaiodobenzylguanidine SPECT have reported promising results. Studies exploring innovative techniques based on CSF have reported interesting findings for the combination of amyloid beta (abeta) isoforms as well as alpha-synuclein, and there are interesting results emerging from preliminary studies applying proteomic techniques. Data from studies using structural MRI, perfusion SPECT, genetics and EEG studies show differences between DLB and AD but only at a group level.. Several potential biomarkers for the differential diagnosis of probable DLB and AD have shown good diagnostic accuracy in the research setting. Data from large multicentre studies and from studies with autopsy confirmation exist for scintigraphy of the dopamine transporter system. Future studies should explore its value in possible DLB and for clinical management and health economics.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cognition Disorders; Diagnosis, Differential; Dopamine Plasma Membrane Transport Proteins; Early Diagnosis; Electroencephalography; Humans; Iodine Radioisotopes; Lewy Body Disease; Neuropsychological Tests; Phosphorylation; Positron-Emission Tomography; Severity of Illness Index; Tomography, Emission-Computed, Single-Photon; Tropanes; Ubiquitin

Topics: 3-Iodobenzylguanidine; Aged; alpha-Synuclein; Brain; Dopamine Plasma Membrane Transport Proteins; Female; Heart; Humans; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Radionuclide Imaging; Radiopharmaceuticals; Tropanes

To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease.. We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline.. The presence of diabetes mellitus was associated with higher motor scores (. Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype.

Topics: Adult; Aged; alpha-Synuclein; Blood Glucose; Cognition Disorders; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Disease Progression; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Longitudinal Studies; Male; Middle Aged; Motor Disorders; Parkinson Disease; tau Proteins; Tomography, Emission-Computed, Single-Photon; Tropanes

The present study investigated associations between dopamine transporter (DAT) availability and α-synuclein levels in cerebrospinal fluid, as well as synuclein gene (SNCA) transcripts, and the effect of single nucleotide polymorphism of SNCA on DAT availability in healthy subjects.. The study population comprised healthy controls who underwent ¹²³I-FP-CIT single-photon emission computed tomography screening. Five SNCA probes were used to target the boundaries of exon 3 and exon 4 (SNCA-E3E4), transcripts with a long 3'UTR region (SNCA-3UTR-1, SNCA-3UTR-2), transcripts that skip exon 5 (SNCA-E4E6), and the rare short transcript isoforms that comprise exons 1-4 (SNCA-007).. In total, 123 healthy subjects (male 75, female 48) were included in this study. DAT availability in the caudate nucleus (p=0.0661) and putamen (p=0.0739) tended to differ according to rs3910105 genotype. In post-hoc analysis, DAT availability in the putamen was lower in subjects of TT genotype than those of CC/CT (p=0.0317). DAT availability in the caudate nucleus also showed a trend similar to that in the putamen (p=0.0597). Subjects of CT genotype with rs3910105 showed negative correlations with DAT availability in the putamen with SNCA-E3E4 (p=0.037, rho=-0.277), and SNCA-E4E6 (p=0.042, rho=-0.270), but not those of CC/TT genotypes.. This is the first study to investigate the association of rs3910105 in SNCA with DAT availability. rs3910105 had an effect on DAT availability, and the correlation between DAT availability and SNCA transcripts were significant in CT genotypes of rs3910105.

Topics: Adult; alpha-Synuclein; Cerebrospinal Fluid; Dopamine Plasma Membrane Transport Proteins; Female; Gene Expression; Genotype; Healthy Volunteers; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Tomography, Emission-Computed, Single-Photon; Tropanes

To investigate whether REM sleep behavior disorder (RBD) is associated with worse motor and cognitive decline in Parkinson disease (PD) METHODS: Four-hundred twenty-one drug-naive patients with early-stage PD and 196 controls without PD were included in this study. All participants underwent a [. At cross-sectional analyses, patients with PD and probable RBD (PD-RBD) had lower CSF β-amyloid 1-42 (Aβ. The presence of RBD in PD is associated with faster motor progression in patients with greater synuclein and dopaminergic pathology, and with higher risk of cognitive decline in patients with greater synuclein and amyloid pathology. Our findings provide an important direction toward understanding phenotypes and their prognosis in PD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Brain; Cognition Disorders; Cohort Studies; Disease Progression; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; REM Sleep Behavior Disorder; Severity of Illness Index; Statistics, Nonparametric; tau Proteins; Tomography, Emission-Computed, Single-Photon; Tropanes

The p.A53T point mutation in the α-synuclein gene (SNCA) is a rare but highly relevant cause of autosomal dominant Parkinson's disease (PD).. The objective of this study was to assess striatal dopaminergic denervation in a cohort of symptomatic carriers of the p.A53T SNCA mutation as compared to PD patients.. Data from the Parkinson's Progression Markers Initiative database of 11 symptomatic p.A53T SNCA mutation carriers who underwent 123I-FP-CIT SPECT [(123) I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane single photon emission computed tomography] imaging at our site were compared with those of 33 age-, sex-, and disease duration-matched PD patients.. The p.A53T mutation carriers had significantly lower caudate nucleus binding ratio both contralaterally and ipsilaterally to the most affected side (P = .002 and P = .006) and a decreased contralateral caudate/putamen signal ratio (P = .007) as compared to PD. A similar degree of striatal asymmetry was observed in both subgroups. No correlation between scores in neuropsychological tests and caudate nucleus dopaminergic denervation could be demonstrated.. PD patients harboring the p.A53T SNCA mutation show evidence of a more severe nigrostriatal denervation, especially evident in the caudate nucleus. The lack of significant differences in the putaminal binding ratios may reflect a floor effect or a true preferential targeting of the caudate terminals in p.A53T SNCA-associated PD. © 2018 International Parkinson and Movement Disorder Society.

Topics: Adult; Alanine; alpha-Synuclein; Cognition Disorders; Cohort Studies; Corpus Striatum; Dopamine; Female; Functional Laterality; Humans; Male; Middle Aged; Mutation; Parkinson Disease; Threonine; Tomography, Emission-Computed, Single-Photon; Tropanes

The objective of this study was to investigate the discriminating value of a range of CSF α-synuclein species for dementia with Lewy bodies compared with Alzheimer's disease, PD, and cognitively normal controls.. We applied our recently published enzyme-linked immunosorbent assays to measure the CSF levels of total α-synuclein, oligomeric α-synuclein, and phosphorylated α-synuclein in dementia with Lewy bodies (n = 42), Alzheimer's disease (n = 39), PD (n = 46), and controls (n = 78). General linear models corrected for age and sex were performed to assess differences in α-synuclein levels between groups. We used backward-elimination logistic regression analysis to investigate the combined discriminating value of the different CSF α-synuclein species and Alzheimer's disease biomarkers.. CSF levels of total α-synuclein were lower in dementia with Lewy bodies and PD compared with Alzheimer's disease as well as controls (P < 0.001). In contrast, CSF levels of oligomeric α-synuclein were higher in dementia with Lewy bodies and PD compared with Alzheimer's disease (P < 0.05) and controls (P < 0.001). No group differences were found for phosphorylated α-synuclein. In dementia with Lewy bodies and PD, CSF total α-synuclein levels positively correlated with tau and phosphorylated tau (both r > 0.40, P < 0.01), but not with amyloid-β. CSF α-synuclein species could be useful as part of a biomarker panel for dementia with Lewy bodies. Evaluating both oligomeric α-synuclein and total α-synuclein in CSF helps in the diagnosis of dementia with Lewy bodies. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Electroencephalography; Female; Humans; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; Psychiatric Status Rating Scales; Retrospective Studies; tau Proteins; Tomography, Emission-Computed, Single-Photon; Tropanes

Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson's disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alpha-syn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT (ρ = -0.377, p = 0.048), with olfactory function (ρ = -0.668, p = 0.002), and positively correlated with the total LR for RBD to present prodromal PD (ρ = 0.531, p = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs.

Topics: Aged; alpha-Synuclein; Biomarkers; Biopsy; Brain; Case-Control Studies; Dopamine Plasma Membrane Transport Proteins; Female; Fluorescent Antibody Technique; Humans; Leg; Male; Middle Aged; Parkinson Disease; Phosphorylation; Prodromal Symptoms; Prospective Studies; Radiopharmaceuticals; REM Sleep Behavior Disorder; Skin; Smell; Tomography, Emission-Computed, Single-Photon; Tropanes

Topics: alpha-Synuclein; Female; Humans; Lewy Body Disease; Locus Coeruleus; Middle Aged; Mutation; Parkinson Disease; Substantia Nigra; Tomography, Emission-Computed, Single-Photon; Tropanes

Topics: alpha-Synuclein; Fluorodeoxyglucose F18; Humans; Kidney Diseases; Parkinson Disease; Tropanes

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

Topics: Aged; alpha-Synuclein; Cognition Disorders; Dopamine Plasma Membrane Transport Proteins; Female; Gene Expression Regulation; Genetic Testing; Humans; Male; Microarray Analysis; Middle Aged; Neuroimaging; Parkinson Disease; Radionuclide Imaging; RNA, Messenger; Severity of Illness Index; Tropanes

alpha-Synuclein gene (SNCA) multiplication was found in familial Parkinson disease (PD). We examined SNCA multiplication in patients with familial and sporadic PD and multiple system atrophy (MSA).. We screened 1,106 patients with parkinsonism (PD = 906, MSA = 200) for SNCA multiplication by multiplex PCR. Fluorescent in situ hybridization was done to confirm the multiplication. [(123)I]N-omega-Fluoropropyl-2 beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]FP-CIT) SPECT was done in the patients with SNCA multiplication and their family members.. Three patients were identified as having SNCA duplication. One patient had a positive family history, and two patients were sporadic. Each patient had asymptomatic carriers in their families. The familial case had early onset parkinsonism with rapidly progressive course, cognitive impairment, and dysautonomia. Sporadic cases were more typical of PD. [(123)I]FP-CIT SPECT was abnormal in the patients and normal in the asymptomatic carriers.. SNCA multiplication is present in sporadic Parkinson disease (PD) and needs to be screened. Low penetrance, clinical heterogeneity, and normal dopamine transporter imaging in asymptomatic carriers may suggest the presence of other genetic modifiers or environmental triggers that play a role in the pathogenesis of PD due to SNCA duplication.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha-Synuclein; Child; DNA Mutational Analysis; Exons; Family Health; Female; Humans; In Situ Hybridization, Fluorescence; Iodine Radioisotopes; Male; Middle Aged; Multiple System Atrophy; Mutation; Parkinson Disease; Tomography, Emission-Computed, Single-Photon; Tropanes