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Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies.

ABSTRACT: The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen ¹⁸ F-DOPA and cardiac ¹⁸ F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.

SUBMITTER: Goldstein DS

PROVIDER: S-EPMC8529535 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Central catecholamine deficiency characterizes ?-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86?±?0.09 (SEM), 1.00?±?0.09, 1.32?±?0.12?nmol/l] than controls (2.15?±?0.18?nmol/l; P?<?0.0001; P?<?0.0001; P?=?0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82?±?0.44, 7.75?±?0.42, 5.82?±?0.65?nmol/l) than controls (11.0?±?0.62?nmol/l; P?=?0.009, P?<?0.0001, P?<?0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid dihydroxyphenylacetic acid seems to provide a sensitive means to identify even early Parkinson's disease.

Project description:Introduction:Given the challenges concerning the differential diagnosis of dementia, we investigated the possible added value of monoaminergic compounds to the standard cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Particularly, regarding the AD versus dementia with Lewy bodies (DLB) comparison, monoamines or their metabolites might have added discriminative value as there is a more severe neuropathological burden in the locus coeruleus of DLB patients, the principal site of noradrenaline synthesis. Methods:We applied enzyme-linked immunosorbent assay (ELISA) to analyze CSF amyloid ? peptide of 42 amino acids, total tau, and tau phosphorylated at threonine 181, in patients with AD, frontotemporal dementia, DLB/Parkinson's disease dementia, and controls. Reversed-phase high-performance liquid chromatography with electrochemical detection was implemented to study monoamine and metabolite levels in CSF and serum. Stepwise forward conditional logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic accuracy of these newly fitted models containing the most discriminative indicators of disease status. Results:Most significant differences in CSF and serum were confined to the noradrenergic system. More specifically, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were higher, whereas serum MHPG levels were lower, in DLB patients compared with all other groups. Addition of CSF and serum MHPG levels to the CSF AD biomarker panel significantly increased diagnostic accuracy between DLB/Parkinson's disease dementia and AD. Interestingly, a model only including CSF and serum MHPG without the classic AD biomarker panel reached similar area under the curve values. Discussion:We hypothesize that varying degrees of neuronal loss in the locus coeruleus of DLB/Parkinson's disease dementia versus AD patients result in differentially altered MHPG levels, making this metabolite a valuable biomarker.

Project description:BackgroundA small proportion of patients with clinical parkinsonism have normal transporter-single photon emission computed tomography (DaTSPECT) which is commonly defined as scans without evidence of dopaminergic deficits (SWEDD). A better understanding of SWEDD can improve the current therapeutic options and appropriate disease monitoring.AimWe aimed to assess CSF biomarkers levels including α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in SWEDD and investigate the longitudinal alteration in the CSF profile.MethodsIn total, 406 early-stage PD, 58 SWEDD, and 187 healthy controls (HCs) were entered into our study from PPMI. We compared the level of CSF biomarkers at baseline, six months, one year, and two years. Furthermore, the longitudinal alteration of CSF biomarkers was explored in each group using linear mixed models.ResultsThere was no significant difference in the level of CSF α-syn Aβ1-42, t-tau, and p-tau between HCs and SWEDD at different time points. Investigating the level of CSF α-syn in PD and SWEDD showed a significant difference at one (p = 0.016) and two years (p = 0.006). Also, we observed a significant difference in the level of CSF Aβ1-42 between SWEDD and PD at one year (p = 0.012). Moreover, there was a significant difference in the level of CSF t-tau between SWEDD and PD subjects at one (p = 0.013) and two years (p = 0.017). Furthermore, there was a significant difference in the level of CSF p-tau between SWEDD and PD groups at two years visits (p = 0.030). Longitudinal analysis showed a significant decrease after one (p = 0.029) and two years (p = 0.002) from baseline in the level of CSF α-syn only in the PD group. Also, we observed that the level of CSF Aβ1-42 significantly increased after one year in SWEDD (p = 0.031) and decreased after two years from baseline in PD subjects (p = 0.005). Moreover, there was a significant increase in the level of CSF t-tau after two years (p = 0.036) and CSF p-tau after six months from baseline in SWEDD subjects (p = 0.011).ConclusionThis finding suggests a faster neurodegeneration process in PD patients compared to SWEDD at least based on these biomarkers. Future studies with longer follow-up duration and more sample sizes are necessary to validate our results.

Project description:The goal of this study is to investigate the value of tau phosphorylated at threonine 181 (P-tau181P) in the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker panel for differential dementia diagnosis in autopsy confirmed AD and non-AD patients. The study population consisted of 140 autopsy confirmed AD and 77 autopsy confirmed non-AD dementia patients. CSF concentrations of amyloid-? peptide of 42 amino acids (A?1-42), total tau protein (T-tau), and P-tau181P were determined with single analyte ELISA-kits (INNOTEST(®), Fujirebio, Ghent, Belgium). Diagnostic accuracy was assessed through receiver operating characteristic (ROC) curve analyses to obtain area under the curve (AUC) values and to define optimal cutoff values to discriminate AD from pooled and individual non-AD groups. ROC curve analyses were only performed on biomarkers and ratios that differed significantly between the groups. Pairwise comparison of AUC values was performed by means of DeLong tests. The A?1-42/P-tau181P ratio (AUC?=?0.770) performed significantly better than A?1-42 (AUC?=?0.677, P?=?0.004), T-tau (AUC?=?0.592, P?<?0.001), and A?1-42/T-tau (AUC?=?0.678, P?=?0.001), while P-tau181P (AUC?=?0.720) performed significantly better than T-tau (AUC?=?0.592, P?<?0.001) to discriminate between AD and the pooled non-AD group. When comparing AD and the individual non-AD diagnoses, A?1-42/P-tau181P (AUC?=?0.894) discriminated AD from frontotemporal dementia significantly better than A?1-42 (AUC?=?0.776, P?=?0.020) and T-tau (AUC?=?0.746, P?=?0.004), while P-tau181P/T-tau (AUC?=?0.958) significantly improved the differentiation between AD and Creutzfeldt-Jakob disease as compared to A?1-42 (AUC?=?0.688, P?=?0.004), T-tau (AUC?=?0.874, P?=?0.040), and A?1-42/P-tau181P (AUC?=?0.760, P?=?0.003). In conclusion, this study demonstrates P-tau181P is an essential component of the AD CSF biomarker panel, and combined assessment of A?1-42, T-tau, and P-tau181P renders, to present date, the highest diagnostic power to discriminate between AD and non-AD dementias.

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Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies.

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