The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson’s disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize ...alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre-mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (
p
< 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length-dependent reduction of intraepidermal small nerve fibers (
p
< 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (
p
< 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity.
► We established a cohort comprising 78 drug-naïve PD and 48 healthy subjects (HC). ► We analyzed the samples by two different enzyme-linked immunoabsorbent assays (ELISA). ► One assay represents a ...renewable antibody-based commercial test. ► We show a significant decrease in total CSF α-synuclein values in drug-naïve PD patients versus HC.
Several studies demonstrated reduced CSF α-synuclein values in patients with advanced Parkinson's disease (PD). Values in drug-naïve PD subjects and healthy controls (HC) have not yet been reported. We measured CSF values including α-synuclein in a cohort of 78 previously untreated PD patients and 48 HC subjects. Measurements of total α-synuclein concentrations were performed using two independently operated immunoassays, i.e., one academia-based and previously validated (ELISA 1), the other industry-based, renewable and commercially available (ELISA 2). Mean values for CSF α-synuclein were significantly lower in de novo PD patients when compared to HC subjects, as demonstrated by both assays (ELISA 1, p=0.049; ELISA 2, p=0.005; combined, p=0.002). Using the renewable ELISA 2, CSF α-synuclein concentrations of 1884.31pg/ml or less showed a sensitivity of 0.91 and a specificity of 0.25 for the diagnosis of Parkinson's disease. The corresponding area-under-the-curve value was 0.65 (confidence interval, 0.554–0.750), which was statistically significant (p=0.004). Total CSF α-synuclein is reduced early in the course of Parkinson's disease, as measured by two independent ELISA platforms at the time of enrolment, and this reduction appears independent from drug treatment. Follow-up investigations will determine the usefulness of CSF α-synuclein values as markers of progression in individual subjects.
This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n = 123) and ...age-matched, neurologically healthy controls (HC; n = 106).
Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI).
A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinson's Disease Rating Scale I (d 0.39; CI 0.09-0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; CI 0.06-0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24-0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25-0.64), and RBD by PSG (d 0.37; CI 0.19-0.55) as well as VBM units of cortical gray matter (d -0.2; CI -0.3 to -0.09) and hippocampus (d -0.15; CI -0.27 to -0.03). Markers with a relative improvement included the Nonmotor Symptom (Severity) Scale (d -0.19; CI -0.36 to -0.02) and 2 depression scales (Beck Depression Inventory d -0.18; CI -0.36 to 0; Montgomery-Åsberg Depression Rating Scale d -0.26; CI -0.47 to -0.04). Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD vs HC participants.
Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.
To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD).
This is a large single-center study of the DeNoPa cohort, ...including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis.
Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval CI 0.878-0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886-0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943-0.982).
We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of >0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.
PDF
