Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early α-Synucleinopathy.

BACKGROUND: Skin biopsy is a potential tool for the premortem confirmation of an α-synucleinopathy. OBJECTIVE: The aim was to assess the aggregation assay real-time quaking-induced conversion (RT-QuIC) of skin biopsy lysates to confirm isolated rapid eye movement sleep behavior disorder (iRBD) as an α-synucleinopathy. METHODS: Skin biopsies of patients with iRBD, Parkinson's disease (PD), and controls were analyzed using RT-QuIC and immunohistochemical detection of phospho-α-synuclein. RESULTS: α-Synuclein aggregation was detected in 97.4% of iRBD patients (78.4% of iRBD biopsies), 87.2% of PD patients (70% of PD biopsies), and 13% of controls (7.9% of control biopsies), with a higher seeding activity in iRBD compared to PD. RT-QuIC was more sensitive but less specific than immunohistochemistry. CONCLUSIONS: Dermal RT-QuIC is a sensitive method to detect α-synuclein aggregation in iRBD, and high seeding activity may indicate a strong involvement of dermal nerve fibers in these patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Detection of neuron-derived pathological α-synuclein in blood.

To date, no reliable clinically applicable biomarker has been established for Parkinson's disease. Our results indicate that a long anticipated blood test for Parkinson's disease may be realized. Following the isolation of neuron-derived extracellular vesicles of Parkinson's disease patients and non-Parkinson's disease individuals, immunoblot analyses were performed to detect extracellular vesicle-derived α-synuclein. Pathological α-synuclein forms derived from neuronal extracellular vesicles could be detected under native conditions and were significantly increased in all individuals with Parkinson's disease and clearly distinguished disease from the non-disease state. By performing an α-synuclein seeding assay these soluble conformers could be amplified and seeding of pathological protein folding was demonstrated. Amplified α-synuclein conformers exhibited ß-sheet-rich structures and a fibrillary appearance. Our study demonstrates that the detection of pathological α-synuclein conformers from neuron-derived extracellular vesicles from blood plasma samples has the potential to evolve into a blood-biomarker of Parkinson's disease that is still lacking so far. Moreover, the distribution of seeding-competent α-synuclein within blood exosomes sheds a new light of pathological disease mechanisms in neurodegenerative disorders.

Cognitive parameters can predict change of walking performance in advanced Parkinson's disease - Chances and limits of early rehabilitation.

Introduction: Links between cognition and walking performance in patients with Parkinson's disease (PD), which both decline with disease progression, are well known. There is lack of knowledge regarding the predictive value of cognition for changes in walking performance after individualized therapy. The aim of this study is to identify relevant predictive cognitive and affective parameters, measurable in daily clinical routines, for change in quantitative walking performance after early geriatric rehabilitation. Methods: Forty-seven acutely hospitalized patients with advanced PD were assessed at baseline (T1) and at the end (T2) of a 2-week early rehabilitative geriatric complex treatment (ERGCT). Global cognitive performance (Montreal Cognitive Assessment, MoCA), EF and divided attention (Trail Making Test B minus A, delta TMT), depressive symptoms, and fear of falling were assessed at T1. Change in walking performance was determined by the difference in quantitative walking parameters extracted from a sensor-based movement analysis over 20 m straight walking in single (ST, fast and normal pace) and dual task (DT, with secondary cognitive, respectively, motor task) conditions between T1 and T2. Bayesian regression (using Bayes Factor BF10) and multiple linear regression models were used to determine the association of non-motor characteristics for change in walking performance. Results: Under ST, there was moderate evidence (BF10 = 7.8, respectively, BF10 = 4.4) that lower performance in the ∆TMT at baseline is associated with lower reduction of step time asymmetry after treatment (R 2 adj = 0.26, p ≤ 0.008, respectively, R 2 adj = 0.18, p ≤ 0.009). Under DT walking-cognitive, there was strong evidence (BF10 = 29.9, respectively, BF10 = 27.9) that lower performance in the ∆TMT is associated with more reduced stride time and double limb support (R 2 adj = 0.62, p ≤ 0.002, respectively, R 2 adj = 0.51, p ≤ 0.009). There was moderate evidence (BF10 = 5.1) that a higher MoCA total score was associated with increased gait speed after treatment (R 2 adj = 0.30, p ≤ 0.02). Discussion: Our results indicate that the effect of ERGT on change in walking performance is limited for patients with deficits in EF and divided attention. However, these patients also seem to walk more cautiously after treatment in walking situations with additional cognitive demand. Therefore, future development of individualized treatment algorithms is required, which address individual needs of these vulnerable patients.

Metabolic Fingerprints of Circulating IGF-1 and the IGF-1/IGFBP-3 Ratio: A Multifluid Metabolomics Study.

OBJECTIVE: IGF-1 is known for its various physiological and severe pathophysiological effects on human metabolism; however, underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time, we associated serum IGF-1 levels with multifluid untargeted metabolomics data. METHODS: Plasma/urine samples of 995 nondiabetic participants of the Study of Health in Pomerania were characterized by mass spectrometry. Sex-specific linear regression analyses were performed to assess the association of IGF-1 and IGF-1/IGF binding protein 3 ratio with metabolites. Additionally, the predictive ability of the plasma and urine metabolome for IGF-1 was assessed by orthogonal partial least squares analyses. RESULTS AND CONCLUSIONS: We revealed a multifaceted image of associated metabolites with large sex differences. Confirming previous reports, we detected relations between IGF-1 and steroid hormones or related intermediates. Furthermore, various associated metabolites were previously mentioned regarding IGF-1-associated diseases, eg, betaine and cortisol in cardiovascular disease and metabolic syndrome, lipid disorders, and diabetes, or have previously been found to associate with differentiation and proliferation or mitochondrial functionality, eg, phospholipids. bradykinin, fatty acid derivatives, and cortisol, which were inversely associated with IGF-1, might establish a link of IGF-1 with inflammation. For the first time, we showed an association between IGF-1 and pipecolate, a metabolite linked to amino acid metabolism. Our study demonstrates that IGF-1 action on metabolism is tractable, even in healthy subjects, and that the findings provide a solid basis for further experimental/clinical investigation, eg, searching for inflammatory or cardiovascular disease- or metabolic syndrome-associated biomarkers and therapeutic targets.