Methods for determining misfolded alpha-synuclein in a sample

Abstract

The present invention relates to a method for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, comprising: (a) obtaining an IR spectrum of the sample in a cell comprising an infrared sensor element linked to an antibody capable of binding to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form, wherein said antibody binds to an epitope within amino acid residues 126-140 of human alpha-synuclein using the numbering according to SEQ ID NO:1; and (b) determining a value in the obtained infrared spectrum indicative for the proportion of alpha- synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample, wherein said value may be an amide I band maximum, an amide I band center of mass, a ratio of signal at 1650 cm-1 to the signal at 1630 cm-1, a ratio of signal at 1656 cm-1 to the signal at 1623.5 cm- 1, and / or a ratio of signal at 1651.5 cm-1 to the signal at 1623.5 cm-1. The invention further covers the sensor elements and devices used in said methods as well as the uses thereof for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha- synuclein in a sample obtained from a human subject.

Description

[0001] B18403WO 31 October 2024 METHODS FOR DETERMINING MISFOLDED ALPHA-SYNUCLEIN IN A SAMPLE Field of the Invention The present invention is in the field of molecular diagnostics and more specifically biosensors and relates to methods for the determination of the protein conformational states, in particular the proportion of alpha-synuclein fibrils / aggregates in a sample, the sensor elements and devices useful for such methods as well as the related uses. Background Neurodegenerative diseases that are associated with intracellular deposits of alpha-synuclein are commonly referred to as synucleinopathies. While the most well-known of these synucleinopathies is Parkinson’s disease (PD), there are a variety of other diseases including, but not limited to, Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson’s disease dementia (PDD)), diffuse Lewy body disease (DLBD), sporadic Alzheimer’s disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1 , PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer’s disease, and Down syndrome. Alpha-synuclein is a 140 amino acid long, cytosolic protein abundantly and predominantly expressed in the CNS and localized in pre-synaptic terminals. Alpha-synuclein is a natively unfolded protein but adopts secondary structure of mostly helical nature upon association with lipid vesicles or membranes and can also misfold and aggregate into larger oligomeric and fibrillar forms which are linked to the pathogenesis of synucleinopathies, such as PD. Although the physiological function of alpha-synuclein has not been completely elucidated to date, it is hypothesized that it may be involved in the regulation of synaptic activity and plasticity, neurotransmitter release, dopamine production and metabolism, vesicle trafficking, synaptic vesicle pool maintenance and chaperone-like activity. Alpha-synuclein can be subdivided into three distinct domains. The N-terminal region spanning amino acid residues 1-60 containing 11-mer amphipathic imperfect repeat residues with a highly conserved hexamer has been implicated in regulating its association to lipid membranes and its internalization. The region spanning residues 61-95 is the hydrophobic Non-Amyloid Component (NAC) domain and essential for alpha-synuclein fibrilization. The C-terminal part of alpha-synuclein consisting of amino acids 96- 140 is highly acidic and proline-rich and lacks distinct structural propensity. The C-terminal part is also the part that undergoes essentially all of the known post-translational modifications, including truncations, phosphorylation, ubiquitination, sumoylation, oxidation, nitration, acetylation, glycation, glycosylation, and / or transglutaminase covalent cross linking. There is some evidence that some of these modifications, in particular the phosphorylation, glycosylation, nitration and C-terminal truncation, may affect fibril formation and aggregation, as all of these have been detected in Lewy bodies and / or alpha-synuclein aggregates. In in vitro models, alpha-synuclein readily assembles into filaments resembling those isolated from brain of patients with Lewy Body dementia and familial PD. Parkinson’s disease (PD) is the most common neurodegenerative motor disorder. PD is mainly an idiopathic disease, although in at least 5% of the PD patients the pathology is linked to mutations in one or several specific genes. Several point mutations have been described in the alpha-synuclein gene which cause familial PD with autosomal dominant inheritance. Furthermore, duplications and triplications of the alpha-synuclein gene have been described in patients that developed. The pathogenesis of PD remains elusive, however, growing evidence suggests a role for the pathogenic folding of the alpha-synuclein protein that leads to the formation of amyloid-like fibrils. Indeed, the hallmarks of PD are the presence of intracellular alpha-synuclein aggregate structures called Lewy Bodies in the nigral neurons, as well as the death of dopaminergic neurons in the substantia nigra and elsewhere. Studies have implicated small soluble oligomeric and protofibrillar forms of alpha-synuclein as the most neurotoxic species, although the precise role of alpha-synuclein in the neuronal cell toxicity remains to be clarified. Evidence from cellular and animal models does suggest that pathological and / or aggregated alpha-synuclein can spread from one neuron to another. Once inside the new cell alpha-synuclein aggregates act as seeds, recruiting endogenous alpha-synuclein and advancing protein aggregation. The transsynaptic spreading of pathological and / or aggregated alpha- synuclein could explain the progressive advancing of Lewy pathology through defined anatomical connected brain areas in PD. To date, the diagnosis of Parkinson’s disease is still largely clinical and depends on the presence of a specific set of symptoms and signs (the initial core feature being bradykinesia, rigidity, rest tremor and postural instability), a slowly progressive course, and a response to drug treatment. The final confirmation of the diagnosis is made by post-mortem neuropathological analysis. There is some evidence that alpha-synuclein misfolding already occurs in very early stages of the disease, many years before the disease clinically manifests. As the detection of such early stages may provide new treatment options and also be a means for risk stratification for developing a synucleinopathy in the future, there is an ongoing need for novel methods that allow sensitive determination of misfolded alpha-synuclein at low levels, long before any disease symptoms occur. Although biomarkers for PD, including alpha-synuclein, have been investigated in different body fluids (cerebrospinal fluid (CSF), plasma, saliva), so far none of these biomarkers alone or in combination has been established for use as a determinant diagnostic test. This may be at least partially related to the fact that techniques such as enzyme-linked immune-sorbent assays (ELISA), surface plasmon resonance spectroscopy (SPR), surface fluorescence intensity distribution analysis (sFIDA) or mass spectroscopy, usually do not provide direct information about the secondary structure of the analytes, and, if they do, can typically only detect one of the multiple forms of the analyte. Other (spectroscopic) techniques are hampered by the need for highly purified protein samples that may be difficult to obtain with reasonable efforts, in particular if sample volumes and analyte concentrations are low. Infrared attenuated total reflection spectroscopy has been reported for analysis of amyloid beta and related proteins in biological fluids (WO 2015 / 121339 A1; Nabers et al., Analytical Chemistry, 88: 2755- 2762 (2016)). While this technique is highly suitable for analyzing the secondary structure profile of peptides potentially transitioning between several conformational states, it is dependent on provision of suitable capture antibodies that recognize and bind alpha-synuclein substantially independent of its conformational state. Summary of the invention The inventors have developed a method based on infrared attenuated total reflection spectroscopy that allows determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a complex sample and relies on antibodies that bind alpha-synuclein in its different conformational states. The inventors have further found that the method allows the determination of a specific threshold value that allows the distinction between normal and pathologically relevant increased levels of alpha-synuclein fibrils / aggregates in a sample. In a first aspect, the present invention is therefore directed to a method for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, comprising: (a) obtaining an IR spectrum of the sample in a cell comprising an infrared sensor element linked to an antibody capable of binding to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form, wherein said antibody binds to an epitope within amino acid residues 65-77 or 126-140 of human alpha-synuclein using the numbering according to SEQ ID NO:1; (b) determining a value in the obtained infrared spectrum indicative for the proportion of alpha- synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample. In various embodiments, the antibody has specificity for alpha-synuclein over beta- and gamma- synuclein. This may mean that it binds to alpha-synuclein preferably over any one of beta- and gamma- synuclein. The binding preference may, for example, be an affinity for alpha-synuclein that is at least 100-fold, optionally at least 1000-fold higher than that for the beta- and gamma-synuclein. In various embodiments, the antibody shows no cross-reactivity with beta- and gamma-synuclein. This may mean that under the assay conditions under which the method is performed it does not bind beta- and gamma- synuclein to any significant extent. In various embodiments, the capability of the antibody to bind to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form may entail that its affinity for alpha-synuclein in its monomeric, non-fibril form on the one hand and its fibril / aggregated form on the other hand is essentially the same. In various embodiments, this may mean that the affinity ratio of the antibody for monomeric alpha-synuclein and alpha-synuclein fibrils is in the range of 1.5:1 to 1:1.5, for example 1.1:1 to 1:1.1. In various embodiments of the method, the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form determined in step (b) is an amide I band maximum (b1). In such embodiments, the amide I band maximum decreases with an increasing proportion of alpha-synuclein in fibril and / or aggregated form. In various other embodiments, the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form determined in step (b) is an amide I band center of mass (b2). In such embodiments, the center of mass decreases with an increasing proportion of alpha-synuclein in fibril and / or aggregated form. In still various other embodiments, the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form determined in step (b) is a ratio of signal at 1650 cm-1to signal at 1630 cm-1(b3). In such embodiments, the ratio decreases with an increasing proportion of alpha-synuclein in fibril and / or aggregated form. In still various other embodiments, the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form determined in step (b) is a ratio of signal at 1656 cm-1to signal at 1623.5 cm-1(b4). In such embodiments, the ratio decreases with an increasing proportion of alpha-synuclein in fibril and / or aggregated form. In still various other embodiments, the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form determined in step (b) is a ratio of signal at 1651.5 cm-1to signal at 1623.5 cm-1(b5). In such embodiments, the ratio decreases with an increasing proportion of alpha-synuclein in fibril and / or aggregated form. In various embodiments, the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form may be a combination of any two, three, four or all five of the above values. In various embodiments of the methods disclosed herein, the infrared sensor element comprises an internal reflection element, optionally of trapezoid or parallelogram shape, which is transparent to infrared light and provides for more than one passage of the infrared light through the reflection element. In such embodiments, the antibody may be immobilized on a surface of the internal reflection element. In various embodiments of the disclosed methods, step (b) may comprises comparing the obtained IR spectrum with a reference IR spectrum of alpha-synuclein. The reference IR spectrum may be obtained from a sample with a known proportion of alpha-synuclein in fibril and / or aggregated form. In various embodiments, the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample may be used as a biomarker for detecting a disease or disorder characterized by alpha-synuclein aggregation or for determining the risk of developing a disease or disorder characterized by alpha-synuclein aggregation. In such embodiments, the method further comprises a step (c) of determining, based on the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample, whether the human subject is afflicted by or has a risk of developing a disease or disorder characterized by alpha-synuclein aggregation. For example, (c1) an amide I band maximum below 1639 cm-1, optionally below 1638cm-1, (c2) an amide I band center of mass of below 1641 cm-1, optionally below 1640 cm-1, (c3) a ratio of signal at 1650 cm-1to the signal at 1630 cm-1of the alpha-synuclein below 0.99, optionally below 0.98, (c4) a ratio of signal at 1656 cm-1to the signal at 1623.5 cm-1of the alpha-synuclein below 1.15, optionally below 1.10, and / or (c5) a ratio of signal at 1651.5 cm-1to the signal at 1623.5 cm-1of the alpha-synuclein below 1.20, optionally below 1.15 may be indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation. In various embodiments, the method further comprises a step (c) of determining, based on the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample, whether the human subject is afflicted by or has a risk of developing a disease or disorder characterized by alpha-synuclein aggregation, wherein (c3) a ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1is determined. In such embodiments, a ratio below 1.065 is indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation. In such embodiments, a ratio of greater than 1.14 is indicative for not being afflicted by a disease or disorder characterized by alpha-synuclein aggregation or for low risk of developing a disease or disorder characterized by alpha-synuclein aggregation. In such embodiments, a ratio of equal to or lower than 1.14 and equal to and higher than 1.065 is indicative for not being clearly afflicted by a disease or disorder characterized by alpha-synuclein aggregation but for having an elevated risk of developing a disease or disorder characterized by alpha-synuclein aggregation. In various embodiments, the sample used is a sample obtained from a human subject suspected of being afflicted by a disease or disorder characterized by alpha-synuclein aggregation or at risk of developing such a disease or disorder. Such diseases or disorders include, but are not limited to, Lewy body disease and Parkinson’s disease. The sample may be a cerebrospinal fluid sample, a blood sample, or a tissue homogenate sample, including, for example, brain and skin tissue homogenate sample. The sample may, in various embodiments, be cerebrospinal fluid, blood or tissue homogenate. The sample may be an unpurified sample or may have been subjected to one or more purification steps prior to analysis by the disclosed methods. In various embodiments, the sample is a complex sample, e.g. comprises a substantial background of proteins other than alpha-synuclein. This may mean that the majority of the proteins in the sample, e.g. more than 70 wt.-%, more than 80 wt.-% or even more than 90 wt.-%, are not alpha- synuclein. In various embodiments, in step (b) an amide I band maximum is analyzed and a downshift to below a threshold of 1639 cm-1, optionally below 1638 cm-1, may be considered indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation . In other embodiments, in step (b) an amide I band center of mass is analyzed and a downshift to below a threshold of 1641 cm-1, optionally below 1640 cm-1, may be considered indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation . In still further embodiments, in step (b) a ratio of signal at 1650 cm-1to the signal at 1630 cm-1is analyzed and a decrease to below a threshold value of 0.99, optionally below 0.98, may be considered indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation . In still further embodiments, in step (b) a ratio of signal at 1656 cm-1to the signal at 1623.5 cm-1is analyzed and a decrease to below a threshold value of 1.15, optionally below 1.10, may be considered indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation . In still further embodiments, in step (b) a ratio of signal at 1651.5 cm-1to the signal at 1623.5 cm-1is analyzed and a decrease to below a threshold value of 1.20, optionally below 1.15, may be considered indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation . In various embodiments, any 2, 3, 4 or all 5 of the above values may be analyzed. This may further increase specificity of the method and / or may be used to verify the result obtained by analyzing another value. In another aspect, the present invention is directed to a method of determining whether a human subject is afflicted by or has a risk of developing a disease or disorder characterized by alpha-synuclein aggregation, comprising: (a) obtaining an IR spectrum of the sample in a cell comprising an infrared sensor element linked to an antibody capable of binding to the alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form; (b) analyzing the obtained infrared spectrum to determine a value in the obtained infrared spectrum indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample, and (c) based on the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample, determining whether the human subject is afflicted by or has a risk of developing a disease or disorder characterized by alpha-synuclein aggregation, wherein (c1) an amide I band maximum below 1639 cm-1, optionally below 1638 cm-1, (c2) an amide I band center of mass of below 1641 cm-1, optionally below 1640 cm-1, (c3) a ratio of signal at 1650 cm-1to the signal at 1630 cm-1of the alpha-synuclein below 0.99, optionally below 0.98, (c4) a ratio of signal at 1656 cm-1to the signal at 1623.5 cm-1of the alpha-synuclein below 1.15, optionally below 1.10, and / or (c5) a ratio of signal at 1651.5 cm-1to the signal at 1623.5 cm-1of the alpha-synuclein below 1.20, optionally below 1.15, is indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha- synuclein aggregation. In a still further aspect, the present invention also encompasses an infrared sensor element for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, comprising an antibody capable of binding to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form, wherein said antibody binds to an epitope within amino acid residues 65-77 or 126-140 of human alpha- synuclein using the numbering according to SEQ ID NO:1, wherein said antibody is linked to the infrared sensor element. In still another aspect, the invention is directed to a device for determining the proportion of alpha- synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, comprising: (a) an infrared source, (b) an infrared sensor element according to the present invention, and (c) an infrared detector. The invention further features the use of an antibody binding to an epitope within amino acid residues 65-77 or 126-140 of human alpha-synuclein using the numbering according to SEQ ID NO:1, for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject. In various embodiments of the methods, infrared sensor elements and uses of the invention, the antibody (a) comprises three variable heavy chain complementarity determining regions VH-CDR1, VH-CDR2 and VH-CDR3 and three variable light chain complementarity determining regions VL-CDR1, VL-CDR2 and VL-CDR3, wherein: (a1) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:2, VH-CDR2 comprises the amino acid sequence of SEQ ID NO:3, VH-CDR3 comprises the amino acid sequence of SEQ ID NO:4, VL-CDR1 comprises the amino acid sequence of SEQ ID NO:5, VL-CDR2 comprises the amino acid sequence of SEQ ID NO:6, and VL-CDR3 comprises the amino acid sequence of SEQ ID NO:7; or (a2) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:8, VH-CDR2 comprises the amino acid sequence of SEQ ID NO:9, VH-CDR3 comprises the amino acid sequence YSF, VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10, VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11, and VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; or (b) comprises a heavy chain variable domain having an amino acid sequence that has at least 90%, preferably 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO:13 over its entire length and a light chain variable domain having an amino acid sequences that has at least 90%, preferably 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO:14 over its entire length; or (c) comprises a heavy chain variable domain having an amino acid sequence that has at least 90%, preferably 100 %, sequence identity to the amino acid sequence set forth in SEQ ID NO:15 over its entire length and a light chain variable domain having an amino acid sequences that has at least 90%, preferably 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO:16 over its entire length. In various embodiments, the infrared sensor element or the device as disclosed herein may be used for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject. In various other embodiments, the infrared sensor element or the device as disclosed herein may be used for detecting a disease or disorder characterized by alpha-synuclein aggregation or for determining the risk of developing a disease or disorder characterized by alpha-synuclein aggregation by determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject. Brief description of drawings Figure 1 shows the exemplary result of an ThT b(thioflavin T)-assay of alpha-synuclein monomers and PFFs (pre-formed fibrils) generated after the protocol of Polinksi et al. (doi: 10.3233 / JPD-171248). Excitation scan was recorded from 300-470 nm and emission scan from 460-600 nm with a step size of 0.1 nm (CLARIOstar Plus plate reader, BMG Labtech). Upon fibrilization, an excitation maximum shift from 415 to 443 nm and fluorescence increase (factor:46x) is observed. Both effects are derived from intercalation of ThT into ß-sheets of the PFFs. Figure 2 shows sample binding and wash kinetics of alpha-synuclein species to an aSyn-antibody surface. Target protein extraction by antibody was monitored using the amide-II-absorption band at 1550 cm-1. Both alpha-synuclein monomer and PFF (pre-formed fibril) bind on the antibody surface and reach a saturation in the circulation step of 60 minutes. The decline in the washing step over 60 minutes is stronger for the monomeric form in comparison to the PFFs indicating a stronger wash-off of monomers over time under these conditions and in this setup. Figure 3 shows normalized absorbance-spectra (1700-1600 cm-1) of alpha-synuclein monomers and PFFs as average wash spectra. There is a clear difference visible in the secondary structure sensitive amide-I-band, revealing that upon fibrilization the alpha-helical / random-coil-structures of the monomers are changing into structures dominated by beta-sheets. Figures 4A and 4B show normalized absorbance-spectra (1710-1500 cm-1) of alpha-synuclein monomers and PFFs bound to surfaces with different aSyn-antibodies. Figure 4A shows binding to a surface treated with an antibody according to the invention that binds to an epitope within residues 126- 140 of alpha synuclein, while Figure 4B shows surfaces treated with antibodies binding to epitopes within residues 121-125 (S5566) or 103-108 (4B12). Figure 5 shows sample binding and wash kinetics of CSF samples to an aSyn-antibody surface. Target protein extraction by antibody was monitored using the amide-II-absorption band at 1550 cm-1. Both alpha-synuclein present in a sample from a disease control (DC) and a Parkinson´s disease patient (PD) bind on the antibody surface and reach a saturation in the circulation step of 120 minutes. Figure 6 shows normalized DC-and PD-CSF samples in the amide-I-region from 1600-1700 cm-1. The shift of the amide-I-peak maximum and center of mass as well as the difference spectra reveal increased ß-sheet structures and decreased alpha-helical / random-coil structures, bound by the alpha-synuclein antibody on the surface, in PD-CSF sample. Figure 7 shows immune-infrared sensor surface characterization by synthetic alpha synuclein antigens. Figure 7A: The secondary structure sensitive Amide-I band absorbance of capture-antibody-bound alpha synuclein monomers (Stressmarq Bioscience Inc SPR-321), alpha synuclein oligomers (Stressmarq Bioscience Inc SPR-466), and alpha synuclein PPFs (Stressmarq Bioscience Inc SPR- 322) in PBS at high concentration of 500 ng / ml and scaled (x1.5-4) for comparison. Their structural differences are indicated by the significant wavenumber shift (cm-1) ranging from 1652 cm-1for alpha- helical / random-coil (monomers) over 1647 cm-1(oligomers) to beta-sheet dominated structures absorbing at 1624 cm-1. Figure 7B: The inertness measures on the blocking solution (BS) layer at high concentrations (500-5000 ng / ml) without the capture antibody. No signal is observed without the antibody on the blocking layer demonstrating sufficient inertness for pg-ng / ml concentrations of alpha synuclein in CSF. Abbreviations: aSyn, alpha-synuclein; BS, blocking solution; PFF, pre-formed fibril. Figure 8 shows an indirect ELISA for EC50-value determination of native and labeled capture antibody according to given protocol (ESI Materials). EC50-values were determined from blank corrected absorbance difference at 450 - 620nm using a 4-parameter logistic fit model on normalized data. Values demonstrate the fit results of the native and labeled antibody towards aSyn-M (Stressmarq Bioscience INC. SPR-321) and aSyn-PFF (Stressmarq Bioscience INC. SPR-322), as used in the ThT and ATR- FTIR experiments. EC50 values from the 4-parameter logistic fit model are 0.20 ± 0.002 nM and 0.22 ± 0.007 nM for native antibody, while labeled antibody shows EC50 values of 0.27 ± 0.010 nM and 0.27 ± 0.025 nM. The antibody used is a monoclonal anti-alpha-synuclein antibody with VH amino acid sequence of SEQ ID NO:13 and VL amino acid sequence of SEQ ID NO:14 binding to an alpha- synuclein epitope within amino acids 126-140 of SEQ ID NO:1. Figure 9 shows immune-infrared sensor analysis of alpha synuclein secondary structure distribution in CSF. Figure 9A: The group-level changes in the Amide-I-band as normalized and zoomed difference spectra. When calculating the difference spectra (normalized misfolding (n=62) – control group (n=72)), positive absorbance values at 1623.5 cm-1reflect increased beta-sheet structures, while negative absorbance values at 1656.0 cm-1reveal the connected decrease in alpha-helical / random-coil structures for PD / MSA samples compared to control samples. Figure 9B: A Boxplot of the best performing spectral feature (1656.0 / 1623.5-ratio) for the combined dataset, including 62 cases classified as misfolding positive (PD / MSA diagnosis) and 72 cases as controls where every point represents a single patient. A single threshold (1.093) discriminates both groups. A Mann-Witney-U test revealed statistically significant group differences with p<0.0001 (****; CI=95 %). Box and whisker plots show median value (vertical line), interquartile range (boxes), and standard deviation (whisker). Figure 10 shows immune-infrared sensor double threshold for classification into high and low misfolding and an intermediate group. Figure10A: Boxplot of the 1656.0 / 1623.5-ratio dependent on the misfolding status determined by the measurement and categorized into three subgroups where every diamond represents a single patient. High, intermediate, and low misfolding were determined with thresholds of 1.065 and 1.14 for the 1656.0 / 1623.5 spectral ratio. Box and whisker plots show median value (vertical line), interquartile range (boxes), and standard deviation (whisker). Figure 10B: The AUC performance of the high misfolding group versus the low misfolding group (n=68 / 134) according to the clinical diagnosis and expected misfolding status. The AUC value reached 0.95± 0.03 with a sensitivity of 97 % and a specificity of 92 %. Abbreviations: AUC, area under the curve; aSyn, alpha-synuclein; iRS, immuno-infrared-sensor. Detailed description The terms used herein have, unless explicitly stated otherwise, the meanings as commonly understood in the art. "At least one", as used herein, relates to one or more, in particular 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. The methods described herein may be used to diagnose or predict the risk of developing a synucleinopathy and / or to monitor or predict the efficacy of a given treatment. In one aspect, the present invention relates to a method for determining the proportion of alpha- synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, comprising: (a) obtaining an IR spectrum of the sample in a cell comprising an infrared sensor element linked to an antibody capable of binding to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form, wherein said antibody binds to an epitope within amino acid residues 65-77 or 126-140of human alpha-synuclein using the numbering according to SEQ ID NO:1; (b) determining a value in the obtained infrared spectrum indicative for the proportion of alpha- synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample. “Alpha-synuclein”, as used herein, relates, if not indicated otherwise, to the 140 aa long human alpha- synuclein protein, including all isoforms thereof. The protein in its native form is monomeric and either unstructured or adopts an alpha-helical conformation in particular in its N-terminal and middle domain (while the C-terminal domain remains unstructured). The amino acid sequence may be the one set forth in Uniprot databank entry P37480. The protein may have the amino acid sequence as set forth in SEQ ID NO:1 but, in various embodiments, may comprise a certain level of deviations from the primary sequence set forth therein to account for polymorphisms and / or mutations. In various embodiments, the term thus also covers protein variants to the amino acid sequence set forth in SEQ ID NO:1 that share a sequence identity of at least 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5 % to the sequence of SEQ ID NO:1 over its entire length. Determination of the sequence identity of nucleic acid or amino acid sequences can be done by a sequence alignment based on well-established and commonly used BLAST algorithms (See, e.g. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. (1990) "Basic local alignment search tool." J. Mol. Biol.215:403-410, and Altschul, Stephan F., Thomas L. Madden, Alejandro A. Schaffer, Jinghui Zhang, Hheng Zhang, Webb Miller, and David J. Lipman (1997): "Gapped BLAST and PSIBLAST: a new generation of protein database search programs"; Nucleic Acids Res., 25, S.3389- 3402). Such an alignment is based on aligning similar nucleotide or amino acid sequences stretches with each other. Another algorithm known in the art for said purpose is the FASTA algorithm. Alignments, in particular multiple sequence comparisons, are typically done by using computer programs. Commonly used are the Clustal series (See, e.g., Chenna et al. (2003): Multiple sequence alignment with the Clustal series of programs. Nucleic Acid Research 31, 3497-3500), T-Coffee (See, e.g., Notredame et al. (2000): T-Coffee: A novel method for multiple sequence alignments. J. Mol. Biol. 302, 205-217) or programs based on these known programs or algorithms. Also possible are sequence alignments using the computer program Vector NTI® Suite 10.3 (Invitrogen Corporation, 1600 Faraday Avenue, Carlsbad, CA, USA) with the set standard parameters, with the AlignX module for sequence comparisons being based on the ClustalW. If not indicated otherwise, the sequence identity is determined using the BLAST algorithm. Such a comparison also allows determination of the similarity of the compared sequences. Said similarity is typically expressed in percent identify, i.e. the portion of identical nucleotides / amino acids at the same or corresponding (in an alignment) sequence positions relative to the total number of the aligned nucleotides / amino acids. For example, if in an alignment 90 amino acids of a 100 aa long query sequence are identical to the amino acids in corresponding positions of a template sequence, the sequence identity is 90%. If not indicated otherwise, sequence identity relates to the entire length of the aligned sequence. Alpha-synuclein is a soluble protein that has the propensity to spontaneously aggregate and form soluble oligomers or soluble / insoluble protofibrils or mature fibrils or detergent-insoluble aggregates under certain conditions. The term “alpha-synuclein in fibril and / or aggregated form”, as used herein, relates to alpha-synuclein that is misfolded insofar that its secondary structure deviates from its native (functional) state in that it comprises parts in a beta-sheet secondary structure. Such beta-sheet conformation in its tertiary structure result in the formation of fibrils and aggregates of alpha-synuclein aggregates. Specifically, alpha-synuclein aggregates are multimeric beta-sheet rich assemblies of alpha-synuclein monomers that can form either soluble oligomers or soluble / insoluble protofibrils or mature fibrils which coalesce into intracellular deposits detected as a range of Lewy pathologies in Parkinson’s disease and other synucleinopathies. Alpha-synuclein under physiological conditions does not adopt an ordered tertiary structure, rather it is classified as a natively unfolded protein which can exist as a mixture of dynamic and flexible structural conformations. Misfolded alpha-synuclein can form multimeric intermediate oligomeric structures which eventually assemble into highly ordered fibrillar aggregates. The term “aggregated alpha-synuclein” as used herein, thus refers to insoluble or soluble oligomeric and / or polymeric structures composed of alpha-synuclein misfolded monomers and / or multimers and / or assemblies of monomers. Similarly, the term “alpha-synuclein fibril” as used herein, thus refers to oligomeric and / or polymeric structures composed of misfolded alpha-synuclein assembled into a fibrillar structure, including mature fibrils as well as protofibrils. As used herein, the term “alpha- synuclein oligomers” generally relates to aggregates comprising 2 to 70 alpha-synuclein molecules and thus having a molecular mass in the range of 28 to 1000 kDa. These oligomeric aggregates may be soluble and can adopt many different conformations making them highly heterogenic and transient. As used herein, the term “fibrils” or “mature fibrils” relates to high molecular aggregates in fibrillar form that have molecular masses of greater than 2000 kDa and thus comprise more than about 138 molecules of alpha-synuclein. Smaller soluble fibrils or “protofibrils”, as used herein, relates to fibrillary forms that may still be soluble and typically have molecular masses in the range of greater than 1000 kDa to lower than 2000 kDa. The term “aggregate”, as used herein, covers all multimeric forms of alpha-synuclein defined above, while the general term “fibril” as used herein in relation to alpha-synuclein is intended to cover all fibrillary forms of alpha-synuclein, i.e. the protofibrils and mature fibrils defined above. Similar definitions are known in the art (See, e.g., Kumar et al. (2020a), Conway et al. (2020), Kaylor et al. (2005), and Vidovic & Rikalovic (2022), all of which are included by reference herein in their entirety). “Proportion”, as used in relation to alpha-synuclein in fibril and / or aggregated form, means the portion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein. While the proportion may be given as an absolute (numerical) value, it may also be given as a relative (numerical) value relative to a reference. In certain embodiments, for example, the information that the proportion is “higher” than in a reference sample that only comprises monomeric, non-fibril alpha- synuclein or is a sample from a subject not afflicted by any synucleinopathy may per se already be valuable and useful. In the methods of the invention, the alpha-synuclein is analyzed by IR spectroscopy to record an IR spectrum which is then analyzed to determine a value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample. To record such an IR spectrum, the sample including the alpha-synuclein is introduced into a cell that may comprise an IR source, an IR detector and an IR sensor element. The general setup of an IR spectrometer is generally known. In the present methods, the IR sensor element is that part of the setup that is specifically designed to allow determining the proportion of the different conformational forms of alpha-synuclein in the sample. The sensor element may be an optical sensor element as generally described in WO 2015 / 121339 A1 or a variant thereof. In various embodiments, the sensor element may comprise an internal reflection element, in particular an attenuated total internal reflection element. Said internal reflection element may have a trapezoid or parallelogram shape, hemi-cylindrical, polyhedral, fiber or rod-shaped geometry, for example a trapezoid shape. Said internal reflection element may be a (mono)crystal of any suitable material that is sufficiently transparent to IR light (i.e. light with a wavelength of between 780 nm and 1 mm or at least between 780 nm and 25 µm). In various embodiments, the material used includes, but is not limited to plastic, glass, diamond, gold, silver, palladium, germanium, silicon, silicon dioxide, silver halides, GaAs, ZnSe, ZnS, thallium(I) mixed halides (e.g. KRS-5), and AMTIRs. “AMTIR” is an amorphous material transmitting infrared radiation which is known in the art. A suitable AMTIR may be Ge33As12Se55 (AMTIR-1). Particularly suitable materials include germanium, gallium arsenide, silicon, zinc selenide, and diamond. These materials may be used in form of crystals, for example monocrystals. In various embodiments, the material is therefore a silicon crystal or a germanium crystal, for example a silicon crystal. In various embodiments, the internal reflection element is arranged such that it allows for more than one passage of IR light through the reflection element. The number of passages in such embodiments may range from 2 to 20 or more, optionally 3 to 30 or 4 to 25, such as at least 5 passages. The higher number of passages ensures that a sufficient signal-to-noise ratio is obtained. In various embodiments, 20-30 reflections may be used, optionally with 10 to 20 actively sensed reflections. This may for example be achieved by using a multireflection crystal internal reflection element, for example in trapezoid or parallelogram shape. The sensor element comprises a capture reagent immobilized on its surface that is able to bind the alpha-synuclein in the sample and thus immobilize it on the sensor element surface. In the methods described herein, the capture reagent is an antibody. Suitable chemical means to (covalently) immobilize an antibody on such as sensor element surface are generally known in the art and include different chemistries, such as silane and thiol chemistry. A more detailed description of these immobilization chemistries can be found in WO 2015 / 121339 A1. In various embodiments, the sensor element comprises: a solid base element, a first layer comprising a linker A, a second layer comprising a peptide compound, a third layer comprising a linker B, and a fourth layer comprising the antibody, wherein the peptide compound is covalently bound to the base element via linker A and the antibody is covalently bound to the peptide compound via linker B. Such a sensor element, in various embodiments, thus has a structure, wherein a plurality of linkers A, and optionally a matrix compound, forms a first layer on the surface of the base element, a plurality of peptide compounds forms a second layer on the first layer, a plurality of linker B forms a third layer on the second layer, and a plurality of antibodies forms a fourth layer on the third layer. The first and the third layer comprising the linkers A and B, respectively, can be understood as linkage layers which link the solid base element to the peptide compound of the second layer and the peptide compound to the antibody. The second layer comprising the peptide compound can have the function of a blocking layer. The term “layer”, as used in this context, is not to be construed as restricting the first layer, second layer, third layer, and fourth layer to specific dimensions or to a specific aggregation state. The solid base element is a solid support which is covalently bound to linker A and is typically the surface of the sensor element, such as an optical sensor element or internal reflection element, in particular an attenuated total internal reflection element, as described herein above. Suitable materials for the solid base element are those listed above for the internal reflection elements. The solid base element may be at least partially surface-modified, e.g. by an oxide layer (e.g. silicon dioxide layer). The surface modification may aid the attachment of linker A. According to one embodiment of the present invention, at least a part of the solid base element has an oxide surface layer, and the peptide is covalently bound to the oxide surface layer via linker A. The oxide surface layer is preferably a metal oxide surface layer or a metalloid oxide surface layer. A “metalloid oxide” is an oxide of an element selected from the group consisting of boron, silicon, germanium, arsenic, antimony and tellurium. According to one embodiment of the present invention, at least a part of the solid base element has a silicon dioxide surface layer, and wherein the peptide is covalently bound to the silicon dioxide surface layer via linker A. According to one embodiment of the present invention, the solid base element is a silicon crystal, wherein at least a part of the silicon crystal has a silicon dioxide surface layer, and wherein the peptide compound is covalently bound to the silicon dioxide surface layer via linker A. In this case, it is further preferred that linker A comprises a silyl group which is covalently bound to the silicon dioxide surface. The solid base element may be covalently bound to a surface attachment group of linker A. For example, the surface attachment group of linker A may be a silicon-containing group or a sulfur-containing group. The surface attachment group of linker A can be selected in view of the material of the solid base element. For example, if the solid base element is a silicon crystal which is at least partially surface-modified with silicon dioxide or a germanium crystal which is at least partially surface-oxidized, the surface attachment group of linker A may be a silicon- containing group. If the solid base element is a germanium crystal, the surface attachment group of linker A may be a sulfur- containing group. Linker A covalently binds the peptide compound to the solid base element. This means that linker A has a surface attachment group which is covalently bound to the solid base element and a peptide attachment group which is covalently bound to the peptide compound, and wherein the surface attachment group is covalently bound to the peptide attachment group via a linking moiety. Linker A is not particularly limited in terms of its chemical structure as long as linker A is suitable for covalently binding a peptide compound as defined herein to the solid base element. The surface attachment group of linker A can be selected in view of the material of the solid base element as defined herein above. Linker A may comprise a surface attachment group which is a silicon- or sulfur-containing group. According to one embodiment of the invention, linker A comprises a surface attachment group which is covalently bound to the solid base element, and wherein the surface attachment group is a silicon- containing group or a sulfur-containing group. The surface attachment group may have the formula: BE−Y1− / , wherein BE indicates attachment of linker A to the solid base element; Y1is S or –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, O-BE, and –O- Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element, and indicates the attachment point to the remaining part of linker A. According to one embodiment, the solid base element is a silicon crystal, which is optionally at least partially surface-modified by silicon dioxide, wherein the surface attachment group has the formula BE−Y1− / , wherein BE indicates attachment of linker A to the solid base element; Y1is –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, O-BE, and –O-Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element, and indicates the attachment point to the remaining part of linker A. According to one embodiment, linker A comprises an alkylene oxide unit or an poly(alkylene oxide) unit, for example an ethylene glycol unit or an polyethylene glycol unit. For example, linker A can comprise a –(OCH2CH2)k– group, wherein k is an integer from 1 to 100, preferably from 1 to 50, and more preferably from 1 to 16. According to one embodiment, linker A comprises a surface attachment group which is covalently bound to the solid base element and a peptide attachment group which is covalently bound to the peptide compound, and wherein the surface attachment group is covalently bound to the peptide attachment group via a linking moiety, and wherein the linking moiety comprises a −(OCH2CH2)k– group, wherein k is an integer from 1 to 100, preferably from 1 to 50, and more preferably from 1 to 16. Additionally or alternatively, linker A may comprise a group which is obtainable by a bioorthogonal ligation reaction. Bioorthogonal ligation reactions are known to the skilled person. The skilled person is also familiar with the chemical structures of the functional groups which are obtainable by said reactions. Bioorthogonal ligation reactions include, but are not limited to, reactions between an azide and phosphine or phosphite (“Staudinger ligation”), [2+3]-cycloadditions between azide and alkyne (“click reaction), between azide and cycloalkyne (“copper-free click reaction”), between nitrone and cycloalkyne, [2+4]-cycloadditions between tetrazine and a trans-alkene (“tetrazine ligation”), oxime / hydrazone formation from aldehyde and ketone, and the like. Hence, the bioorthogonal ligation reaction can be one of the following reactions: (i) a reaction between an azide and a phosphine or phosphite; (ii) a reaction between an azide and an alkyne (including cycloalkynes); (iii) a reaction between an azide and a cycloalkyne; (iv) a reaction between a tretrazine and a trans-alkenes; (v) an oxime- and / or hydrazone-forming reaction. According to one embodiment, linker A comprises an optionally substituted N-heterocyclic group, wherein the N-heterocyclic group is selected from triazoles (e.g. 1,2,3-triazoles), dihydropyridazines, and pyridazines. Preferably, linker A comprises an optionally substituted triazole group which is obtainable by a [2+3]- cycloaddition between an azide compound and an alkyne compound (“Click ligation”) or linker A comprises an optionally substituted dihydropyridazine which is obtainable by a [2+4]-cycloaddition between an tetrazine compound and a trans-alkene compound (“Click ligation”). According to one embodiment, linker A comprises a surface attachment group which is covalently bound to the solid base element and a peptide attachment group which is covalently bound to the peptide compound, and wherein the surface attachment group is covalently bound to the peptide attachment group via a linking moiety, and wherein the linking moiety comprises a group which is obtainable by a bioorthogonal ligation reaction, and preferably wherein the linking moiety comprises an optionally substituted N-heterocyclic group, wherein the N-heterocyclic group is selected from triazoles (e.g.1,2,3- triazoles), dihydropyridazines, and pyridazines. Linker A may comprise a peptide attachment group, which may be any group which is suitable for attaching a linker to a peptide compound, and optionally to an amino, thiol or alcohol group of a peptide compound, and optionally to an amino group of a peptide compound (e.g. an amino group of a lysine residue). The peptide attachment group may be an ester group, an amide group or a succinimide group or a ring- opened product of a succinimide group, and optionally is an amide group. The peptide attachment group may be one of: wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, and the wavy line indicates the attachment point to the remaining part of linker A. According to one embodiment of the present invention, linker A comprises a surface attachment group which is covalently bound to the solid base element, and a peptide attachment group which is covalently bound to the peptide compound, wherein the surface attachment group is covalently bound to the peptide attachment group via a linking moiety; wherein the surface attachment group is a silicon- or sulfur-containing group, and wherein the peptide attachment group is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, preferably the peptide attachment group is one of: wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, and the wavy line indicates the attachment point to the remaining part of linker A. According to one embodiment of the present invention, linker A comprises a surface attachment group which is covalently bound to the solid base element, and a peptide attachment group which is covalently bound to the peptide compound, wherein the surface attachment group is covalently bound to the peptide attachment group via a linking moiety; wherein the surface attachment group is a silicon- or sulfur-containing group, wherein the linking moiety comprises an optionally substituted N-heterocyclic group selected from triazoles (e.g.1,2,3-triazoles), dihydropyridazines and pyridazines, which is optionally obtainable by a cycloaddition reaction (e.g. a [2+3]- or [2+4]-cycloaddition); and wherein the peptide attachment group is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, preferably the peptide attachment group is one of: wherein Q1is NH, O or S of an amino acid of the peptide, PEP is the peptide compound, and the wavy line indicates the attachment point to the remaining part of linker A. According to one embodiment of the present invention, linker A comprises a surface attachment group which is covalently bound to the solid base element, and a peptide attachment group which is covalently bound to the peptide compound, wherein the surface attachment group is covalently bound to the peptide attachment group via a linking moiety; wherein the surface attachment group is a silicon- or sulfur-containing group, wherein the linking moiety comprises a –(OCH2CH2)k– group, wherein k is an integer from 1 to 100, preferably from 1 to 50, and more preferably 1 to 16; and wherein the peptide attachment group is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, preferably the peptide attachment group is one of: wherein Q1is NH, O or S of an amino acid of the peptide, PEP is the peptide compound, and the wavy line indicates the attachment point to the remaining part of linker A. According to one preferred embodiment of the present invention, linker A comprises a surface attachment group which is covalently bound to the solid base element, and a peptide attachment group which is covalently bound to the peptide compound, wherein the surface attachment group is covalently bound to the peptide attachment group via a linking moiety; wherein the surface attachment group is a silicon- or sulfur-containing group, wherein the linking moiety comprises (i) an optionally substituted N-heterocyclic group selected from triazoles (e.g.1,2,3-triazoles), dihydropyridazines and pyridazines, which is optionally obtainable by a cycloaddition reaction (e.g. a [2+3]- or [2+4]-cycloaddition), and / or (ii) a –(OCH2CH2)k– group, wherein k is an integer from 1 to 100, preferably 1 to 50, and more preferably 1 to 16, and preferably the linking moiety comprises feature (i) and (ii); and wherein the peptide attachment group is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, preferably the peptide attachment group is one of: wherein Q1is NH, O or S of an amino acid of the peptide, PEP is the peptide compound, and the wavy line indicates the attachment point to the remaining part of linker A. It was previously found that by connecting the surface of the solid base element to the peptide compound via a linker A which is sequentially prepared by click ligation, and therefore comprises an optionally substituted N-heterocyclic group selected from triazoles (e.g.1,2,3-triazoles), dihydropyridazines and pyridazines, in its linking moiety, it is possible to provide a better and more dense functionalization of the surface of the base element. According to one preferred embodiment, linker A has a structure according to any one of formula (LA-I) to (LA-III-b) or a salt thereof, and preferably has a structure according to formula (LA-II) or (LA-II-b) or a salt thereof: (LA-I) (LA-I-b) , (LA-II) (LA-II-b) , (LA-III) (LA-III-b) , wherein BE indicates attachment of linker A to the solid base element; Y1is S or –O-Si(R2)2-, wherein R2is each independently selected from OH, alkyl, alkoxy, O-BE, and – O-Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element; L1and L2are each a linking moiety; Y2is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound; ring A, if present, is an optionally substituted 8-membered carbocycle or an optionally substituted 8- membered heterocycle (e.g. an optionally substituted 8-membered N-heterocycle); and R1, if present, is selected from H, an optionally substituted alkyl and an optionally substituted aryl. According to one preferred embodiment, the linking moiety L1in any one of above formula (LA-I) to (LA- III-b) comprises an ethylene glycol group or a PEG group, and more preferably a (OCH2CH2)k– group, wherein k is an integer from 1 to 100, preferably 1 to 50, and more preferably from 1 to 16. The optional additional silane compound being attached to the surface of the solid base element may be the matrix compound as defined herein below. According to one embodiment, linker A has a structure according to formula (LA-IV) or a salt thereof: , wherein BE indicates attachment of linker A to the solid base element; Y1is S or –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, OBE, and –O- Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element; n1ais an integer from 1 to 6; X1ais a bond, -C(O)NH- or –NHC(O)-; n2ais an integer from 1 to 16; X2ais a bond or –(OCH2CH2)n4a-, wherein n4ais an integer from 1 to 16; X3ais a bond or –CH2-; X4ais a bond; n3ais an integer from 1 to 5; X5ais a bond or –(OCH2CH2)n5a-, wherein n5ais an integer from 1 to 16; X6ais a bond or –(CH2)n6a-, wherein n6ais an integer from 1 to 5; and Y2is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound. Where a substituent may be a “bond”, this means “covalent bond”. As will be understood by those skilled in the art, where two or more adjacent substituents are selected to be a bond, this means that the two adjacent substituents form one bond. For example, if X5aand X6aare both selected to be a bond, this means X5aand X6aform one bond which binds the methylene group (“CH2-”) to Y2. This understanding applies to each embodiment disclosed herein where two or more adjacent substituents can be selected to be a bond. According to one preferred embodiment, linker A has a structure according to formula (LA-V) or a salt thereof: wherein BE indicates attachment of linker A to the solid base element; Y1is S or –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, OBE, and –O- Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element; n1bis an integer from 1 to 6; X1bis a bond, -C(O)NH- or –NHC(O)-; n2bis an integer from 1 to 16; X2bis a bond or –(OCH2CH2)n4b-, wherein n4bis an integer from 1 to 16; X3bis a bond or –CH2-; ring A is an optionally substituted 8-membered carbocycle or an optionally substituted 8-membered heterocycle; X4bis a bond, O, –C(O)- or a carbon atom which forms a cyclopropyl group with two adjacent carbons of ring A; n3bis an integer from 1 to 5; X5bis a bond or –(OCH2CH2)n5b-, wherein n5bis an integer from 1 to 16; X6bis a bond or –(CH2)n6b-, wherein n6bis an integer from 1 to 5; and Y2is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound. According to one embodiment, linker A has a structure according to formula (LA-VI) or a salt thereof: wherein BE indicates attachment of linker A to the solid base element; Y1is S or –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, OBE, and –O- Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element; n1cis an integer from 1 to 6; X1cis a bond, -C(O)NH- or –NHC(O)-; n2cis an integer from 1 to 16; X2cis a bond or –(OCH2CH2)n4c-, wherein n4is an integer from 1 to 16; X3cis a bond, –CH2-, or phenyl; ring A is an optionally substituted 8-membered carbocycle or an optionally substituted 8-membered heterocycle; R1is an optional alkyl or aryl substituent; X4cis a bond, O, –C(O)- or a carbon atom which forms a cyclopropyl group with two carbons of ring A; n3cis an integer from 1 to 5; X5cis a bond or –(OCH2CH2)n5c-, wherein n5cis an integer from 1 to 16; X6cis a bond or –(CH2)n6c-, wherein n6cis an integer from 1 to 5; and Y2is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound. According to one preferred embodiment, linker A has a structure according to Formula (LA-VII) or a salt thereof or a [2+3]-cycloaddition regioisomer thereof: (LA-VII), wherein BE indicates attachment of linker A to the solid base element; Y1is S or –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, OBE, and –O- Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element; n1dis an integer from 1 to 6, preferably 2 to 4 (e.g.3); X1dis a bond, -C(O)NH- or –NHC(O)-; n2dis an integer from 1 to 16; X2dis a bond or –(OCH2CH2)n4d-, wherein n4dis an integer from 1 to 16; X3dis a bond, –CH2-; R1dis one to four optional substituents, and preferably R1dis absent; Z1is N, O or CH, Z2is CH2, CH, or C(O), X4dis a bond, O, –C(O)- or a carbon atom which forms a cyclopropyl group with Z1and Z2; n3dis an integer from 1 to 5; X5dis a bond or –(OCH2CH2)n5d-, wherein n5dis an integer from 1 to 16; X6dis a bond or –(CH2)n6d-, wherein n6dis an integer from 1 to 5; and wherein Q1is NH, O or S of an amino acid of the peptide compound and PEP is the peptide compound. According to one embodiment, the linker A has a structure according to Formula (LA-VII) or a salt thereof or a [2+3]-cycloaddition regioisomer thereof: wherein BE indicates attachment of linker A to the solid base element; Y1is –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, OBE, and –O-Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element n1dis an integer from 1 to 6, preferably 2 to 4 (e.g.3); X1dis -C(O)NH- or –NHC(O)-; n2dis an integer from 1 to 16, preferably 2 to 4 (e.g.2); X2dis –(OCH2CH2)n4d-, wherein n4dis an integer from 1 to 16; X3dis a bond or –CH2-; R1dis one to four optional substituents, and preferably R1dis absent; Z1is N, O or CH; Z2is CH2, CH, or C(O); X4dis a bond, O, –C(O)- or a carbon atom which forms a cyclopropyl group with Z1and Z2; n3dis an integer from 1 to 5; X5dis a bond or –(OCH2CH2)n5d-, wherein n5dis an integer from 1 to 16; X6dis a bond or –(CH2)n6d-, wherein n6dis an integer from 1 to 5; and wherein Q1is NH, O or S of an amino acid of the peptide compound and PEP is the peptide compound. According to one embodiment, linker A has a structure according to Formula (LA-VII) or a salt thereof or a [2+3]-cycloaddition regioisomer thereof: wherein BE indicates attachment of linker A to the solid base element; Y1is –O-Si(R2)-, wherein R2is each independently selected from OH, alkyl, alkoxy, OBE, and –O-Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element n1dis an integer from 2 to 4 (e.g.3); X1dis –NHC(O)-; n2dis an integer from 2 to 4 (e.g.2); X2dis –(OCH2CH2)n4d-, wherein n4dis an integer from 1 to 16; X3dis a bond; R1dis absent; Z1is N; Z2is CH2; X4dis –C(O)-; n3dis an integer from 1 to 5 (e.g.2); X5dis a bond; X6dis a bond; and , wherein Q1is NH, O or S of an amino acid of the peptide compound and PEP is the peptide compound. According to one more specific embodiment, linker A has a structure according to Formula (LA-VII) or a salt thereof or a [2+3]-cycloaddition regioisomer thereof: wherein BE indicates attachment of linker A to the solid base element; R2is each independently selected from OH, alkyl, alkoxy, OBE, and –O-Six, wherein Sixis a silicon atom of another linker A or a silicon atom of an optional additional silane compound being attached to the surface of the solid base element n1eis an integer from 2 to 4, optionally 3; n2eis an integer from 3 to 8, optionally 5; and wherein Q1is NH, O or S of an amino acid of the peptide compound and PEP is the peptide compound. According to one embodiment, linker A has a structure according to Formula (LA-VII) or a salt thereof or a [2+3]-cycloaddition regioisomer thereof:

[0002] wherein BE indicates attachment of linker A to the solid base element; Y1is S; n1dis an integer from 1 to 6 X1dis a bond n2dis an integer from 1 to 16; X2dis a bond or –(OCH2CH2)n4d-, wherein n4dis an integer from 1 to 16; X3dis a bond, –CH2-; R1dis one to four optional substituents, and preferably R1dis absent; Z1dis N, O or CH, Z2dis CH2, CH, or C(O), X4dis a bond, O, –C(O)- or a carbon atom which forms a cyclopropyl group with Z1and Z2; n3dis an integer from 1 to 5; X5dis a bond or –(OCH2CH2)n5d-, wherein n5dis an integer from 1 to 16; X6dis a bond or –(CH2)n6d-, wherein n6dis an integer from 1 to 5; and wherein Q1is NH, O or S of an amino acid of the peptide compound and PEP is the peptide compound. According to one embodiment, linker A has a structure according to Formula (LA-IX) or a salt thereof or a [2+3]-cycloaddition regioisomer thereof: wherein BE indicates attachment of linker A to the solid base element; n1fis an integer from 1 to 16, optionally 11, and Q1is NH, O or S of an amino acid of the peptide compound and PEP is the peptide compound. According to one embodiment, linker A has a structure according to Formula (LA-X) or a salt thereof or a [2+3]-cycloaddition regioisomer thereof: (LA-X) , wherein BE indicates attachment of linker A to the solid base element; n1fis an integer from 1 to 16, optionally 11, n2fis an integer from 1 to 16, and Q1is NH, O or S of an amino acid of the peptide compound and PEP is the peptide compound. When linker A has a structure according to any one of Formula (LA-I) to (LA-VII) or a salt thereof or a or a [2+3]-cycloaddition regioisomer thereof, and wherein the Y1group is –Si(R2)-, then the solid base element is preferably a silicon crystal or a germanium crystal, preferably a silicon crystal, and more preferably is a silicon crystal wherein at least a part of the silicon crystal has a silicon dioxide surface, and wherein the Y1group is covalently bound to the silicon dioxide. Alternatively, when linker A has a structure according to any one of Formula (LA-I) to (LA-VII) or a salt thereof or a or a [2+3]-cycloaddition regioisomer thereof, and wherein the Y1group is -S-, then the solid base element is preferably a germanium crystal. According to one embodiment, linker A is obtainable or obtained by the steps a) to c) of the process described below. According to one embodiment, linker A is obtainable or obtained by the step a), steps b1) to b4), and step c) of the process described below. In addition to linker A, the first layer can further comprise a matrix compound, which is covalently bound to the solid base element. The matrix compound may be a compound comprising a silicon-containing group which is covalently bound to the solid base element. The matrix compound is preferably a compound comprising a PEG group or mPEG group, and a silicon-containing group, wherein the silicon-containing group is covalently bound to the solid base element. According to one embodiment, the matrix compound is a PEG-containing or mPEG-containing silane, and preferably a mPEG-containing silane. Additionally or alternatively, the matrix compound can be an optionally substituted alkyl sulfide, preferably an optionally substituted C1-C30-alkyl sulfide. Hence, according to one embodiment, the matrix compound is: (i) a PEG-containing or mPEG-containing silane, preferably a mPEG-containing silane, and / or (ii) an optionally substituted alkyl sulfide, preferably an optionally substituted C1-C30 alkyl sulfide. According to one embodiment, the first layer comprises a matrix compound, which is covalently bound to the solid base element, wherein the matrix compound is a compound according to formula (MA-I) or a salt thereof: (MA-I): BE−Y−X, wherein BE indicates attachment of the compound to the solid base element; Y is S or –O-Si(R2g)-, wherein R2gis each independently selected from OH, alkyl, alkoxy, OBE, and –O- Siy, wherein Siyis a silicon atom of a linker A or a silicon atom of another silane being attached to the surface of the solid base element, and X is a group comprising a PEG group, mPEG group, or a alkyl group (e.g. a C1-C30 alkyl group). According to one embodiment, the matrix compound is a compound according to formula (MA-II) or salt thereof: wherein BE indicates attachment of the compound to the solid base element; Y1gis S or –O-Si(R2g)-, wherein R2gis each independently selected from OH, alkyl, alkoxy, OBE, and – O-Siy, wherein Siyis a silicon atom of a linker A or a silicon atom of another silane being attached to the surface of the solid base element, n1gis an integer from 1 to 6; X1gis a bond, -C(O)NH- or –NHC(O)-; n2gis an integer from 1 to 15; X2gis a bond or –(OCH2CH2)n4g-, wherein n4gis an integer from 1 to 16; X3gis a bond, O or –CH2-; and X4gis OH or CH3. It was previously found that the additional compound can function as a matrix on the surface of the base element which further reduces non-specific binding of media or sample components to the surface. Furthermore, the use of a matrix compound in combination with linker A allows for fine tuning the amount of linker A to be bound to the surface of the base element and allows for spacing the linker A on the surface of the base element. Therefore, attaching the “matrix compound” to the surface of the base element in addition to linker A can improve the performance of detection. According to one embodiment, the matrix compound is a compound according to formula (MA-II) or salt thereof: wherein BE indicates attachment of the compound to the solid base element; Y1gis –O-Si(R2g)-, wherein R2gis each independently selected from OH, alkyl, alkoxy, OBE, and –O-Siy, wherein Siyis a silicon atom of a linker A or a silicon atom of another silane being attached to the surface of the solid base element; n1gis an integer from 1 to 6, optionally 2 to 4 (e.g.3); X1gis a -C(O)NH- or –NHC(O)-; n2gis an integer from 1 to 15, optionally 2 to 6 (e.g.2); X2gis–(OCH2CH2)n4g-, wherein n4gis an integer from 1 to 16, optionally 1 to 5 (e.g.2); X3gis a bond, O, or –CH2-; and X4gis OH or CH3. According to one embodiment, the matrix compound is a compound according to formula (MA-II) or salt thereof: (MA-II): , wherein BE indicates attachment of the compound to the solid base element; Y1gis –O-Si(R2g)-, wherein R2gis each independently selected from OH, alkyl, alkoxy, OBE, and –O-Siy, wherein Siyis a silicon atom of a linker A or a silicon atom of another silane being attached to the surface of the solid base element; n1gis an integer from 2 to 4 (e.g.3); X1gis –NHC(O)-; n2gis an integer from 2 to 6 (e.g.2); X2gis–(OCH2CH2)n4g-, wherein n4gis an integer from 1 to 5 (e.g.2); X3gis a O; and X4gis CH3. According to one embodiment, the matrix compound is a compound according to formula (MA-II) or salt thereof: (MA-II): , wherein BE indicates attachment of the compound to the solid base element; Y1gis S; n1gis an integer from 1 to 6; X1gis a bond; n2gis an integer from 1 to 15; X2gis a bond; X3gis a bond; and X4gis CH3. When the compound according to Formula (MA-II) has a Y1ggroup being –Si(R2g)-, then the solid base element is preferably a silicon crystal or a germanium crystal, preferably a silicon crystal, and more preferably is a silicon crystal wherein at least a part of the silicon crystal has a silicon dioxide surface, and wherein the Y1ggroup is covalently bound to the silicon dioxide. Alternatively, when the compound according to Formula (MA-II) has a Y1ggroup being -S-, then the solid base element is preferably a germanium crystal. The peptide compound is covalently bound to the solid base element via linker A and to the antibody via linker B. Preferably, the second layer has the function of a blocking layer. The second layer can further comprise peptide compounds which are covalently bound to the solid base element via linker A but which are not attached to an antibody. In other words, the second layer can comprise peptide compounds which are not functionalized by an antibody via linker B, but which solely function as part of a blocking layer. Hence, according to one preferred embodiment, the second layer comprises peptide compounds which are covalently bound to the solid base element via linker A but which are not attached to an antibody. The second layer can comprise a single type of peptide compound or a mixture of peptide compounds. According to one embodiment, the second layer comprises or consists of a single type of peptide compound. According to one preferred embodiment, the second layer comprises or consists of a mixture of peptide compounds. In case the second layer comprises or consists of a mixture of peptide compounds, different peptide compounds can be attached to the solid base element via linker A. According to one preferred embodiment, the peptide compound of the second layer is selected from the group consisting of peptides, substituted peptides, proteins, protein fragments, and mixtures thereof. A substituted peptide can be, for example, a PEGylated peptide. The peptide compound is preferably a peptide compound which has no or essentially no binding affinity for the target analyte. i.e. alpha-synuclein, or a fluid containing said target analyte, such as a body fluid (e.g. CSF). The peptide compound is preferably a peptide compound which is inert towards alpha- synuclein or a fluid containing alpha-synuclein, such as a body fluid (e.g. CSF). The peptide compound may be an optionally substituted natural, semi-synthetic or synthetic peptide, optionally having an amino acid chain length between 2 to 600 amino acids, optionally 2 to 400 amino acids, optionally 2 to 200 amino acids, optionally 2 to 100 amino acids, and optionally 4 to 100 amino acids. The peptide compound may be a natural, semi-synthetic or a synthetic peptide having an amine acid chain length between 2 to 100 amino acids, and optionally 4 to 100 amino acids. Preferably, the peptide compound comprises one or more amino acids, which contain an H2N-, HO- or HS-group in its / their side chain. The peptide compound can be a fragment of a protein. The fragment of the protein can be obtainable or obtained by protein hydrolysis. Thus, the peptide compound may be obtainable or obtained from a protein hydrolysate. For example, the peptide compound can be obtainable or obtained from a hydrolysate of albumin, casein, BSA, serum proteins (e.g. animal serum such as swine, horse, or goat serum), milk proteins, or mixtures thereof. Preferably, the peptide compound is obtainable or obtained from a casein hydrolysate. The peptide compound may be an optionally substituted peptide, optionally having an amino acid chain length between 2 to 600 amino acids, optionally 2 to 400 amino acids, optionally 2 to 200 amino acids (e.g.2 to 100 or 4 to 100), wherein the peptide is obtainable or obtained from a protein hydrolysate. The peptide compound may be an optionally substituted peptide having an amino acid chain length between 2 to 600 amino acids, optionally 2 to 400 amino acids, optionally 2 to 200 amino acids (e.g.2 to 100 or 4 to 100), wherein the peptide is obtainable or obtained from a protein hydrolysate, wherein the protein is selected from the group of albumin, casein, BSA, serum proteins, milk proteins, and mixtures thereof. Preferably, the peptide compound is an optionally substituted peptide having an amino acid chain length between 2 to 100 amino acids, wherein the peptide is obtainable or obtained from a casein hydrolysate. The casein hydrolysate may be a hydrolysate of high purity casein. A suitable casein hydrolysate is the commercially available “The blocking solution” from Candor Bioscience GmbH. According to one embodiment, the second layer comprises a mixture of peptide compounds, wherein the mixture of peptide compounds is a mixture of peptides which are obtainable or obtained from a protein hydrolysate, and wherein the peptides are optionally substituted, e.g. PEGylated. According to one embodiment, the second layer comprises a mixture of peptide compounds, wherein the mixture of peptide compounds is a mixture of peptides which are obtainable or obtained from a casein hydrolysate, and wherein the peptides are optionally substituted, e.g. PEGylated. Linker B is covalently bound to the peptide compound and to the antibody. Linker B is not particularly limited in terms of its chemical structure as long as linker B is suitable for covalently binding a peptide compound as defined herein to an antibody. According to one embodiment, linker B comprises a peptide attachment group which is covalently bound to the peptide compound, and an antibody attachment group which is covalently bound to the antibody, and wherein the peptide attachment group is covalently bound to the antibody attachment group by a linking moiety, wherein the linking moiety comprises a group which is obtainable by a bioorthogonal ligation reaction. Preferably, the linking moiety comprises an optionally substituted N-heterocyclic group, wherein the N- heterocyclic group is optionally selected from triazoles (e.g. 1,2,3-triazoles), dihydropyridazines, and pyridazines. Preferably, the linking moiety comprises an optionally substituted triazole group which is obtainable or obtained by a [2+3]-cycloaddition between an azide compound and an alkyne compound (“Click ligation”) or the linking moiety comprises an optionally substituted dihydropyridazine which is obtainable or obtained by a [2+4]-cycloaddition between an tetrazine compound and a trans-alkene compound (“Click ligation”). According to one embodiment, linker B comprises a peptide attachment group which is covalently bound to the peptide compound, an antibody attachment group which is covalently bound to the antibody, wherein the peptide attachment group is covalently bound to the antibody attachment group via a linking moiety; wherein the linking moiety comprises an optionally substitiuted N-heterocyclic group selected from triazoles, dihydropyridazines and pyridazines, which is optionally obtainable or obtained by a cycloaddition reaction, and wherein the peptide attachment group is an ester group, an amide group, or a succinimide group or a ring-opened product thereof. According to one embodiment, linker B has a structure according to any one of formula (LB-I) to (LB- VII) or a salt thereof: wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably Y3is one of: thereof, wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, L3and L4, if present, are each a linking moiety, Y4is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the antibody, MP is the antibody, ring B, if present, is an optionally substituted 8-membered carbocycle or an optionally substituted 8- membered heterocycle; R11, if present, is H, optionally substituted alkyl or optionally substituted aryl. According to one embodiment, linker B has a structure according to any one of formula (LB-VIII) to (LB- XIV) or a salt thereof for a : (LB-VIII) , (LB-IX) , , wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably Y3is one of: salt thereof, wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, L3and L4, if present, are each a linking moiety, Y4is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the antibody, MP is the antibody, ring B, if present, is an optionally substituted 8-membered carbocycle or an optionally substituted 8- membered heterocycle; R11, if present, is H, optionally substituted alkyl or optionally substituted aryl; X1his a bond, or (CH2)n1h, wherein n1his an integer between 1 to 10, X2his a bond, or (OCH2CH2)n2h, wherein n2his an integer between 1 to 15, X3his a bond, C(O), or (CH2)n3h, wherein n3his an integer between 1 to 10. According to one embodiment, linker B has a structure according to formula (LB-X) or (LB-XIII) or a salt thereof: , wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably Y3is one of: thereof, wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, L4is a linking moiety, MP is the antibody, ring B is an optionally substituted 8-membered carbocycle or an optionally substituted 8-membered heterocycle; X1his a bond, or (CH2)n1h, wherein n1his an integer between 1 to 10, X2his a bond, or (OCH2CH2)n2h, wherein n2his an integer between 1 to 15, X3his a bond, C(O), or (CH2)n3h, wherein n3his an integer between 1 to 10. According to one embodiment, linker B has a structure according to formula (LB-X)or a salt thereof: wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably Y3is one of: thereof, wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, L4is a linking moiety, MP is the antibody, ring B is an optionally substituted 8-membered carbocycle or an optionally substituted 8-membered heterocycle; X1his (CH2)n1h, wherein n1his an integer between 1 to 10, and preferably between 1 and 4, X2his (OCH2CH2)n2h, wherein n2his an integer between 1 to 15, and preferably between 2 to 10, and X3his a bond. According to one embodiment, linker B has a structure according to formula (LB-XIII) or a salt thereof: (LB-XIII) , wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably Y3is one of: or a salt thereof, wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, L4is a linking moiety, MP is the antibody, ring B is an optionally substituted 8-membered carbocycle or an optionally substituted 8-membered heterocycle; X1his (CH2)n1h, wherein n1his an integer between 1 to 10, X2his a bond, and X3his C(O). According to one embodiment, linker B has a structure to formula (LB-XV), or a salt thereof or a [2+3] cycloaddition regioisomer thereof: wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably Y3is one of: thereof, wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, L4is a linking moiety, MP is the antibody, X1iis a bond, or (CH2)n1i, wherein n1iis an integer between 1 to 10, preferably is (CH2)n1i, wherein n1iis an integer between 1 to 4, X2iis a bond, or (OCH2CH2)n2i, wherein n2iis an integer between 1 to 15, and preferably is (OCH2CH2)n2i, wherein n2iis an integer between 2 to 10, X3iis a bond or (CH2)n3i, wherein n3iis an integer between 1 to 10, preferably is a bond, R1iis from one to four optional substituents, and preferably R1iis absent, Z3is N or CH, preferably N. Z4is CH2. According to one embodiment, linker B has a structure to formula (LB-XVI), or a salt thereof or a [2+3] cycloaddition regioisomer thereof: (LB-XVI) wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably Y3is one of: thereof, wherein Q1is NH, O or S of an amino acid of the peptide compound, PEP is the peptide compound, L4is a linking moiety, and preferably a linking moiety comprising (i) a PEG linker, and (ii) an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the antibody, MP is the antibody, X1iis a bond, or (CH2)n1i, wherein n1iis an integer between 1 to 10, preferably is (CH2)n1i, wherein n1iis an integer between 1 to 10, X2iis a bond, or (OCH2CH2)n2i, wherein n2iis an integer between 1 to 15, and preferably is a bond, X3iis C(O), R1iis from one to four optional substituents, and preferably R1iis absent, Z3is N or CH, preferably N. Z4is CH2. According to one embodiment, linker B has a structure to formula (LB-XV), or a salt thereof or a [2+3] cycloaddition regioisomer thereof:

[0003] (LB-XV) , wherein Y3is an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the peptide compound, and preferably NH of an amino acid of the peptide compound, PEP is the peptide compound, L4is a linking moiety, and preferably a linking moiety comprising (i) a PEG linker, and (ii) an ester group, an amide group, or a succinimide group or a ring-opened product thereof, each of which is covalently bound to the antibody, MP is the antibody, X1iis a bond, or (CH2)n1i, wherein n1iis an integer between 1 to 10, preferably is (CH2)n1i, wherein n1iis an integer between 1 to 4 (e.g.2), X2iis a bond, or (OCH2CH2)n2i, wherein n2iis an integer between 1 to 15, and preferably is (OCH2CH2)n2i, wherein n2iis an integer between 2 to 10 (e.g.7), X3iis a bond or (CH2)n3i, wherein n3iis an integer between 1 to 10, preferably is a bond, R1iis from one to four optional substituents, and preferably R1iis absent, Z3is N or CH, preferably N. Z4is CH2. The sensor elements with the above-described linker chemistry may be prepared by a process comprising the steps of: a) providing a solid base element; b) preparing a linker A precursor which is covalently bound to the surface of the solid base element; c) reacting the linker A precursor with a peptide compound to covalently bind the peptide compound to the solid base element via linker A; d) preparing a linker B precursor which is covalently bound the peptide compound; and e) reacting the linker B precursor with an antibody to covalently bind the antibody to the peptide via linker B. In step a), a solid base element is provided. The solid base element has been defined above. According to one embodiment, the solid base element is obtained by oxidizing at least a part of the surface of the IR-transparent optical element (e.g. silicon crystal or germanium crystal). During the oxidative treatment (e.g. chemical oxidant or plasma treatment), at least a part of the surface of the is converted to an oxide layer which can improve attachment of linker compounds in subsequent step b). According to one preferred embodiment, the solid base element is obtained by oxidizing at least a part of the surface of a silicon crystal, e.g. by a chemical oxidizing agent or plasma treatment. During the oxidative treatment, at least a part of the surface of the silicon crystal is converted to silicon dioxide. Before carrying out the plasma treatment, the surface of the silicon crystal may be polished. In step b), a linker A precursor is prepared which is covalently bound to the surface of the solid base element. Preferably, the linker A precursor comprises a peptide-reactive group, preferably an amine-reactive group (e.g. an active ester), which allows for covalently binding a peptide compound. “Peptide-reactive groups” are known in the art. Such groups are used to attach a compound to functional residues (e.g. amine acid residues) of a peptide such as amino groups (e.g. of a lysine residue), thiol (e.g. of cysteine), alcohol (e.g. of serine), and the like. The linker A precursor may be prepared in a stepwise manner. Preferably, the linker A precursor is prepared by first reacting the surface of the solid base element with a linker A1 to obtain a surface which is at least partially functionalized by a click-reactive group, and then reacting the at least partially functionalized surface with a linker A2 by a click ligation to obtain a linker A precursor which is covalently bound to the surface of the solid base element. “Click-reactive groups” are well known in the art. Click-reactive groups are, but not limited to, alkynes, strained cycloalkynes (e.g. cyclooctynes wherein optionally one or more carbon atom of the ring is substituted by a heteroatom such as N), strained cycloalkenes (e.g. trans-cyclooctenes), azides, tetrazines, nitrones, and the like. Click-reactive groups can be reacted with one another in specific combinations (“Click reactions” or “Click ligations”), which are all well known to the person of skill in the art (e.g. azide with alkynes optionally under copper catalysis or azide with strained alkynes, etc). According to one preferred embodiment, step b) comprises the steps of: b1) providing a linker A1 comprising (i) a silyl group or a thiol group, and (ii) an azide group or an optionally substituted tetrazine group, preferably an azide group, b2) optionally activating linker A1 provided in step b1), b3) reacting the linker A1 provided in step b1) or the compound obtained in step b2) with the solid base element to obtain an at least partially functionalized surface, b4) reacting the at least partially functionalized surface of the solid base element obtained in step b3) with a linker A2 comprising (i) an alkyne group or a trans-alkene group, (ii) and a peptide-reactive group selected from carboxylic acid, esters, active esters and maleimide, to obtain a linker A precursor which is covalently attached to the surface of the base element. It was previously found that, functionalizing the surface of the solid base element (e.g. a waveguide for an optical biosensor such as a silicon crystal) with a click reactive group such as an azide or a tetrazine group, it is possible to obtain a stable and densely functionalized surface. The functionalized surface may be prepared and stored before using the same to provide the antibody functionalized element according to the invention. This is particularly advantageous for preparing shortly before use an antibody functionalized element which is highly reactive, which in turn improves the suitability of the antibody functionalized element according to one embodiment of the invention for an implementation in point-of- care (POC) testing devices. In step b1), a linker A1 is preferably provided, wherein the linker A1 comprises (i) a silyl group or a thiol group, and (ii) an azide group or an optionally substituted tetrazine group, preferably an azide group. According to one embodiment, linker A1 has a structure according to formula (LA1-I) or a salt thereof: (LA1-I) , wherein Ya1is –SH or –SiZ3, wherein each Z is independently selected from –O-(CH2)x-CH3, –(CH2)y-CH3, and halogen, wherein x is an integer between 0 to 4, and y is an integer between 0 to 6, Lais a linking moiety, and , wherein R* is an optional alkyl substituent (e.g. methyl). According to one embodiment, linker A1 has a structure according to formula (LA1-I) or a salt thereof: , wherein Ya1is –SiZ3, wherein each Z is independently selected from –O-(CH2)x-CH3, –(CH2)y-CH3, and halogen, wherein x is an integer between 0 to 4, and y is an integer between 0 to 6, and preferably wherein each Z is –OCH3 or –OCH2CH3, Lais a linking moiety, and , wherein R* is an optional alkyl substituent (e.g. methyl), and preferably wherein Ya2is –N3. According to one embodiment, linker A1 has a structure according to formula (LA1-II) or a salt thereof: (LA1-II) wherein Ya1is –SH or –SiZ3, wherein each Z is independently selected from –O-(CH2)x-CH3, –(CH2)y-CH3, and halogen, wherein x is an integer between 0 to 4, and y is an integer between 0 to 6, na1is an integer from 1 to 6; Xa1is a bond, -C(O)NH- or –NHC(O)-; na2is an integer from 1 to 16; Xa2is a bond or –(OCH2CH2)z-, wherein z is an integer from 1 to 16; Xa3is a bond or –CH2-; and , wherein R* is an optional alkyl substituent (e.g. methyl). According to one embodiment, linker A1 has a structure according to formula (LA1-II) or a salt thereof: , wherein Ya1is–SiZ3, wherein each Z is independently selected from –O-(CH2)x-CH3, –(CH2)y-CH3, and halogen, wherein x is an integer between 0 to 4, and y is an integer between 0 to 6, and preferably wherein each Z is –OCH3 or –OCH2CH3, na1is an integer from 1 to 6; Xa1is a bond, -C(O)NH- or –NHC(O)-; na2is an integer from 1 to 16; Xa2is a bond or –(OCH2CH2)z-, wherein z is an integer from 1 to 16; Xa3is a bond or –CH2-; and , wherein R is an optional alkyl substituent (e.g. methyl), and preferably wherein Ya2is –N3. In a specific embodiment, linker A1 has the following structure: In optional step b2), linker A1 provided in b1) is activated. Activation step b2) may convert linker A1 in an intermediate, which is more reactive towards the surface of the solid base element. Specific conditions of activation step b2) depend on the chemical structure of linker A1 and can be chosen by the person of skill. In step b3), the linker A1 provided in step b1) or the compound obtained in step b2) is reacted with the base element to obtain an at least partially functionalized surface. Preferably, linker A1 is selected to obtain an azide-functionalized surface in step b3). In step b4), the at least partially functionalized surface of the solid base element obtained in step b3) is reacted with a linker A2 comprising (i) an alkyne group or a trans-alkene group, (ii) and a peptide- reactive group selected from carboxylic acid, carboxylic acid esters, active esters and maleimide, to obtain a linker A precursor which is covalently attached to the surface of the solid base element. The alkyne group (i) of linker A2 can be selected from optionally substituted 8-membered cycloalkynes, which optionally comprise heteroatoms in the 8-membered cycle. Such compounds are known to react with azides in strain-promoted click reaction. Strain promoted click reactions are reactions between a strained internal cyclic alkyne and an azide, and are known to the person of skill. The alkyne group (i) of linker A2 can be, but is not limited to, DBCO, DIBO, DIFO, or BCN. These abbreviations are well- known in the art. For illustration, DBCO is , and DIFO is . “Active esters” are well-known in the art, and can be reacted with an amino group to form an amide bond. According to one embodiment, linker A2 has a structure according to formula (LA2-I) or a salt thereof: wherein ring C is an optionally substituted 8-membered cycloalkyne optionally comprising one or more heteroatoms, and ring D is an optionally substituted 8- membered cyclo-trans-alkene optionally comprising one or more heteroatoms, Lbis a linking moiety, and Yb2is a peptide-reactive group selected from carboxylic acid, esters, active esters and N-linked maleimide, and optionally the peptide-reactive group Yb2is selected from –COOH, -COOR, -COOR’ and N-linked maleimide, wherein R is optionally substituted aryl or alkyl, more preferably optionally substituted C6-aryl or C1-6-alkyl, and R’ is –NHS or –pentafluorophenyl (PFP). “N-linked maleimide” means that the linker L is covalently bound to the nitrogen of the maleimide. According to one embodiment, linker A2 has a structure according to formula (LA2-II) or a salt thereof: (LA2-II) wherein wherein ring C is an optionally substituted 8-membered cycloalkyne optionally comprising one or more heteroatoms, and ring D is an optionally substituted 8- membered cyclo-trans-alkene optionally comprising one or more heteroatoms, Xb1is a bond, O, C(O), or a carbon atom which forms a cyclopropyl ring with two carbon atoms of ring A, nb1is an integer from 1 to 5, and Xb2is a bond, O, or –(OCH2CH2)v-, wherein v is an integer from 1 to 15, Xb3is a bond or (CH2)w, wherein w is an integer from 1 to 5, Yb2is a peptide-reactive group selected from carboxylic acid, esters, active esters and N-linked maleimide, and optionally the peptide-reactive group Yb2is selected from –COOH, -COOR, -COOR’ and N-linked maleimide, wherein R is optionally substituted aryl or alkyl, more preferably optionally substituted C6-aryl or C1-6-alkyl, and R’ is –NHS or –pentafluorophenyl (PFP). According to one embodiment, linker A2 has a structure according to formula (LA2-II) or a salt thereof: (LA2-II) , wherein wherein ring C is an optionally substituted 8-membered cycloalkyne optionally comprising one or more heteroatoms, and ring D is an optionally substituted 8- membered cyclo-trans-alkene optionally comprising one or more heteroatoms, and optionally Yb1is ring C which is , Xb1is C(O), nb1is an integer from 1 to 5, and Xb2is a bond or –(OCH2CH2)v-, wherein v is an integer from 1 to 15, Xb3is a bond or (CH2)w, wherein w is an integer from 1 to 5, Yb2is a peptide-reactive group selected from carboxylic acid, esters, active esters and N-linked maleimide, and optionally the peptide-reactive group Yb2is selected from –COOH, -COOR, -COOR’ and N-linked maleimide, wherein R is optionally substituted aryl or alkyl, more preferably optionally substituted C6-aryl or C1-6-alkyl, and R’ is –NHS or –pentafluorophenyl (PFP). According to one specific example, linker A2 has the following structure: . In step b4), a linker A precursor is preferably obtained which is covalently bound to the surface of the base element and which comprises a peptide-reactive group (e.g. an amine-reactive group such as an active ester). The reactivity of the peptide-reactive group can be exploited in subsequent step c) of the process according to the invention for covalently binding the peptide to the base element via a linker A, as defined herein above for the sensor element. It is also possible to switch the click-reactive groups of linker A1 and linker A2. In such case, linker A1 can comprise the alkyne or trans-alkene group, and linker A2 can comprise the azide group or the optionally substituted tetrazine group. Thus, according to another embodiment, step b) comprises the steps of: b1) providing a linker A1 comprising (i) a silyl group or a thiol group, and (ii) an alkyne group or a trans-alkene group, b2) optionally activating linker A1 provided in b1), b3) reacting the linker A1 provided in step b1) or the compound obtained in step b2) with the solid base element to obtain an at least partially functionalized surface, b4) reacting the at least partially functionalized surface of the solid base element obtained in step b3) with a linker A2 comprising (i) an azide group or an optionally substituted tetrazine group, preferably an azide group, (ii) and a peptide-reactive group selected from carboxylic acid, esters, active esters and maleimide, to obtain a linker A precursor which is covalently attached to the surface of the base element. The process further comprises an optional step of reacting a matrix precursor compound with the solid base element to covalently attach a matrix compound to the surface of the base element. The matrix compound has already been defined above. This step can be carried before, during and / or after step b), and is preferably carried out during step b). The step can be carried out simultaneously with step b1), optional step b2) and step b3). In case the step is carried out simultaneously with step b1), optional step b2) and step b3), the matrix precursor compound can be provided in form of a mixture with linker A1 in step b1). This mixture may then be used in optional step b2) and step b3 as defined above. The mixture may have a molar ratio of linker A1: matrix precursor compound of in the range of 1:99 to 99.9:0.1, optionally 25:75 to 99.9:0.1, optionally 50:50 to 99.9:0.1, optionally 75:25 to 99.9:0.1, optionally 90:10 to 99:1. The matrix precursor compound may be a compound which comprises (i) a silyl group and (ii) a PEG group or mPEG group, or a compound which comprises (i) a thiol group and (ii) an optionally substituted alkyl group (e.g. an optionally substituted C1-C30 alkyl group). The matrix precursor compound can have a structure according to formula (MA2-I) or a salt thereof: , wherein Yc1is –SH or –SiZ3, wherein each Z is independently selected from –O-(CH2)x-CH3, –(CH2)y-CH3, and halogen, wherein x is an integer between 0 to 4, and y is an integer between 0 to 6, nc1is an integer from 1 to 6; Xc1is a bond, -C(O)NH- or –NHC(O)-; nc2is an integer from 1 to 16; Xc2is a bond or –(OCH2CH2)r-, wherein r is an integer from 1 to 16; Xc3is a bond, –CH2-; and Yc2is OH, OCH3, or CH3. The matrix precursor compound can have a structure according to formula (MA2-I) or a salt thereof: (MA2-I) , wherein Yc1is –SiZ3, wherein each Z is independently selected from –O-(CH2)x-CH3, –(CH2)y-CH3, and halogen, wherein x is an integer between 0 to 4, and y is an integer between 0 to 6, nc1is an integer from 1 to 6; Xc1is -C(O)NH- or –NHC(O)-; nc2is an integer from 1 to 16; Xc2is –(OCH2CH2)r-, wherein r is an integer from 1 to 16; Xc3is a bond, –CH2-; and Yc2is OCH3. Specific embodiments of the matrix precursor compound have the following structures: . In step c), the linker A precursor is reacted with a peptide compound to covalently bind the peptide compound to the solid base element via linker A. The reaction of the peptide compound with the activated surface obtained in step b) or step b4) can block the surface of the solid base element. Thus, according to one embodiment, step c) is a blocking step. The peptide compound may be provided in pure form or as part of a mixture such as a protein hydrolysate. According to one embodiment, the peptide compound is provided as part of a protein hydrolysate, and optionally is part of a hydrolysate of albumin, casein, BSA, serum proteins (e.g. animal serum such as swine, horse, or goat serum), milk proteins, or mixtures thereof. Preferably, the peptide is provided in form a casein hydrolysate. The protein hydrolysate comprising the peptide compound can be contacted with the linker A precursor obtained in step b) or b4) to react the peptide compound with the linker A precursor. Preferably, the peptide compound is provided as part of a casein hydrolysate. In step d), a linker B precursor is prepared which is covalently bound to the peptide compound. Preferably, the linker B precursor comprises a click-reactive group, e.g. selected from alkynes, strained cycloalkynes (e.g. cyclooctynes wherein optionally one or more carbon atom of the ring is substituted by a heteroatom such as N), strained cycloalkenes (e.g. trans-cyclooctenes), azides, tetrazines, nitrones, and the like, which allows for covalently binding the antibody by a click ligation. The linker B precursor may be prepared by reacting the peptide compound with a linker B1 as defined herein below. According to one embodiment, linker B1 comprises (i) a peptide-reactive group (e.g. an amine-reactive group) selected from carboxylic acid, esters, active esters and maleimide, (ii) click-reactive group selected from alkynes, strained cycloalkynes, strained cycloalkenes, azides, and tetrazines. According to one embodiment, linker B1 has a structure according to formula (LB1-I) or a salt thereof: wherein Yd1is a peptide-reactive group selected from carboxylic acid, esters, active esters and N-linked maleimide, and optionally the peptide-reactive group Yd2is selected from –COOH, -COOR, -COOR’ and N-linked maleimide, wherein R is an optionally substituted aryl or alkyl, more preferably optionally substituted C6-aryl or C1-6-alkyl, and R’ is –NHS or –pentafluorophenyl (PFP), Ldis a linking moiety, optionally comprising a PEG group, Yd2is an optionally substituted click-reactive group selected from alkynes, strained cycloalkynes, strained cycloalkenes, azides, and tetrazines, and optionally is selected from –N3, or , wherein R* is an optional alkyl or aryl substituent (e.g. methyl), wherein ring C is an optionally substituted 8-membered cycloalkyne optionally comprising one or more heteroatoms, and ring D is an optionally substituted 8-membered cyclo-trans-alkene optionally comprising one or more heteroatoms. According to one embodiment, linker B1 has a structure according to formula (LB1-II) or a salt thereof: wherein Yd1is a peptide-reactive group selected from carboxylic acid, esters, active esters and N-linked maleimide, and optionally the peptide-reactive group Yd2is selected from –COOH, -COOR, -COOR’ and N-linked maleimide, wherein R is an optionally substituted aryl or alkyl, more preferably optionally substituted C6-aryl or C1-6-alkyl, and R’ is –NHS or –pentafluorophenyl (PFP), Xd1is a bond or (CH2)s, wherein s is an integer from 1 to 10, Xd2is a bond or (OCH2CH2)t, wherein t is an integer from 1 to 15, Xd3is a bond, C(O), or (CH2)q, wherein q is an integer from 1 to 10, Yd2is an optionally substituted click-reactive group selected from alkynes, strained cycloalkynes, strained cycloalkenes, azides, and tetrazines, and optionally is selected from –N3, or , wherein R* is an optional alkyl or aryl substituent (e.g. methyl), wherein ring C is an optionally substituted 8-membered cycloalkyne optionally comprising one or more heteroatoms, and ring D is an optionally substituted 8-membered cyclo-trans-alkene optionally comprising one or more heteroatoms. According to one embodiment, linker B1 has a structure according to formula (LB1-II) or a salt thereof: wherein Yd1is a peptide-reactive group selected from –COOH, -COOR, -COOR’ and N-linked maleimide, wherein R is optionally substituted C6-aryl or C1-6-alkyl, and R’ is –NHS or –pentafluorophenyl (PFP), Xd1is (CH2)s, wherein s is an integer from 1 to 10, Xd2is a bond or (OCH2CH2)t, wherein t is an integer from 1 to 15, Xd3is a bond, C(O), Yd2is click-reactive group selected from , wherein R* is an optional methyl, wherein ring C is an optionally substituted 8-membered cycloalkyne optionally comprising one or more heteroatoms, and ring D is an optionally substituted 8-membered cyclo-trans- alkene optionally comprising one or more heteroatoms. According to one specific embodiment, linker B1 has one of the following structures: . It may be that after step c) and / or step d), there are remaining reactive linker A precursors on the surface of the solid base element. In such case, it is possible, and sometimes preferred, to react the surface with a small molecule such as an amine compound (e.g. ethanol amine) to quench the remaining reactive linker A precursor after step c) and / or step d). According to one embodiment, the process comprises the additional step of adding a quenching reagent between step c) and step d) and / or between step d) and step e). The quenching reagent may be any reagent which reacts with a peptide-reactive group (such as an active ester). For example, the quenching reagent may be an amine compound, e.g. ethanol amine. It is possible, and sometimes preferred, to add the quenching reagent before reacting the antibody with the linker B precursor in step e). According to one embodiment, the process comprises the additional step of adding a quenching reagent between step d) and step e). According to one embodiment, the process comprises adding a quenching reagent (e.g. an amine compound such as ethanolamine) before step e). In step e), the linker B precursor is reacted with an antibody to covalently bind the antibody to the peptide compound via linker B. The antibody can be activated before reacting it with the linker B precursor. The antibody can be activated by attaching a click reactive group onto the antibody, which is suitable for a reaction with the click reactive group of the linker B precursor. A skilled person knows which combinations of click reactive groups react with each other in a click reaction. According to one embodiment, the antibody is activated before step e) by reacting the antibody with a linker B2 comprising a click reactive group selected from selected from alkynes, strained cycloalkynes (e.g. cyclooctynes wherein optionally one or more carbon atom of the ring is substituted by a heteroatom such as N), strained cycloalkenes (e.g. trans-cyclooctenes), azides, and tetrazines. According to one embodiment, the antibody is activated before step e) by reacting the antibody with a linker B2 comprising a click reactive group selected from strained cycloalkynes (e.g. cyclooctynes wherein optionally one or more carbon atom of the ring is substituted by a heteroatom such as N) and an azide. The antibody may be activated before step e) by reacting the antibody with an NHS-azide or NHS-DBCO. NHS-azide and NHS-DBCO can react with amines of the antibody, e.g. with a lysine residue of the antibody. The antibody is generally immobilized such that its antigen-binding regions are accessible to the sample and come into contact with any potential analyte that may be comprised therein. In various embodiments, the antibody is immobilized to one surface of the sensor element, more specifically the internal reflection element, that lies opposite to the surface facing the IR source and thus the incident IR light. This leads to a situation where the incident light enters the internal reflection element and interacts with the antibody (covalently) bound to the opposite surface before being reflected and passing through the internal reflection element again. This passage and thus interaction may be repeated multiple times, as described above, before the reflected IR light is detected and analyzed. Depending on the analytes bound to the antibodies on the surface of the sensor element the IR spectrum recorded varies. Since the methods of the invention aim at determining the proportion of the alpha-synuclein in fibril / aggregated form relative to the total amount of the alpha-synuclein in the sample, it is an important feature of the invention that the antibody used as a capture reagent has high specificity for all forms of alpha-synuclein but little affinity for other proteins, for example related proteins such as beta- and gamma-synuclein. This may mean that its affinity for alpha-synuclein is significantly higher than that for any other protein, in particular beta and / or gamma-synuclein. Said difference in affinity may, in various embodiments, be at least 100-fold, but may optionally be greater such as at least 1000-fold, at least 10000-fold, at least 100000-fold or at least 1000000-fold. Said difference in affinity may help to avoid any relevant cross-reactivity with other proteins that may be present in the sample, such as beta- and / or gamma-synuclein. Accordingly, in various embodiments, under assaying conditions the affinity difference is so high and thus the cross-reactivity so low that binding to proteins other than alpha- synuclein is less than 1% of total protein bound, optionally less than 0.1%. Further, to allow binding of the different forms of alpha-synuclein even if more than one of them are present in a sample, the antibody has the capability to bind to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form. This may mean that its affinity for alpha-synuclein in its monomeric, non-fibril form on the one hand and its fibril / aggregated form on the other hand is essentially the same. In various embodiments, this may mean that the affinity (dissociation constant KD) ratio of the antibody for (1) monomeric alpha-synuclein and (2) alpha-synuclein fibrils is in the range of 10:1 to 1:10, 5:1 to 1:5, 3:1 to 1:3, 2.5:1 to 1:2.5, 2:1 to 1:2, 1.8:1 to 1:1.8, 1.7:1 to 1:1.7, 1.6:1 to 1:11.6, 1.5:1 to 1:1.5, 1.4:1 to 1:1.4, 1.3:1 to 1:1.3, 1.2:1 to 1:1.2, 1.1:1 to 1:1.1 or about 1:1. Alternatively, this missing selectivity for the different confirmations of alpha-synuclein may be measured in terms of dissociation (or “off”) rates (kd). Thus, the antibodies used according to the invention may display similar dissociation rates (kd) from monomeric, non-fibril and fibril / aggregated alpha-synuclein. For example, the dissociation rate ratio may be in the range of 10:1 to 1:10, for example 5:1 to 1:5, 3:1 to 1:3, 2.5:1 to 1:2.5, 2:1 to 1:2, 1.8:1 to 1:1.8, 1.7:1 to 1:1.7, 1.6:1 to 1:11.6, 1.5:1 to 1:1.5, 1.4:1 to 1:1.4, 1.3:1 to 1:1.3, 1.2:1 to 1:1.2, 1.1:1 to 1:1.1 or about 1:1. In certain embodiments, a binding molecule or an antibody provided herein has a dissociation constant (KD) of ≤ 1 mM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g.10-8M or less, e.g. from 10-8M to 10-13M, e.g., from 10-9M to 10-13M) with respect to binding alpha-synuclein, in either (proto)fibril / aggregated or monomeric, non-fibril form. KD and kd may be measured according to methods well known in the art, including, but not limited to, using surface plasmon resonance assays using a BIACORE®-2000 or a BIACORE @-3000 (BIAcore, Inc., Piscataway, NJ) at 25°C with immobilized antigen CM5 chips at -10 response units (RU). In various embodiments, the antibodies are characterized in that binding to either alpha-synuclein in its monomeric or aggregated / fibril form leads to a detectable difference in the amide I band as determined by IR spectroscopy, as described herein below, in particular a detectable difference in the amide I band maximum, its center of mass or the ratios of the signals at 1650 and 1630, 1656 and 1623.5 or 1651.5 and 1623.5 cm-1, as described herein. It has been found that the requirements for the methods described herein are met by antibodies that bind epitopes in a specific region of alpha-synuclein, namely the extreme C-terminus of the native protein comprising amino acids 126-140 of SEQ ID NO:1, and a part of alpha-synuclein comprising amino acids 65-77 according to the positional numbering of SEQ ID NO:1. It was surprisingly found that such antibodies bind the different forms (conformations) of alpha-synuclein, in particular the monomeric, non-fibril form and the fibril / aggregated form, with essentially the same affinity and are less prone to interference that occurs from other proteins binding to the antibody or captured together with the alpha-synuclein (as they may be associated with alpha-synuclein in the sample). As a result, it was found that such antibodies allow the specific analysis of alpha-synuclein also before the background of complex biological samples. In contrast to this finding, other antibodies binding different epitopes were found to either not bind alpha-synuclein independent of whether it is in monomeric, non-fibril or fibril / aggregated form or to not prevent alpha-synuclein association with other proteins that may be present in the sample, which prevents the desired determination of the proportion of alpha-synuclein in fibril / aggregated form. In various embodiments, antibodies used in the methods of the present invention are thus characterized by their property to recognize and bind an epitope within amino acid residues 126-140 of alpha- synuclein, using the numbering according to SEQ ID NO:1. The epitope may be a linear epitope. The epitope may be within the amino acids at positions 127-140, 128-135 or 131-140 of human alpha- synuclein. In some embodiments, the antibody may bind to an epitope comprising amino acids (1) 126, 127, 135, and 136, or (2) 126 and 127 or (3) 135 and 136 of human alpha-synuclein as critical residues for binding, using the positional numbering of SEQ ID NO:1. In various embodiments, the epitope bound by the antibody comprises residues 135 and 136 as critical determinants for binding. In various embodiments, the epitope may be within amino acid residues at positions 126-131, 127-132, 128-133, 129-134, 130-135, 131-136, 132-137,133-138, 134-139, 135-140, 126-130, 127-131, 128-132, 129-133, 130-134, 131-135, 132-136, 133-137, 134-138, 135-139, and 136-140. In various embodiments, the epitope consists of any one of the amino acid sequences at positions 126-131, 127-132, 128-133, 129- 134, 130-135, 131-136, 132-137-,133-138, 134-139, 135-140, 126-130, 127-131, 128-132, 129-133, 130-134, 131-135, 132-136, 133-137, 134-138, 135-139, and 136-140 of human alpha-synuclein (using the positional numbering according to SEQ ID NO:1). In various other embodiments, antibodies used in the methods of the present invention are characterized by their property to recognize and bind an epitope within amino acid residues 65-77 of alpha-synuclein, using the numbering according to SEQ ID NO:1. The epitope may be a linear epitope. In various embodiments, the epitope may be within amino acid residues at positions 65-76, 65- 75, 65-74, 65-70, 66-71, 67-72, 68-73, 69-74, 70-75, 71-76, and 72-77, in particular 65-74. In various embodiments, the epitope consists of any one of the amino acid sequences at positions 65-76, 65-75, 65-74, 65-70, 66- 71, 67-72, 68-73, 69-74, 70-75, 71-76, or 72-77, in particular 65-74, of human alpha-synuclein (using the positional numbering according to SEQ ID NO:1). The term “antibody” as used herein, is used in its broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies, such as bispecific antibodies, fully human antibodies and antibody fragments so long as they exhibit the desired antigen-binding activity. The term also covers chimeric antibodies, recombinant antibodies, antigen-binding fragments of (recombinant) antibodies, humanized antibodies or antibodies displayed upon the surface of a phage or displayed upon the surface of a chimeric antigen receptor(CAR) T-cell. In various embodiments, the antibodies are IgG antibodies. In various embodiments, the antibodies are monoclonal antibodies. The antibodies may be mouse antibodies, humanized antibodies, chimeric or human antibodies. An "antigen-binding fragment" of an antibody refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments. The term “monoclonal antibody" as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. The modified "monoclonal" indicates the character of the antibody as being amongst a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. As mentioned above, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method. Accordingly, in context of the present invention, the term “antibody” relates to full immunoglobulin molecules as well as to parts of such immunoglobulin molecules (i.e., ”antigen-binding fragment thereof”). Furthermore, the term relates, as discussed above, to modified and / or altered antibody molecules. The term also relates to recombinantly or synthetically generated / synthesized antibodies. The term also relates to intact antibodies as well as to antibody fragments thereof, like, separated light and heavy chains, Fab, Fv, Fab', Fab’-SH, F(ab’)2. The term “antibody” also comprises but is not limited to fully human antibodies, chimeric antibodies, humanized antibodies, CDR-grafted antibodies and antibody constructs, like single chain Fvs (scFv) or antibody-fusion proteins. Humanized antibodies are modified antibodies that are also referred to as reshaped human antibodies. A humanized antibody is constructed by transferring the CDRs of an antibody derived from an immunized animal to the complementarity determining regions of a human antibody. Conventional genetic recombination techniques for such purposes are known (see European Patent Application Publication No. EP 239400; International Publication No. WO 96 / 02576 ; International Publication No. WO 99 / 51743 ). The term “CDR” as employed herein relates to “complementary determining region”, which is well known in the art. The CDRs are parts of immunoglobulins that determine the specificity of said molecules and make contact with a specific ligand. The CDRs are the most variable part of the molecule and contribute to the diversity of these molecules. There are three CDR regions CDR1 , CDR2 and CDR3 in each V domain. VH-CDR, or CDR-H depicts a CDR region of a variable heavy chain and VL-CDR or CDR-L relates to a CDR region of a variable light chain. VH means the variable heavy chain and VL means the variable light chain. The CDR regions of an Ig-derived region may be determined as described in Kabat “Sequences of Proteins of Immunological Interest”, 5th edit. NIH Publication no. 91-3242 U.S. Department of Health and Human Services (1991 ); Chothia J., Mol. Biol. 196 (1987), 901 -917 or Chothia, Nature 342 (1989), 877-883. An "Fc" region contains two heavy chain fragments comprising the CH2 and CHS domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CHS domains. A "Fab' fragment” contains one light chain and a portion of one heavy chain that contains the VH domain and the CH1 domain and also the region between the CH1 and CH2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab')2 molecule. A "F(ab')2 fragment" contains two light chains and two heavy chains containing a portion of the constant region between the CH1 and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab')2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains. The "Fv region" comprises the variable regions from both the heavy and light chains but lacks the constant regions. Accordingly, in the context of this invention, antibody molecules or antigen-binding fragments thereof are provided, which are humanized and can successfully be employed in pharmaceutical compositions. An "antibody that binds to an epitope" within a defined region of a protein is an antibody that requires the presence of one or more of the amino acids within that region for binding to the protein. In certain embodiments, an "antibody that binds to an epitope" within a defined region of a protein is identified by mutation analysis, in which amino acids of the protein comprising the epitope but outside the epitope are mutated, and binding of the antibody to the resulting altered protein (e.g., an altered protein comprising the unaltered epitope) is determined to be at least 20% of the binding to unaltered protein. In some embodiments, an "antibody that binds to an epitope" within a defined region of a protein is identified by mutation analysis, in which amino acids of the protein are mutated, and binding of the antibody to the resulting altered protein (e.g., an altered protein comprising the epitope) is determined to be at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the binding to unaltered protein. In certain embodiments, binding of the antibody is determined by FACS, WB or by a suitable binding assay such as ELISA. The term “binding to” as used in the context of the present invention defines a binding (interaction) of at least two “antigen-interaction-sites” with each other. The term “antigen-interaction-site” defines, in accordance with the present invention, a motif of a polypeptide, i.e., a part of the antibody or antigen- binding fragment of the present invention, which shows the capacity of specific interaction with a specific antigen or a specific group of antigens of alpha- synuclein. Said binding / interaction is also understood to define a “specific recognition”. The term “specifically recognizing" means in accordance with this invention that the antibody is capable of specifically interacting with and / or binding to at least two amino acids of alpha-synuclein as defined herein (also known as “critical residues”), in particular interacting with / binding to at least two amino acids within residues at positions 65-70, 66-71, 67-72, 68-73, 69-74, 70-75, 71-76, 72-77, 126-131, 127-132, 128-133, 129-134, 130-135, 131-136, 132-137-,133-138, 134- 139, 135-140, 126-130, 127-131, 128-132, 129-133, 130-134, 131-135, 132-136, 133-137, 134-138, 135-139, and 136-140 of human alpha- synuclein using the positional numbering according to SEQ ID NO: 1. The residues may form a linear or a non-linear epitope. Cross-reactivity of antigen-binding molecules, in particular a panel of antibodies or antigen-binding fragments thereof under investigation may be tested, for example, by assessing binding of said panel of antibodies or antigen-binding fragments thereof under conventional conditions (see, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, (1988) and Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, (1999)) to the (poly)peptide of interest as well as to a number of more or less (structurally and / or functionally) closely related (poly)peptides. Only those constructs (i.e. antibodies, antigen-binding fragments thereof and the like) that bind to the certain structure of alpha- synuclein as defined herein, e.g., a specific epitope or (poly)peptide / protein of alpha-synuclein as defined herein but do not or do not essentially bind to any of the other epitope or (poly)peptides of the same alpha-synuclein, are considered specific for the epitope or (poly)peptide / protein of interest and selected for further studies in accordance with the method provided herein. These methods may comprise, inter alia, binding studies, blocking and competition studies with structurally and / or functionally closely related molecules. These binding studies also comprise FACS analysis, surface plasmon resonance (SPR, e.g. with BIACORETM), analytical ultracentrifugation, isothermal titration calorimetry, fluorescence anisotropy, fluorescence spectroscopy or by radiolabeled ligand binding assays. Accordingly, specificity can be determined experimentally by methods known in the art and methods as described herein. Such methods comprise, but are not limited to Western Blots, ELISA-, RIA-, ECL-, IRMA-tests and peptide scans. It may be understood by a person skilled in the art that the epitopes may be comprised in the alpha- synuclein protein but may also be comprised in a degradation product thereof or may be a chemically synthesized peptide. The amino acid positions are only indicated to demonstrate the position of the corresponding amino acid sequence in the sequence of the alpha-synuclein protein. The invention encompasses all peptides comprising the epitope. The peptide may be a part of a polypeptide of more than 100 amino acids in length or may be a small peptide of less than 100, such as less than 50, less than 25 amino acids, or less than 18 amino acids. In order to test whether an antibody in question and the antibody of the present invention recognize the same or similar epitope, many assays are known in the art, including, but not limited to, alanine scanning mutagenesis, as for example described in the examples of WO 2020 / 212593 A1. Whether an antibody recognizes the same epitope as or an epitope overlapping with an epitope that is recognized by another antibody as defined herein can be confirmed by competition between the two antibodies against the epitope. Competition between the antibodies can be evaluated by competitive binding assays using means such as enzyme-linked immunosorbent assay (ELISA), fluorescence energy transfer method (FRET), and fluorometric microvolume assay technology (FMAT®). The amount of antibodies bound to an antigen indirectly correlate with the binding ability of candidate competitor antibodies (test antibodies) that competitively bind to the same or overlapping epitope. In other words, as the amount of or the affinity of test antibodies against the same or overlapping epitope increases, the amount of antibodies bound to the antigen decreases, and the amount of test antibodies bound to the antigen increases. Specifically, the appropriately labeled antibodies and test antibodies are simultaneously added to the antigens, and then the bound antibodies are detected using the label. The amount of the antibodies bound to the antigen can be easily determined by labeling the antibodies in advance. This label is not particularly limited, and the labeling method is selected according to the assay technique used. Specific examples of the labeling method include fluorescent labeling, radiolabeling, and enzyme labeling. Herein, the "antibody that binds to the overlapping epitope" or "antibody that binds to the same epitope" refers to a test antibody that can reduce the amount of binding of the labeled antibody by at least 50% at a concentration that is usually 100 times higher, preferably 80 times higher, more preferably 50 times higher, even more preferably 30 times higher, and still more preferably 10 times higher than a concentration of the non-labeled antibody at which binding of the non- labeled antibody reduces the amount of binding of the labeled antibody by 50% (IC50). The epitope recognized by the antibody can be analyzed by methods known to those skilled in the art, and for example, it can be performed by Western blotting and such. In some embodiments, the antibody comprises three variable heavy chain complementarity determining regions VH-CDR1, VH-CDR2 and VH-CDR3 and three variable light chain complementarity determining regions VL-CDR1, VL-CDR2 and VL-CDR3, wherein: (1) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:2, VH-CDR2 comprises the amino acid sequence of SEQ ID NO:3, VH-CDR3 comprises the amino acid sequence of SEQ ID NO:4, VL-CDR1 comprises the amino acid sequence of SEQ ID NO:5, VL-CDR2 comprises the amino acid sequence of SEQ ID NO:6, and VL-CDR3 comprises the amino acid sequence of SEQ ID NO:7; or (2) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:8, VH-CDR2 comprises the amino acid sequence of SEQ ID NO:9, VH-CDR3 comprises the amino acid sequence YSF, VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10, VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11, and VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12. In various embodiments, VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3 consist of the above-given amino acid sequences, i.e. (1) VH-CDR1 consists of the amino acid sequence of SEQ ID NO:2, VH-CDR2 consists of the amino acid sequence of SEQ ID NO:3, VH-CDR3 consists of the amino acid sequence of SEQ ID NO:4, VL-CDR1 consists of the amino acid sequence of SEQ ID NO:5, VL-CDR2 consists of the amino acid sequence of SEQ ID NO:6, and VL-CDR3 consists of the amino acid sequence of SEQ ID NO:7; or (2) VH-CDR1 consists of the amino acid sequence of SEQ ID NO:8, VH-CDR2 consists of the amino acid sequence of SEQ ID NO:9, VH-CDR3 consists of the amino acid sequence YSF, VL-CDR1 consists of the amino acid sequence of SEQ ID NO:10, VL-CDR2 consists of the amino acid sequence of SEQ ID NO:11, and VL-CDR3 consists of the amino acid sequence of SEQ ID NO:12 In various embodiments: SEQ ID NO:2 is TYAMH. SEQ ID NO:3 is RIRSKGSNYATNYADSVKD. SEQ ID NO:4 is GHGSSYFSY. SEQ ID NO:5 is SASSSVSY. SEQ ID NO:6 is DTSNLAS. SEQ ID NO:7 is QQWNSHPPT. SEQ ID NO:8 is DAWM. SEQ ID NO:9 is EIRNKAHNHATNYAESVKG. SEQ ID NO:10 is KASQSVTNYVA. SEQ ID NO:11 is SASNRYS. SEQ ID NO:12 is QQDYRIPYT. In various embodiments, the antibody comprises a heavy chain variable domain having an amino acid sequence that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:13 over its entire length and a light chain variable domain having an amino acid sequences that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:14 over its entire length. In various embodiments the amino acid sequence of the heavy chain variable domain has at least 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity to the amino acid sequence of SEQ ID NO:13. In various embodiments the amino acid sequence of the light chain variable domain has at least 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity to the amino acid sequence of SEQ ID NO:14. In various embodiments, the antibody comprises a heavy chain variable domain having an amino acid sequence that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:15 over its entire length and a light chain variable domain having an amino acid sequences that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:16 over its entire length. In various embodiments the amino acid sequence of the heavy chain variable domain has at least 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity to the amino acid sequence of SEQ ID NO:15. In various embodiments the amino acid sequence of the light chain variable domain has at least 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity to the amino acid sequence of SEQ ID NO:16. In accordance with the above, in certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding. In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and framework regions (FRs). Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity. However, as the antibodies are used in the methods of the invention as capture reagents only, many of the properties that are of relevance for therapeutic antibodies, such as immunogenicity, altered effector function (e.g. Fc variant antibodies) and the like, are of no particular interest for the antibodies to be used in the present invention. However, it is understood that such antibodies that may have been developed with a therapeutic application in mind may still be useful in the methods described herein and are thus to be covered by the invention. Amino acids are referred to herein using the one letter code. The amino acid sequence “YSF” thus relates to the amino acids, in N- to C-terminal orientation, tyrosine, serine, phenylalanine, connected by peptide bonds. In various embodiments, the antibodies and variants thereof disclosed herein have a KD of 10-9M to 10- 13 M with respect to binding alpha-synuclein, in either (proto)fibril / aggregated or monomeric, non-fibril form. In various embodiments, the antibodies and variants thereof disclosed herein have a cross-reactivity so low that binding to proteins other than alpha-synuclein is less than 1% of total protein bound, preferably less than 0.1%. In various embodiments, the antibodies and variants thereof disclosed herein have the capability to bind to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form, wherein the ratio of the affinity (in terms of the dissociation constant KD) for alpha-synuclein in its monomeric, non-fibril form and for its fibril / aggregated form is in the range of 100:1 to 1:100, 80:1 to 1:80, 50:1 to 1:50, 30:1 to 1:30, 20:1 to 1:20, 10:1 to 1:10, preferably 5:1 to 1:5, more preferably 3:1 to 1:3, 2.5:1 to 1:2.5, 2:1 to 1:2, 1.8:1 to 1:1.8, 1.7:1 to 1:1.7, 1.6:1 to 1:11.6, 1.5:1 to 1:1.5, 1.4:1 to 1:1.4, 1.3:1 to 1:1.3, 1.2:1 to 1:1.2, 1.1:1 to 1:1.1 or about 1:1. The antibodies disclosed herein may be used for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject. Such uses of the disclosed antibodies also form part of the present invention. In step (b) of the described methods, a value in the obtained infrared spectrum is determined that is indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample. Said value may be a band or parameter in the IR spectrum that is dependent on the presence and amount of misfolded alpha-synuclein, i.e. in fibril / aggregated form, relative to the total amount of alpha-synuclein in a sample. It is important that said value detectably differs between states in which the relative amount of misfolded alpha-synuclein is low enough to not be considered indicative for the affliction of the subject by a synucleinopathy or predictive for an increased risk to develop such and states in which it is high enough to be considered indicative or predictive for said synucleinopathy. In various embodiments, step (b) comprises comparing the obtained IR spectrum with a reference IR spectrum of alpha-synuclein. Said reference IR spectrum may have been recorded for a sample with a known proportion of alpha-synuclein in fibril and / or aggregated form and may serve as a benchmark. Alternatively, the reference IR spectrum may have been obtained from a subject that is either known to be afflicted by or at risk of developing a synucleinopathy or has been found to be not afflicted by or at risk of developing a synucleinopathy. It has been found that in the methods described herein, the amide I band in the IR spectrum is particularly well-suited to allow a distinction between those samples taken from individuals that are not afflicted by or at risk of developing a synucleinopathy and those samples taken from individuals that are afflicted or at risk of developing such a disease or disorder. Generally, it has been observed that the higher the proportion of misfolded alpha-synuclein in a sample, i.e. the relative amount of alpha- synuclein in fibril / aggregated form, the more the amide I band is shifted to lower values. A comparison between a reference that contain proportions of alpha-synuclein in fibril / aggregated form considered not indicative for a synucleinopathy or the risk of developing such, for example in that they originate from subjects that are not afflicted by such a disease or disorder and did not develop such in the future, and the actual sample analyzed may thus provide information that may help to diagnose or exclude an existing synucleinopathy or determine or exclude an increased risk of developing such in the future. Accordingly, in various embodiments of the methods described herein the IR spectrum recorded has sufficient signal to noise ratio to resolve at least the amide I band. The IR spectrum recorded is typically a Fourier Transform IR (FTIR) spectrum, in particular an ATR-FTIR spectrum. The method thus involves FTIR, transmission IR spectroscopy and (immuno)-ATR-FTIR spectroscopy, respectively. The term “amide I band” as used herein, relates to a known FTIR signal observable in all peptides (including polypeptides). The amide I and amide II bands are two major bands of the protein infrared spectrum. The amide I band (typically found between 1600 and 1700 cm-1) is mainly associated with the C=O stretching vibration (70-85%) and is related to the backbone conformation. In contrast, the amide II band results from the N-H bending vibration (40-60%) and from the C-N stretching vibration (18-40%). In various embodiments, the determined value in the IR spectrum is an amide I band maximum, typically measurable at a wave number range between 1620 and 1670 cm-1. In such embodiments, an amide I band maximum below 1639 cm-1, optionally below 1638 cm-1or below 1637 cm-1or below 1636.5 cm-1may be considered indicative for the presence or an increased proportion of alpha-synuclein in fibril and / or aggregated form relative to a sample containing only the monomeric, non-fibril form of alpha- synuclein. In such embodiments, the lower the amide I band maximum, the more likely it becomes that the proportion of alpha-synuclein in fibril and / or aggregated form is pathologically relevant. In various other embodiments, the determined value in the IR spectrum is an amide I band center of mass, again typically measurable at a wave number range between 1620 and 1650 cm-1. In such embodiments, a center of mass of below 1641 cm-1, below 1640 cm-1, below 1639 cm-1or below 1638.5 cm-1may be indicative for the presence or an increased proportion of alpha-synuclein in fibril and / or aggregated form relative to a sample containing only the monomeric, non-fibril form of alpha-synuclein. In such embodiments, the lower the amide I band center of mass, the more likely it becomes that the proportion of alpha-synuclein in fibril and / or aggregated form is pathologically relevant. In still other embodiments, the determined value in the IR spectrum is the ratio of the signal at 1650 cm- 1 to the signal at 1630 cm-1. In such embodiments, a ratio of below 0.99, below 0.98, below 0.97 or below 0.96 may be indicative for the presence or an increased proportion of alpha-synuclein in fibril and / or aggregated form relative to a sample containing only the monomeric, non-fibril form of alpha-synuclein. In such embodiments, the lower the ratio, the more likely it becomes that the proportion of alpha- synuclein in fibril and / or aggregated form is pathologically relevant. In still other embodiments, the determined value in the IR spectrum is the ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1. In such embodiments, a ratio of below 1.15, below 1.14, below 1.10, below 1.08, below 1.07, below 1.065, below 1.06, below 1.05 or below 1.00 may be indicative for the presence or an increased proportion of alpha-synuclein in fibril and / or aggregated form relative to a sample containing only the monomeric, non-fibril form of alpha-synuclein. In such embodiments, the lower the ratio, the more likely it becomes that the proportion of alpha-synuclein in fibril and / or aggregated form is pathologically relevant. In such preferred embodiments, where the determined value in the IR spectrum is the ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1, a ratio below 1.065 is highly indicative for a disease or disorder characterized by alpha-synuclein aggregation. It has been found that a ratio below 1.065 indicates high levels of aggregated alpha synuclein, which is in turn indicative for a progressed / late stage of a disease or disorder related to alpha synuclein aggregation, such as MSA and Parkinson’s disease. If the respective subject is not yet afflicted with a disease or disorder related to alpha synuclein aggregation, such a ratio is highly indicative of a high risk of developing a disease or disorder characterized by alpha- synuclein aggregation or that the onset of such disease or disorder is imminent. In contrast to the above ratios that are indicative for a disease / disorder, a ratio of greater than 1.14 is indicative for not being afflicted by a disease or disorder characterized by alpha-synuclein aggregation or for low / reduced risk of developing a disease or disorder characterized by alpha-synuclein aggregation. Such “low” or “reduced” risk of developing a disease or disorder characterized by alpha- synuclein aggregation is understood to be relative to a subject that has a lower ratio, i.e. equal to or lower than 1.14, in particular lower than 1.065. A ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1that is equal to or higher than 1.065 but equal to or lower than 1.14 is inconclusive in that subjects with such a ratio are typically not afflicted by a disease or disorder characterized by alpha-synuclein aggregation but have an elevated risk of developing a disease or disorder characterized by alpha-synuclein aggregation relative to those that have a ratio of greater than 1.14. In still other embodiments, the determined value in the IR spectrum is the ratio of the signal at 1651.5 cm-1to the signal at 1623.5 cm-1. In such embodiments, a ratio of below 1.20, below 1.15, below 1.10 or below 1.05 may be indicative for the presence or an increased proportion of alpha-synuclein in fibril and / or aggregated form relative to a sample containing only the monomeric, non-fibril form of alpha- synuclein. In such embodiments, the lower the ratio, the more likely it becomes that the proportion of alpha-synuclein in fibril and / or aggregated form is pathologically relevant. In various embodiments, 2, 3, 4 or all 5 of the above three values may be determined. It has been found that the amide I band center of mass value and the ratios of the signals at 1650 / 1630, 1656 / 1623.5 and 1651.5 / 1623.5 cm-1are particularly suitable as the determined value, as they have been found to show the best performance. More preferably, the ratio of the signals at 1656 / 1623.5 cm-1is used. Without wishing to be bound to any hypothesis, it is assumed that e.g. the amide I band center of mass performs particularly well as it has advantages for expectedly low analyte signals, for example relative to the absolute amide band I maximum. The ratios are based on the principle that the determined signal at the higher fixed wave number is characteristic for alpha-synuclein with a predominantly alpha-helical and / or random coil secondary structure while the signal at the lower fixed wave number is characteristic for beta sheet secondary structures. The lower the ratio, the higher the signal characteristic for alpha-synuclein molecules with beta sheet secondary structures. In the event more than one value is determined and there are conflicting results, the center of mass and the ratio values may thus be considered have higher reliability than the maximum value. In the methods of the invention, the sample is contacted with the antibody in a cell that comprises the necessary instrumentation to record the IR spectrum and thus comprises at least one IR light source, an IR detection element and the actual sensor element described herein above. Said cell may be in form of a flow cell, e.g. may comprise an inlet and an outlet that allows introduction and incubation of the sample with the antibody-functionalized sensor element as well as one or more optional washing steps. These steps may be automated and may be performed continuously. In such embodiments, the cell may be part of a device that also comprises further elements, such as a pump etc. In other embodiments, the cell is designed such that it has a single opening that is used for introduction and removal of the sample as well as, optionally, multiple washing and / or blocking solutions. In such embodiments, the introduction of the sample into the cell may also be automated but may also be done manually. In various embodiments, introducing the sample into a cell may thus comprise bringing the sample into contact with the antibody under conditions and for a period of time that allow any alpha-synuclein present in the sample to be recognized and bound by the antibody. This typically means that the sample in liquid form is contacted with the sensor element surface on which the antibodies have been immobilized and optionally incubated for a period of time that allow binding to occur. In various embodiments, the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample, or more specifically, the value indicative for said proportion may be used as a biomarker. Said biomarker may be useful for detecting and / or diagnosing a disease or disorder characterized by alpha-synuclein aggregation, for example a synucleinopathy. Additionally, such biomarker may also be useful for risk stratification in determining the risk of developing a disease or disorder characterized by alpha-synuclein aggregation. The values used may be those disclosed in connection with the inventive methods above, such as the ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1in an infrared spectrum. The methods disclosed herein may thus be used for the diagnosis of a disease or disorder characterized by alpha-synuclein aggregation, for example a synucleinopathy, or for risk stratification, involving grading of patients into levels of risk, such as high risk and low risk or high risk, intermediate risk and low risk for developing a disease or disorder characterized by alpha-synuclein aggregation, for example a synucleinopathy. Said risk groups may be graded using the biomarkers given above, such as the signal ratios disclosed herein above. In various embodiments, the ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1is used. In some embodiments, patients with a ratio of lower than 1.065 are graded at being at high risk, patients with a ratio of higher than 1.14 graded as being a low risk and patients with a ratio between these values are graded at being at an intermediate risk. In some embodiments, patients with a ratio of lower than 1.065 are diagnosed with a disease or disorder characterized by alpha- synuclein aggregation, for example a synucleinopathy, patients with a ratio of higher than 1.14 are diagnosed as not being afflicted by a disease or disorder characterized by alpha-synuclein aggregation, for example a synucleinopathy, and patients with a ratio between these values are not clearly diagnosed as being afflicted but having an increased risk to develop such a disease or disorder. In such use as a biomarker, the determined value indicative for the proportion of misfolded alpha- synuclein in the sample is interpreted to be indicative for a certain risk to be afflicted by or for developing a synucleinopathy. This may, for example, mean that a threshold is defined for said value, as described herein, and once said value falls below said threshold (or exceeds said threshold depending on how it is defined), the subject from which the sample has been obtained is determined to have a certain risk to be afflicted by or develop a synucleinopathy. Said determination may be considered in the diagnosis of such disease or disorder and may be combined with other diagnostic means and methods that may help to support or verify the finding. In various embodiments, the value if used as a biomarker is thus indicative for a certain likelihood to be afflicted by or develop a synucleinopathy. As described above, the determined value in the IR spectrum may be an amide I band maximum, an amide I band center of mass, the ratio of the signal at 1650 / 1630 cm-1, the ratio of the signal at 1656 / 1623.5 cm-1and / or the ratio of the signal at 1651.5 / 1623.5 cm-1. The threshold values described herein above can be indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation. In all embodiments disclosed herein, said alpha-synuclein aggregation characterizing the disease or disorder may be in the brain. In alternative embodiments, the methods of the invention may also be used to monitor or determine the efficiency of a treatment of a synucleinopathy that targets the misfolded alpha-synuclein or for screening a compound or molecule that is suspected to target misfolded alpha-synuclein. In such embodiments, the methods may be performed prior to and during or after the treatment to determine whether the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha- synuclein in the sample has been changed by said treatment. Any change that results in a reduced proportion of alpha-synuclein in fibril and / or aggregated form may then be considered to be indicative for the success of the treatment. Similarly, the method may be performed with samples that have been exposed to a candidate compound or molecule or with samples from an organism that has been exposed to a candidate compound or molecule, for example by administration. If said exposure of the sample or the organism from which the sample has been obtained to the candidate compound leads to a change in the proportion of alpha- synuclein in fibril and / or aggregated form relative to an untreated sample or an untreated organism, this may be considered indicative that the candidate compound of molecule is capable of interfering with the ratio of misfolded to functional alpha-synuclein, for example either by capturing and thus removing the misfolded alpha-synuclein or by preventing or decreasing such misfolding. The desirable outcome of such tests would thus be that the proportion of alpha-synuclein in fibril and / or aggregated form is decreased relative to an untreated sample or organism. The thus identified compounds and molecules may then be further developed as treatment options of the various synucleinopathies or as prophylactic treatments to prevent or delay the onset of a synucleinopathy. “Synucleinopathy”, as used herein, relates to any disease, disorder or abnormality that is associated with alpha-synuclein aggregates, fibrils, protofibrils or pathological alpha-synuclein. Known disease include, but are not limited to, Parkinson's disease (sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure and Lewy body dysphagia), Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson’s disease dementia (PDD)), Diffuse Lewy Body Disease (DLBD), sporadic Alzheimer’s disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer’s disease, multiple system atrophy (MSA; Shy-Drager syndrome, striatonigral degeneration and olivopontocerebellar atrophy), inclusion- body myositis, traumatic brain injury, chronic traumatic encephalopathy, dementia pugilistica, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Frontotemporal dementia with Parkinsonism linked to chromosome 17 and Niemann-Pick type C1 disease), Down syndrome, Creutzfeldt-Jakob disease, Huntington’s disease, motor neuron disease, amyotrophic lateral sclerosis (sporadic, familial and ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (Ha!lervorden-Spatz syndrome), prion diseases, Gerstmann-Straussler-Scheinker disease, ataxia telangiectatica, Meige’s syndrome, subacute sclerosing panencephalitis, Gaucher disease, Krabbe disease as well as other lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome), or rapid eye movement (REM) sleep behavior disorder. More particularly, the synucleinopathy may be selected from Parkinson’s Disease, Multiple System Atrophy (MSA), Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson’s disease dementia (PDD)), and Diffuse Lewy Body Disease, optionally from Lewy body disease, MSA and Parkinson’s Disease, for example from MSA and PD. The alpha-synuclein aggregates may include Lewy bodies, Lewy neurites and / or glial cytoplasmic inclusions. In various embodiments, the sample used in the methods described herein is a biological sample. Such biological samples include body fluid samples, such as, in particular, a cerebrospinal fluid sample, a blood sample, a serum sample, or a plasma sample. The sample may also be a tissue sample, for example in form of a homogenate, such as a brain tissues sample or skin tissue sample. The samples may be complex biological samples, such as those described above, that contain multiple other components and which the alpha-synuclein may only be contained in minute amounts. The samples may be used without any pretreatment. In other words, the samples, for example blood samples, may be used as obtained, i.e. unprocessed, without the need to isolate or concentrate the analyte. This allows use of the methods in clinical applications. The invention is further directed to a sensor element, in particular an infrared sensor element, such as for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, with said sensor element comprising an antibody as defined herein. All embodiments of the antibodies and sensor elements used in the methods disclosed herein similarly apply to the sensor elements of the invention. The antibody is typically linked to the infrared sensor element, usually by a covalent bond. Suitable immobilization chemistries on a variety of surfaces are well-known in the art and routinely applied. Suitable chemistries are for example described in WO 2015 / 121339 A1. The sensor element of the invention may comprise an internal reflection element, for example having a trapezoid or parallelogram shape. Said internal reflection element may be a (mono)crystal of any suitable material that is transparent to IR light and the suitable materials include, but are not limited to germanium, gallium arsenide, silicon, zinc selenide, and diamond. As described in relation to the inventive methods above, the antibody is generally immobilized such that its antigen-binding regions are accessible to the sample and come into contact with any potential analyte that may be comprised therein. In various embodiments, the antibody is immobilized to one surface of the sensor element, more specifically the internal reflection element, with said surface lying opposite to the surface facing the IR source and thus the incident IR light. This is the typical setup for ATR-FTIR spectroscopy and leads to a situation where the incident light enters the internal reflection element and interacts with the antibody (covalently) bound to the opposite surface before being reflected and passing through the internal reflection element again, with said passage, interaction and reflection being repeated multiple times to improve the S / N ratio. The invention further relates to devices that comprise the sensor element of the present invention. Said devices may further include an IR light source and an IR detector and optionally further components, such as a data processing unit and / or a pump. The device may comprise a cell that includes the sensor element, for example a flow cells. The IR source may, in various embodiments, be a tunable quantum- cascade laser (QCL). The use of such QCL as the light source may allow the design of a very compact device and makes the use of thermoelectric (Peltier-)cooled mercury cadmium telluride (MCT) or microbolometers as detectors possible. In some embodiments, the device may in addition to the instrumentation for IR spectroscopy further comprise parts that allow detection by another optical method, such as UV / vis fluorescence. In such devices immune-ATR-IR vibrational spectroscopy may be combined with parallel fluorescence spectroscopy. In such setups a light source and detection unit for such other optical detection methods is additionally used. The sensor elements and devices of the invention may be used for determining the proportion of alpha- synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject. Such use as well as the use in the methods described herein forms one different aspect of the present invention. Further, the sensor elements and devices may also be used for detecting a disease or disorder characterized by alpha-synuclein aggregation or for determining the risk of developing a disease or disorder characterized by alpha-synuclein aggregation. This may include determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, as described herein above. All embodiments described herein for any one of the methods, sensor elements, devices and uses of the invention, are similarly applicable for the respective other aspects of the invention and vice versa. The invention is further illustrated by the following non-limiting examples.

[0004] Examples Example 1: Preparation of the antibody-functionalized sensor element Materials Solid base element: Silicon ATR Crystal (internal reflection element), trapezoidal, incidence angle 45°, 52mm x 20mm x 2mm (Tol: + / - 0.1mm), optically polished Linker A1: 1-azido-N-(3-(triethoxysilyl)propyl)-3,6,9,12,15-pentaoxaoctadecan-18-amide Matrix precursor compound: 3-(2-(2-methoxyethoxy)ethoxy)-N-(3-(triethoxysilyl)propyl)propanamide Linker A2: 2,5-dioxopyrrolidin-1-yl 6-{2-azatricyclo[10.4.0.04,9]hexadeca-4,6,8,12,14,16-hexaen- 10-yn-2-yl}-6-oxohexanoate Peptide compound: casein fragment blocking solution, made from bovine casein (Sigma Aldrich / Art.-Nr.: C3400) by alkaline hydrolysis Linker B1: 2,5-dioxopyrrolidin-1-yl 1-{2-azatricyclo[10.4.0.04,9]hexadeca-4,6,8,12,14,16-hexaen- 10-yn-2-yl}-1,4-dioxo-7,10,13,16,19,22,25,28,31,34,37,40,43-tridecaoxa-3-aza-hexatetracontan-46- oate. Linker B2: 2,5-dioxopyrrolidin-1-yl 1-azido-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate Antibody: Monoclonal anti-alpha-synuclein antibody with VH amino acid sequence of SEQ ID NO:13 and VL amino acid sequence of SEQ ID NO:14 binding to an alpha-synuclein epitope within amino acids 126-140 of SEQ ID NO:1. Device: ATR-IR-biosensor Method Pretreatment of the silicon crystal (process step a)) The surface was activated by an oxidative treatment to produce a stable silicon dioxide layer. Silanization of a silicon crystal (process step b)) For silanization of the silicon crystal, a mixture of linker A1 and the matrix precursor compound in 2- propanol was prepared and contacted with a selected surface of the silicon crystal. The crystal was subsequently rinsed with H2O and dried under nitrogen. After completion of the silanization, the ATR- FTIR difference spectrum (before and after silanization) shows an azide band at 2110 cm-1. NHS activation of the azide moieties of the silanized surface (process step b)) Linker A2 was reacted in a SPAAC (strain promoted alkyne-azide cycloaddition) click reaction with the previously silanized crystal surface. The coupling takes place by reaction of the DBCO group with the azide group on the silanized surface. After SPAAC click reaction, reactive NHS groups are available on the silanized silicon crystal which can be reacted with peptide compounds from the casein fragment blocking solution. After completion of the SPAAC click reaction, the ATR-IR difference spectrum (before silanization / after click reaction) showed 3 NHS bands at 1738 cm-1, 1782 cm-1, and 1815 cm-1. The azide band at 2110 cm-1has disappeared in the difference spectrum. Production of azide-labeled antibody (preparation for process step e)) The anti-alpha-synuclein antibody was reacted with linker B2 for preparing an azide-labeled anti-alpha- synuclein antibody. Blocking of surface and immobilization of antibody on blocking layer (process steps c) to e)) After silanization and NHS-activation by the SPAAC click reaction (i.e. process step b)), a protein- reactive silicon crystal was available. In the subsequent surface functionalization, the NHS- functionalized crystal surface was first blocked with the casein fragment solution. Covalent bonding can be achieved via amide bonding of the primary amine group of the lysines of the casein peptides or the N-termini of the casein peptides with the NHS-functional groups of the silicon crystal. The NHS-functionalized crystal was placed with the top (long side) facing up on the crystal holder of the ATR flow-through cuvette. The lid of the cuvette with inserted silicone seal was placed on the crystal. The cuvette was placed on the cuvette holder in the IR spectrometer. The sample compartment of the spectrometer was sealed and purged with dry air. The flow system including the cuvette was flushed with water and then with PBS buffer. Subsequently the casein fragment blocking solution was circulated over the crystal surface, followed by a washing step with PBS in flow-through mode. During the blocking process, complete IR spectra were continuously recorded and referenced against the PBS background. The blocking process was monitored by following an increase of the amide 2 absorbance (1550 cm-1) and simultaneously a decrease of NHS absorbance (1740 cm-1) in time. Next, excess NHS groups were quenched with an ethanolamine solution followed by another washing step. Subsequently, the peptide blocking layer was DBCO-functionalized by reaction with the NHS- and DBCO-containing linker B1 in flow-through mode. In a next step, the previously prepared azide-labeled anti-alpha-synuclein antibody was immobilized on the DBCO-functionalized peptide blocking layer by a SPAAC click reaction between the DBCO moiety and the azide group in flow-through mode. During antibody attachment, complete IR spectra were continuously recorded and compared with the background before antibody attachment. An indication for successful immobilization of the antibody on the surface is the amide 2 signal (1550 cm-1). Example 2: Determination of monomeric and fibril / aggregated forms of alpha-synuclein from artificial antigen preparations Antigen preparation The generation of monomers and pre-formed fibrils (PFFs) was conducted as described in detail by Polinski et al. in the MJFF-protocol (doi: 10.3233 / JPD-171248). Briefly, monomeric alpha-synuclein was prepared by first thawing the alpha-synuclein protein on ice, which was acquired by purchase as peptide film (Stressmarq, others were tested too) and stored at -80°C. Once completely thawed, the peptide was centrifuged at 14400 g for 10 min at 4°C to remove aggregates. The concentration was determined by Bradford assay. For monomer measurements, aliquots were prepared in 1x Dulbecco’s PBS (Invitrogen 14190136) at 0.1 mg / ml, snap frozen in liquid nitrogen, and stored at -80°C until use. For fibrilization, the peptide film was prepared to 5 mg / ml in PBS, mixed, and incubated at 37°C and 1000 rpm shaking for 7 days. Successful fibrilization was reviewed by Thioflavin T assay (ThT from Sigma Aldrich: T3516) and by infrared spectroscopy against the monomer control sample and buffer. PFFs were stored at room temperature for usage within one week or aliquoted, snap frozen in liquid nitrogen and stored at -80°C. Antigen verification by ThT-assay For the fibril verification, one aliquot of the fibrils and monomers were thawed for the ThT-assay.95 µl of a 25 µM ThT-solution, made from 1:40 dilution of a 1 mM stock with PBS, was pipetted into the wells of the 96-well-plate that were assigned for measurement. The PFFs were mixed, followed by application of 2.5 µl into the wells with ThT-solution. Controls were included with 2.5 µl PBS alone (Blank) and 2.5 µl of the monomeric alpha-synuclein (neg. control). All samples were prepared as triplicates and incubated for 60 minutes before readout. The plate was read by excitation at 443 nm and emission at 478 nm or by spectral scan in the range of 300-470 nm for the excitation scan and 460-600 nm for the emission scan. Fibrils were present, if blank-corrected emission was increased at least by a factor of 20. If a spectral scan was conducted, a shift of the excitation maximum (413 to 450 nm) was observed in addition to the emission increase by at least factor of 20 for fibril verification. A representative figure demonstrating monomeric and fibrillary alpha-synuclein in a ThT-excitation and emission-scan and generated by the protocol above, is shown in Figure 1 and the results are summarized in the Table below: Exemplary ThT- ΛmaxExcitation in a.u. ΛmaxEmission (nm) xEmissionFactor at maxima and (nm) 478 nm (a.u.) intensities alpha-synuclein 12.6 (at 416.8 nm) 3.88 (at 524.3 nm) - monomer alpha-synuclein PFF 94.7 (at 434.5 nm) 91.4 (at 478.9 nm) 40.5 The shift of the excitation and the increased fluorescence intensity (in this example by factor of 41) are clearly indicative for successful formation of fibrillary structures by use of the cited protocol. Antibody characterization by ATR-FTIR-spectroscopy with verified antigens Antibody performance and suitability was tested by infrared spectroscopy and additional techniques (e.g. Elisa-assays), and is described exemplarily for the ATR-FTIR-based setup using functionalized surfaces, as described in Experiment A. The antibody-surface featuring the anti-alpha-synuclein antibody was stabilized in flow-through mode with the antigen-buffer (1x PBS with / without 0.05 % Tween20) and spectra were recorded to see potential instabilities or wash-offs (unbound antibody). A new background spectrum was generated in the antigen-buffer to allow subtraction of the buffer background upon antigen binding. Antigen binding was typically done in circulation mode, in which the sample was circulated the over the antibody-surface in buffer (total volume ~ 1ml) for 60 minutes. Spectra were recorded continuously. After circulation and binding of the antigen to the antibody, visualized by the amide II kinetic at 1550 cm-1, the mode was changed to washing. In this step, the antigen buffer was rinsed over the cuvette with the antibody- antigen pair to allow the removal of unbound species and antigen. This step was conducted 60-120 minutes, dependent on the wash-off, and spectra were recorded continuously. The normalized antigen-binding kinetic (Fig.2) and normalized sample spectra (amide-I region, Fig.3) are shown for the two exemplary alpha-synuclein species generated with the previous described protocol. Figure 2 clearly shows binding of different alpha-synuclein conformers to the generated antibody-surface. In this exemplary case, the wash-off is stronger for the monomeric form indicating an affinity and / or possible charge / surface difference resulting in a comparably weaker binding. Figure 3 demonstrates exemplary antigen spectra of alpha-synuclein monomers with a peak maximum of 1647 cm-1indicating alpha-helical / random-coil conformation and PFFs with a peak maximum of 1623 cm-1indicating ß-sheet dominated PFFs. This finding is in concordance with the increased ThT-emission of the fibrils (Figure 1), and allows further in-depth analysis of secondary structure components, e.g. by spectral decomposition of the amide-I-band. Spectra were generated by averaging minute 5-55 of the 60 minutes buffer wash and subsequent normalization in the amide-I / amide-II region. The experiment was repeated with two different antibodies that bind to alpha-synuclein epitope within amino acids 103-108 (antibody 4B12) and 121-125 (antibody S5566). Both antibodies are commercially available anti-alpha synuclein antibodies (4B12: Thermo Fisher Scientific Catalog # MA1-90346; S5566: ID AB_261518; Sigma Aldrich Catalog S5566). The two comparative antibodies were used in the same amount as the inventive antibody that binds to an alpha-synuclein epitope within amino acids 126-140. For this experiment commercial antigens, i.e. alpha synuclein monomers ( ^Syn-M) and alpha synuclein pre-formed fibrils ( ^Syn-PFF) were used. Sample circulation was conducted for 60 minutes and the antibody performance and suitability evaluated by ATR-FTIR as described above. The results of these experiments are shown in Figure 4A (inventive antibody binding to alpha-synuclein epitope within amino acids 126-140) and Figure 4B (antibodies binding to an alpha-synuclein epitope within amino acids 103-108 (antibody 4B12) or 121-125 (antibody S5566)). The results show that the sample signal of the inventive antibodies are significantly higher and displayed a clearer secondary structure profile than antigens bound on surfaces with the comparative antibodies. The antibody binding to the epitope 121-125 of alpha synuclein provided for the least favorable binding in that it essentially failed to provide a signal for the monomeric form and provided a weak signal only for the PFFs. This clearly demonstrates that advantages of using an antibody that binds to an epitope within the region defined herein, namely in that it allows binding of both the monomeric form and PFFs and provides for strong and clearly distinguishable signals depending on the secondary structure. Example 3: Determination of secondary structures distribution of alpha-synuclein from CSF As alpha-synuclein misfolding into toxic oligomers and fibrils is suspected to drive synucleopathies like Parkinson’s disease, and a substantial spectral difference of the conformers was observed (see Example 2), analysis of secondary structure distribution analysis of complex body fluids, in this example cerebrospinal fluid (CSF), was conducted in the next step. The superior inertness of the used surface allowed investigation of antibody-specific target proteins without nonspecific binding to the blocked surface. CSF samples were obtained by different clinical centers with a profound analytical standard operating procedure. The samples were stored at -80°C upon usage. CSF samples were thawed, centrifuged at 4000 g at 4°C for 5 minutes to remove any cellular debris, and aliquoted into 300 µl samples. Samples were snap-frozen and stored at -80°C. When internal measurement stabilization criteria were reached, one aliquot (300 µl) was thawed at RT for 30 minutes, mixed and prepared for measurement in sample circulation mode. The measurement process of complex body fluid sample was the same as described for the antigens above, except that circulation and wash times were doubled (each 120 minutes). No additives or preservatives were used for the measurement. Samples were diluted by the system volume in PBS by a factor of three. The results are shown in Figures 5 and 6 and summarized in the table below: CoM A1-Max 50 / 30-R 51.5 / 23.5-R 56.0 / 23.5-R DC-CSF 1642.1 1642.8 1.05 1.24 1.16 PD-CSF 1636.6 1635.7 0.87 1.00 0.92 A1-Max = amide band I maximum CoM = amide band I center of mass 50 / 30-R = ratio of 1650 / 1630 cm-156 / 23.5-R = ratio of 1656 / 1623.5 cm-151.5 / 23.5-R = ratio of 1651 / 1623.5 cm-1DC-CSF refers to CSF from a disease-free control, while PD-CSF refers to CSF from a subject afflicted by Parkinson’s disease. The mean spectra of the PD and DC-CSF sample, which were normalized to the amide I band maximum, are shown in Figure 6. Water vapor (WV) and baseline-correction were performed in the in-house software for spectra analysis, whereafter an in-house matlab script was utilized for smoothing (fourier self-deconvolution) of the spectra and automated extraction of the spectral parameters like the center of mass, absolute amide-I-peak maximum, the 50 / 30-R, 51.5 / 23.5-R and 56.0 / 23.5-R. The table above summarizes the evaluation parameters given by the Matlab-script. Differences in the CoM and absolute A1-peak-maximum as well as in the ratios, indicating mostly beta-sheets around 1630 and alpha- helical / random-coil structures around 1650 cm-1, are clearly visible, especially when calculating the difference between the PD- and DC-CSF spectrum (black-dotted). Those changes indicate an altered distribution of those structures indicating the presence of more beta-sheet and less alpha-helical- structures within the PD-sample. This discrimination underlines protein changes and increased misfolding in the disease trajectory and thus, are usable as biomarker for the disease. Further CSF sample were obtained from a second study cohort and collected from one German PD specialty center. Samples did not have artificial blood admixtures. The clinical diagnoses of Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia (FTD) were made according to current consensus criteria. CSF samples were collected in the morning under fasting conditions, centrifuged, aliquoted, and stored at -80 °C on clinical sides. For analysis, single-use aliquots (300 µl) of all CSF samples were provided and measured in a blinded manner. After data acquisition and analysis, results were reported to cooperation sites, and clinical diagnosis and additional information were provided for performance evaluation. As described above, in this approach, the structure-sensitive amide-I band of alpha synuclein was read out in the infrared spectral region. This band reflects the C=O stretching vibration of the alpha synuclein peptide backbone. The frequency of this band is downshifted when alpha synuclein misfolds because the structure changes from a mainly random-coil / alpha-helical to beta-sheet enriched secondary structure. To subtract the large water background absorbance masking the much smaller alpha synuclein absorbance, the attenuated total reflection (ATR) technology was applied. The ATR unit was integrated into a Fourier-Transform infrared spectroscopy (FTIR) setup for the infrared absorbance measurements. For the ATR-FTIR measurements, Vertex 80V spectrometers were used (Bruker Optics, Ettlingen, Germany) in combination with a liquid nitrogen-cooled mercury cadmium telluride (MCT) detector and a middle infrared (MIR) source. The ATR unit (Specac Ltd., Slogh, England) was fit into the sample compartment of the FTIR instrument and aligned to an incidence angle of 45° Measurements were conducted under constant dry airflow to prevent the sample chamber's sharp atmospheric water vapor absorbance bands. As described before, multichannel measurements were performed with a motorized stage. The alpha synuclein absorbance spectrum is revealed by difference spectroscopy between alpha synuclein bound spectra and spectra taken before alpha synuclein binding, eliminating the large background absorbance spectra of the surface layer and the water background. The surface functionalization has been described in detail before. In this study, an improved functionalization as described in international patent publications WO2024003213A1 and WO2024003214A2 was used. The improvements generally led to optimized stability and inertness of the ATR surface. Surface functionalization was monitored by recording the respective infrared spectra in each step. This allowed precise control over each reaction step. The binding of all alpha synuclein from the body fluid to the antibody-coated surface was conducted in a circulation mode. In contrast, subsequent washing steps in a flowthrough mode were used to rinse all unbound components present in the sample by buffer. The capture antibody was the inventive antibody described above, binding to an epitope within residues 126-140 of alpha synuclein. Functionalized surfaces without antibodies were used to assess the specificity for alpha synuclein and the inertness of the functionalized surface towards excessive amounts of antigen or CSF. Continuous spectra recording during alpha synuclein binding allowed tracking of minute changes in aqueous background or temperature. One of four independent measurement channels was used as a reference channel by measuring a buffer instead of a sample, allowing for background monitoring and, if necessary, respective correction. After system stabilization in PBS buffer, sample background spectra were measured. CSF samples were circulated over the surface for 120 minutes without additives. After sample circulation, the system was changed to flowthrough mode for sample washing, and loosely bound materials were rinsed away with PBS buffer. Sample wash spectra were recorded and reflected the alpha synuclein bound spectra. For efficacy testing of the setup, the supernatants after circulation mode were collected and snap-frozen for concentration determination of alpha synuclein. Data analysis was performed with an in-house developed spectral software solution and scripts for MATLAB (Mathworks Inc., Natick, MA, US, MatlabR2020b), as described herein above. For the detailed analysis, kinetics at specific wavenumbers indicating alpha synuclein binding, e.g., at 1550 cm-1for bound protein, and whole spectra (4000-1480 cm-1) indicating potential artifacts were analyzed. Raw spectra were averaged and corrected for water vapor and baseline. Difference spectra were calculated between the spectra before sample measurement (sample background) and the spectra of sample wash. The difference spectra were smoothened. The MATLAB script automatically generated spectral parameters, like the absolute amide-I-peak maximum, the amide-I center of mass maximum, or spectral ratios, e.g. 1656.0 / 1623.5-ratio. The different read-outs reflect the overall secondary structure distribution of alpha synuclein. The analysis of the Amide-I / Amide-II-ratio at peak maxima is used as a quality indicator, and spectra were only included in a range of 1.10-1.50. Distorted spectra with a Ratio <1.10 or >1.50 due to minor water background absorbance changes or temperature instabilities during the recording of the sample spectra were excluded from the analysis. Spectra with a S / N < 20 were also excluded from the analysis. S / N was calculated with S as the mean absorbance between 1560 and 1540 cm-1and N as the root-mean-square of the absorbance values between 1800-1900 cm-1 of unsmoothed spectra. Descriptive statistics were used to summarize patient characteristics to compare the age and sex of alpha synuclein misfolding cases and controls by chi-square and Mann-Witney U tests. Receiver- operating characteristic (ROC) analyses, including calculation of area under the curve (AUC), were conducted for discrimination of individuals with alpha synuclein misfolding and controls and by use of the ratio of 1656 cm-1and 1623.5 cm-1, representing the distribution of monomeric alpha-helical / random- coil and beta-sheet enriched protein structures. First, a logistic regression model was calculated with the disease status as the dependent variable and age, sex, and the read-out value as independent variables. The resulting model was then used to predict the probability that each person had Parkinson's disease. The ROC Curves and associated AUC values were then calculated based on these predictions. The same analysis stratified by study was additionally performed. Moreover, the added value of the read-out was analyzed by comparison to age and sex model only. All analyses were conducted two- sided at a significance level of 0.05 using OriginPro 2021b or OriginPro 2024 (OriginLab Corporation, Northampton, MA, USA) and the programming language R (version 4.2.1) Figure 7 shows the binding of the different alpha synuclein conformations by the capture antibody in Figure 7A. In order to determine the secondary structure distribution of alpha synuclein in body fluids, the catcher antibody must be able to bind all different conformers. The structure-sensitive Amide-I band showed its maximum at 1652 cm-1in the case of the alpha-helical / random-coil monomers. The maximum was at 1647 cm-1for dopamine-stabilized oligomers, while the most abundant oligomer species range from 700-1100 kDa. Pre-formed fibrils (PFFs) of alpha synuclein showed a maximum at 1624 cm-1. The results exhibit that the used catcher antibody extracts the different conformers. The expected range of alpha synuclein extracted by capture antibodies from CSF is from 1624 to 1652 cm-1. Common infrared spectroscopy wavenumber ranges for alpha-helices range from 1645-1662 cm- 1, for random-coil motifs from 1640-1645 cm-1, and for beta-sheet motifs between 1615-1638 cm-1. The inertness of the functionalized ATR surface without the capture antibody is displayed in Figure 7B. Excessive amounts of the different antigen conformers, at even much higher concentrations than the physiological concentrations observed in CSF, are blocked and do not bind unspecific to the surface. Notably, the surface has enough binding capacity to bind high amounts specifically by the antibody. Furthermore, cross-reactivity of abundant proteins like HSA or amyloidogenic proteins like beta-amyloid (monomers and fibrils) do not bind even in excessive amounts on the antibody functionalized surface (data not shown). Importantly, the functionalized blocking layer without capture antibody does not indicate an unspecific signal from the CSF matrix either (data not shown). Taken together, the results demonstrate no unspecific binding or strong crossreactivity from CSF to the functionalized surface. Two independent control experiments were performed to determine the extraction of alpha synuclein by the capture antibody. In the first experiment, an already measured CSF sample was measured a second time on a freshly prepared antibody functionalized surface. No infrared signal was observed in the second run, implying complete extraction of alpha synuclein from CSF on the surface within the infrared sensitivity in the first run. A second experiment was performed to eliminate the possibility of remaining, but not measurable, amounts of alpha synuclein. A commercially available quantitative ELISA for total alpha synuclein (BioLegend, Cat. No. 448607) was used. For this, the initial CSF and the CSF supernatants after measurement were compared either on a surface functionalized with or without capture antibody. While the original CSF sample concentration was 1197 ± 37 pg / ml, the concentration in the supernatant decreased over 85 % to 161± 14 pg / ml, implying a high efficiency in binding alpha synuclein from CSF. Notably, the concentration of alpha synuclein was only slightly decreased when measuring on a functionalized surface without capture antibody (1075 ± 19 pg / ml), which agrees with no signal being observed in the iRS read-out. The samples were measured in duplicates. The results show that the functionalized surface with the catcher antibody extracts almost all alpha synuclein from the CSF. In summary, the functionalized surface does bind specific alpha synuclein and does not bind other CSF compounds unspecifically. Further antibody characterization displayed a favorable, balanced antibody binding profile with EC50 values in the sub-nM range (Figure 8). The technique was applied to n=134 CSF samples from different clinical centers. The discovery study encompassed 59 individuals, with 17 out of 59 diagnosed with PD and 42 out of 59 as disease controls without signs of neurodegenerative disorders. The validation cohort comprised 75 individuals from the Paracelsus-Elena-Klinik (Kassel) and is entirely independent of the discovery cohort. Patients with overlapping disorders were included in the validation cohort for a more challenging differential classification. In the Kassel cohort, 40 out of 75 were diagnosed with clinical PD. Since the presence of alpha synuclein aggregates and conclusively alpha synuclein misfolding in MSA patients is known, both PD and MSA subjects were considered as misfolding positive group, while all other subjects were grouped as one disease control group, including CBD, FTD, and PSP subjects. The diseased group showed an average downshifted maximum of ʋav_PD / MSA=1639.54 cm-1compared to the control group with a maximum of ʋav_control=1641.4 cm-1. As read-out, not the absorbance maximum itself, but a center of mass maximum (upper 80-90 % of the band) was taken, which increases robustness in small signals. A difference spectrum between all synucleinopathy (PD / MSA) and all control spectra averaged to one spectrum is performed to quantify the downshift. The difference spectrum (Figure 9A) between the mean control spectra and the mean misfolding spectra marks a shift from random-coil / alpha-helical secondary structures at 1656.0 cm-1as a negative band to the beta-sheet secondary structure at 1623.5 cm-1ratio as a positive band. The positive / negative difference bands have comparable infrared signal integrals of 0.55 and 0.65. This shows clear-cut that the overall signal in the infrared reflects the expected transition for alpha synuclein from random- coil / alpha-helical to beta-sheet conformers. This misfolding is shown directly without amplification in body fluid for the first time as a native environment for alpha synuclein in PD. In the next step, the 1656.0 / 1623.5 ratio from Figure 9A was used as the best-performing measure instead of the downshift in wavenumbers to distinguish between controls and diseased. The ratio significantly distinguishes misfolding positive from negative cases (p<.0001, Figure 9B). A receiver operating characteristic area under curve (ROC-AUC) analysis with the 1656.0-1623.5-ratio is performed in the next step. In the discovery study, an area under the curve (AUC) of 0.90 (95 %-CL 0.85 – 0.96) is obtained, while in the validation study, an AUC of 0.86 (95 %-CL 0.80 - 0.93) is yielded. Combining both datasets yielded an AUC of 0.90 (95 %-CL 0.85 - 0.96). The MSA patients alone could be differentiated from the control group with an AUC of 0.73 (95 %-CL 0.56 – 0.97) but worse from PD with an AUC of 0.71 (95 %-CL 0.49 – 0.93). Accordingly, a Mann-Witney- U test for the MSA and PD groups showed no significant differences (p=0.12). Two thresholds instead of one were introduced, providing three classes (Figure 10), as the misfolding negative and positive groups revealed an overlap. This reflects that the misfolding increases in a continuum between healthy controls and individuals with clinically confirmed synucleinopathies (PD / MSA), which is not accounted for by one threshold only. Individuals with a 1656.0 / 1623.5-ratio <1.065 were stated as a high misfolding and clear synucleinopathy affliction, whereas a ratio of >1.14 reflected low misfolding and no affliction. High- and low-misfolding groups depicted a significant difference (p<.0001, Figure 10A). The individuals in the group between the two thresholds 1.065 and 1.14, fall into the intermediate area. These individuals are not as clearly assigned as individuals of high or low misfolding groups by the readout. The intermediate group reflects the misfolding continuum between a healthy and diseased state. In this line, individuals categorized into the intermediate group may hold an elevated risk for developing synucleinopathies compared to unafflicted individuals but are not yet clearly afflicted. Comparing only individuals with high and low misfolding groups yielded an AUC of 0.95 (95 %-CL 0.89 – 1.01) with a sensitivity of 97 % and specificity of 92 % (Figure 10B). In sum, utilizing the platform assay described herein, the synucleinopathies PD and MSA could be distinguished from controls by misfolding of alpha synuclein when comparing only individuals with high and low misfolding groups yield an AUC of 0.95 (95 %-CL 0.89 – 1.01) with a sensitivity of 97 % and specificity of 92 % or by single decisive threshold (AUC 0.90). The described assay result offers a quantitative measure of the continuum of disease progression. This benefit has the potential to answer the question of whether or not patients with prodromal PD (stage 2 NSD), e.g., REM sleep behavior disorder, progress to PD or associated alpha synuclein aggregation disease through an early risk indication in a disease continuum. So far, the inability to predict the timespan in which these patients develop PD is a significant hurdle for developing disease-modifying therapies and prevention studies. Furthermore, the stratification of PD and the consideration of potentially overlapping neurodegenerative diseases in view of a cross-disease spectrum is essential for predicting a positive therapy response and facilitating the development of individualized therapies, as already seen for cancer. Therefore, secondary structure distribution profiles of overlapping syndromes may differentiate between neurodegenerative diseases. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications and patents specifically mentioned herein are incorporated by reference in their entirety for all purposes in connection with the invention. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Moreover, all aspects and embodiments of the invention described herein are considered to be broadly applicable and combinable with any and all other consistent embodiments, including those taken from other aspects of the invention (including in isolation) as appropriate.

Claims

Claims 1. A method for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, comprising: (a) obtaining an IR spectrum of the sample in a cell comprising an infrared sensor element linked to an antibody capable of binding to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form, wherein said antibody binds to an epitope within amino acid residues 126-140 of human alpha-synuclein using the numbering according to SEQ ID NO:1; (b) determining a value in the obtained infrared spectrum indicative for the proportion of alpha- synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample.

2. The method of claim 1, wherein the antibody has specificity for alpha-synuclein over beta- and gamma-synuclein, optionally shows no cross-reactivity with beta- and gamma-synuclein.

3. The method of claim 1 or 2, wherein the affinity of the antibody for alpha-synuclein in its monomeric and its fibril / aggregated form is essentially the same.

4. The method of claim 3, wherein the affinity ratio of the antibody for monomeric alpha-synuclein and alpha-synuclein fibrils is in the range of 1.5:1 to 1:1.5, optionally 1.1:1 to 1:1.

1.

5. The method of any one of claims 1 to 4, wherein the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form determined in step (b) is (b1) an amide I band maximum; (b2) an amide I band center of mass; (b3) a ratio of signal at 1650 cm-1to signal at 1630 cm-1; (b4) a ratio of signal at 1656 cm-1to signal at 1623.5 cm-1; or (b5) a ratio of signal at 1651.5 cm-1to signal at 1623.5 cm-1.

6. The method of any one of claims 1 to 5, wherein said infrared sensor element comprises an internal reflection element, optionally of trapezoid or parallelogram shape, which is transparent to infrared light and provides for more than one passage of the infrared light through the reflection element, wherein the antibody is optionally immobilized on a surface of the internal reflection element.

7. The method of any one of claims 1 to 6, wherein step (b) comprises comparing the obtained IR spectrum with a reference IR spectrum of alpha-synuclein, wherein optionally the reference IR spectrum is obtained from a sample with a known proportion of alpha-synuclein in fibril and / or aggregated form.

8. The method according to any one of claims 1 to 7, further comprising: (c) based on the value indicative for the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in the sample, determining whether the humansubject is afflicted by or has a risk of developing a disease or disorder characterized by alpha- synuclein aggregation.

9. The method of claim 8, wherein (c1) an amide I band maximum below 1639 cm-1, optionally below 1638 cm-1, (c2) an amide I band center of mass of below 1641 cm-1, optionally below 1640 cm-1, (c3) a ratio of the signal at 1650 cm-1to the signal at 1630 cm-1below 0.99, optionally below 0.98, (c4) a ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1below 1.15, optionally below 1.10, and / or (c5) a ratio of the signal at 1651.5 cm-1to the signal at 1623.5 cm-1below 1.20, optionally below 1.15 is indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha-synuclein aggregation.

10. The method of claim 8 or 9, wherein (c3) a ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1below 1.065 is indicative for a disease or disorder characterized by alpha-synuclein aggregation or for an increased risk of developing a disease or disorder characterized by alpha- synuclein aggregation.

11. The method of any one of claims 8 to 10, wherein (c3) a ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1of greater than 1.14 is indicative for not being afflicted by a disease or disorder characterized by alpha-synuclein aggregation or for low risk of developing a disease or disorder characterized by alpha-synuclein aggregation.

12. The method of any one of claims 8 to 11, wherein (c3) a ratio of the signal at 1656 cm-1to the signal at 1623.5 cm-1of equal to or lower than 1.14 and equal to and higher than 1.065 is indicative for not being clearly afflicted by a disease or disorder characterized by alpha-synuclein aggregation but for having an elevated risk of developing a disease or disorder characterized by alpha-synuclein aggregation.

13. The method of any one of claims 8 to 12, wherein (1) the sample is a sample obtained from a human subject suspected of being afflicted by a disease or disorder characterized by alpha-synuclein aggregation or at risk of developing such a disease or disorder, wherein the disease or disorder is optionally selected from Lewy body disease and Parkinson’s disease; and / or (2) the sample is a cerebrospinal fluid sample, a blood sample, or a tissue homogenate including brain and skin.

14. An infrared sensor element for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject, comprising an antibody capable of binding to alpha-synuclein independent of whether it is in its monomeric or its fibril / aggregated form, wherein said antibody binds to an epitope within amino acid residues 65-77 or 126-140 of human alpha-synuclein using the numbering according to SEQ ID NO:1, wherein said antibody is linked to the infrared sensor element.

15. A device for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein of alpha-synuclein in a sample obtained from a human subject, comprising: (a) an infrared source, (b) an infrared sensor element according to claim 14, and (c) an infrared detector.

16. Use of an antibody binding to an epitope within amino acid residues 126-140 of alpha-synuclein using the numbering according to SEQ ID NO:1, for determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject.

17. Use of the infrared sensor element of claim 14 or the device of claim 15 for (a) determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject; or (b) for detecting a disease or disorder characterized by alpha-synuclein aggregation or for determining the risk of developing a disease or disorder characterized by alpha-synuclein aggregation by determining the proportion of alpha-synuclein in fibril and / or aggregated form relative to the total amount of alpha-synuclein in a sample obtained from a human subject.

18. The method of any one of claims 1-13, the infrared sensor element of claim 14, the device of claim 15 or the use of claim 16 or 17, wherein the antibody (a) comprises three variable heavy chain complementarity determining regions VH-CDR1, VH- CDR2 and VH-CDR3 and three variable light chain complementarity determining regions VL- CDR1, VL-CDR2 and VL-CDR3, wherein: (a1) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:2, VH-CDR2 comprises the amino acid sequence of SEQ ID NO:3, VH-CDR3 comprises the amino acid sequence of SEQ ID NO:4, VL-CDR1 comprises the amino acid sequence of SEQ ID NO:5, VL-CDR2 comprises the amino acid sequence of SEQ ID NO:6, and VL-CDR3 comprises the amino acid sequence of SEQ ID NO:7; or (a2) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:8, VH-CDR2 comprises the amino acid sequence of SEQ ID NO:9, VH-CDR3 comprises the amino acid sequence YSF, VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10, VL-CDR2 comprises the amino acid sequence of SEQ ID NO:11, and VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; or (b) comprises a heavy chain variable domain having an amino acid sequence that has at least 90%, preferably 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO:13 over its entire length and a light chain variable domain having an amino acid sequences that hasat least 90%, preferably 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO:14 over its entire length; or (c) comprises a heavy chain variable domain having an amino acid sequence that has at least 90%, preferably 100 %, sequence identity to the amino acid sequence set forth in SEQ ID NO:15 over its entire length and a light chain variable domain having an amino acid sequences that has at least 90%, preferably 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO:16 over its entire length.

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