Anja Apel

Serum and Cerebrospinal Fluid Levels of Transthyretin in Lewy Body Disorders with and without Dementia

Parkinson’s disease (PD) without (non-demented, PDND) and with dementia (PDD), and dementia with Lewy bodies (DLB) are subsumed under the umbrella term Lewy body disorders (LBD). The main component of the underlying pathologic substrate, i.e. Lewy bodies and Lewy neurites, is misfolded alpha-synuclein (Asyn), and - in particular in demented LBD patients - co-occurring misfolded amyloid-beta (Abeta). Lowered blood and cerebrospinal fluid (CSF) levels of transthyretin (TTR) - a clearance protein mainly produced in the liver and, autonomously, in the choroid plexus - are associated with Abeta accumulation in Alzheimer’s disease. In addition, a recent study suggests that TTR is involved in Asyn clearance. We measured TTR protein levels in serum and cerebrospinal fluid of 131 LBD patients (77 PDND, 26 PDD, and 28 DLB) and 72 controls, and compared TTR levels with demographic and clinical data as well as neurodegenerative markers in the CSF. Five single nucleotide polymorphisms of the TTR gene which are considered to influence the ability of the protein to carry its ligands were also analyzed. CSF TTR levels were significantly higher in LBD patients compared to controls. Post-hoc analysis demonstrated that this effect was driven by PDND patients. In addition, CSF TTR levels correlated negatively with CSF Abeta1–42, total tau and phospho-tau levels. Serum TTR levels did not significantly differ among the studied groups. There were no relevant associations between TTR levels and genetic, demographic and clinical data, respectively. These results suggest an involvement of the clearance protein TTR in LBD pathophysiology, and should motivate to elucidate TTR-related mechanisms in LBD in more detail.

Comparable Autoantibody Serum Levels against Amyloid- and Inflammation-Associated Proteins in Parkinson’s Disease Patients and Controls

Naturally occurring autoantibodies (NAbs) against a number of potentially disease-associated cellular proteins, including Amyloid-beta1–42 (Abeta1–42), Alpha-synuclein (Asyn), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and S100 calcium binding protein B (S100B) have been suggested to be associated with neurodegenerative disorders, in particular Alzheimer’s (AD) and Parkinson’s disease (PD). Whereas the (reduced) occurrence of specific NAbs in AD is widely accepted, previous literature examining the relation of these NAb titres between PD patients and controls, as well as comparing these levels with demographic and clinical parameters in PD patients have produced inconsistent findings. We therefore aimed, in a cross-sectional approach, to determine serum titres of the above NAbs in a cohort of 93 PD patients (31 of them demented) and 194 controls. Levels were correlated with demographic and clinical variables, cerebrospinal fluid Abeta1–42, total tau and phospho-tau levels, as well as with single nucleotide polymorphisms (SNPs) of genes which either have been reported to influence the immune system, the amyloid cascade or the occurrence of PD (ApoE, GSK3B, HLA-DRA, HSPA5, SNCA, and STK39). The investigated NAb titres were neither significantly associated with the occurrence of PD, nor with demographic and clinical parameters, neurodegenerative markers or genetic variables. These results argue against a major potential of blood-borne parameters of the adaptive immune system to serve as trait or state markers in PD.

Inflammatory profile in LRRK2-associated prodromal and clinical PD

BackgroundThere is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.MethodsWe assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.ResultsA large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.ConclusionsConcomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.

Inflammatory profile discriminates clinical subtypes in LRRK2‐associated Parkinson's disease

The presentation of Parkinsons disease patients with mutations in the LRRK2 gene (PDLRRK2) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes.

Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors.

Introduction Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinsons disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). Materials and Methods IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. Results PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Discussion Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders.

GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson's Disease and Lewy Body Dementia.

Based on animal and ex-vivo experiments, Growth/Differentiation Factor-15 (GDF15, also called Macrophage Inhibitory Cytokine-1, MIC1), a member of the transforming growth factor-beta family, and Matrix Metalloproteinase-9 (MMP9), a member of the matrix metalloprotease family may be potential markers for Lewy body disorders, i.e. Parkinson’s disease with (PDD) and without dementia (PDND) and Lewy body dementia (DLB). GDF15 has a prominent role in development, cell proliferation, differentiation, and repair, whereas MMP9 degrades, as a proteolytic enzyme, components of the extracellular matrix. In this study, cerebrospinal fluid GDF15 and MMP9 levels of 59 PDND, 17 PDD and 23 DLB patients, as well as of 95 controls were determined, and associated with demographic, clinical and biochemical parameters. Our analysis confirmed the already described association of GDF15 levels with age and gender. Corrected GDF15 levels were significantly higher in PDD than in PDND patients, and intermediate in DLB patients. Within Lewy body disorders, GDF15 levels correlated positively with age at onset of Parkinsonism and dementia, Hoehn & Yahr stage and cerebrospinal fluid t-Tau and p-Tau levels, and negatively with the Mini Mental State Examination. Remarkably, it does not relevantly correlate with disease duration. MMP9 was not relevantly associated with any of these parameters. Cerebrospinal GDF15, but not MMP9, may be a potential marker of and in Lewy body disorders.

SNPs in Aβ clearance proteins: Lower CSF Aβ1-42levels and earlier onset of dementia in PD

Objective: To evaluate whether genetic variants in β-amyloid (Aβ) clearance proteins are associated with CSF levels of Aβ1-42 on a biological level and the onset of dementia on a clinical level in Parkinson disease (PD). Methods: We analyzed genetic variants known to be involved in Aβ clearance in a PD group comprising 456 patients, 103 of them with dementia. Single nucleotide polymorphisms in the genes APOE, cystatin C (CST), and membrane metalloendopeptidase (MME) were evaluated in relation to demographic variables, clinical phenotypes, and CSF Aβ1-42 levels using a cross-sectional approach. Results: Risk variants in the genes APOE and CST were associated with lower CSF Aβ1-42 levels. Clinically, patients with 2 risk alleles in CST tended to show a shorter interval from age at onset of PD to age at onset of dementia. Conclusions: This study suggests that genetic variants associated with Aβ clearance are involved in the pathogenesis of dementia in PD and possibly influence the onset of dementia.Objective: To evaluate whether genetic variants in &bgr;-amyloid (A&bgr;) clearance proteins are associated with CSF levels of A&bgr;1-42 on a biological level and the onset of dementia on a clinical level in Parkinson disease (PD). Methods: We analyzed genetic variants known to be involved in A&bgr; clearance in a PD group comprising 456 patients, 103 of them with dementia. Single nucleotide polymorphisms in the genes APOE, cystatin C (CST), and membrane metalloendopeptidase (MME) were evaluated in relation to demographic variables, clinical phenotypes, and CSF A&bgr;1-42 levels using a cross-sectional approach. Results: Risk variants in the genes APOE and CST were associated with lower CSF A&bgr;1-42 levels. Clinically, patients with 2 risk alleles in CST tended to show a shorter interval from age at onset of PD to age at onset of dementia. Conclusions: This study suggests that genetic variants associated with A&bgr; clearance are involved in the pathogenesis of dementia in PD and possibly influence the onset of dementia.

In vivo markers of Parkinson’s disease and dementia with Lewy bodies: current value of the 5G4 α-synuclein antibody

additional 35 kDa band on immunoblotting was found only in individuals with DLB. In another recent report, the same group detected a trend towards higher cerebrospinal fluid (CSF) 5G4 α-synuclein levels in four out of seven patients affected by α-synucleinopathies [7]. We tested the same 5G4-Ab for the first time in a large series of living patients (PATHO-Kit, Analytic Jena Roboscreen GmbH, Leipzig, Germany). The study evaluated serum 5G4 and total α-synuclein levels (MONO-kit, same company) in patients with a diagnosis of PD [n = 130, 31 with dementia (PDD)] and DLB (n = 36) according to current clinical criteria (Supplementary material). In the serum, mean 5G4 α-synuclein levels were similar in PD, DLB and healthy controls (n = 101) (Table 1). Total α-synuclein levels were lower in DLB compared to controls (p = 0.001), while the total/5G4α-synuclein ratio was similar in all groups. Separate analysis of outliers did not show relevant associations between the marker and demographic, clinical and neurochemical routine parameters (Supplementary Table 1). The only remarkable finding was an earlier age at Despite the great advances in understanding the molecular mechanisms involved in α-synucleinopathies, translational research is still looking for a reliable in vivo biomarker. As an important step forward in this field, Kovacs et al. [1] published in this Journal in 2012 the isolation of a new monoclonal antibody (5G4-Ab) specific for accumulated misfolded (but not physiological monomeric) α-synuclein, which was found after generation of α-synuclein aggregates by mice immunization. This antibody was tested in comparative immunohistochemical studies in brain tissue of patients with Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). 5G4-Ab showed higher sensitivity and specificity compared to available immunohistochemical assays. An

SERUM NEUROFILAMENT LIGHT CHAIN LEVELS ARE ASSOCIATED WITH CSF NEUROFILAMENT LIGHT CHAIN, COGNITIVE STATUS, AND DISEASE PROGRESSION IN AUTOSOMAL DOMINANT AD

BMI: body mass index; FGF21: fibroblast growth factor 21; HbA1C: Glycated hemoglobin A1C; HDL-C: high density lipoprotein cholesterol HOMA index: Homeostasis Model Assessment index; LDL-C: low density lipoprotein cholesterol; MoCA: Montreal cognitive assessment; SBP: systolic blood pressure. Oliver Preische, Stephanie A. Schultz, Anja Apel, Jens Kuhle, Brian A. Gordon, Guoqiao Wang, Eric McDade, Randall J. Bateman, John C. Morris, Tammie L. S. Benzinger, Mathias Jucker, Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany; Washington University in St. Louis School of Medicine, St. Louis, MO, USA; German Center for Neurodegenerative Diseases, Tuebingen, Germany; Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; University Hospital Basel, Basel, Switzerland; Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA; Washington University School of Medicine, St. Louis, MO, USA; Washington University School of Medicine, Saint Louis, MO, USA. Contact e-mail: saschultz@wustl.edu