Aims

To personalize current and future medical treatment in Parkinson’s disease (PD) there is an urgent need for identification of molecular profiles underlying between-patient differences in phenotype expression, treatment response and susceptibility to adverse drug reactions (ADRs). Here, we present the observational cohort study, named ‘Profiling Parkinson’s disease’ (ProPark), which is designed to identify a ‘ParkCode’ reflecting molecular profiles in PD.

Methods

ProPark is a longitudinal, multicenter cohort study in which 1250 PD patients with a disease duration of <10 years, as well as 265 age- and gender-matched controls will be recruited by a collaborative network in the Netherlands. We will collect phenotypic data, including neurological, neuropsychological and psychiatric assessments at baseline and follow-up (3 years). In addition, we will collect extensive wearable-sensor-derived kinematic data and blood (DNA, serum, plasma and PBMCs) and stool annually, and from a subset of patients also skin biopsies, CSF and brain-MRI.

Results

We will develop a biobank containing comprehensive and uniformly acquired longitudinal clinical data and biological samples for identification and validation of existing and novel (quantitative) biomarkers reflecting the Parkinson’s phenotype. In addition, we will develop data-driven approaches to unravel heterogeneity in the Parkinson’s phenotype. Main study parameters are biomarker concentrations (i.e. blood & stoo microbiome), skin alpha-synuclein aggregation, treatment response, ADR occurrence and cognitive and neuropsychiatric scores.

Conclusions

ProPark will integrate longitudinal clinical and biomarker data into a ‘ParkCode’ which may guide towards a more tailored use of current available symptomatic treatment and the development of disease-modifying therapies.

Aims

Multiple System Atrophy (MSA) is a rapidly progressive neurodegenerative disease with a profound neuroinflammatory component. We hypothesized that reactive astrocytosis as part of MSA-related neuroinflammation is a suitable target for biomarker development and set out to evaluate glial fibrillary acidic protein (GFAP) in plasma and CSF of MSA patients. We further explored [¹⁸F]D2-Deprenyl-PET imaging in MSA patients, a novel PET-Imaging method targeting MAO-B upregulation, as additional correlate of reactive astrocytosis.

Methods

We analyzed 23 plasma samples (8 MSA-P, 15 MSA-C) and 12 CSF samples (4 MSA-P, 8 MSA-C) using the Simoa^® Quanterix Platform. GFAP values were correlated with baseline UMSARS and MoCA scores and longitudinal increase in UMSARS values. In 11 patients, we additionally performed [¹⁸F]D2-Deprenyl-PET imaging (4 MSA-P, 7 MSA-C) and correlated results with fluid biomarkers.

Results

Both, plasma and CSF levels of GFAP showed significant positive correlation with baseline UMSARS values (p < 0.05) and negative correlation with MoCA scores (p < 0.05). There was no correlation of either plasma or CSF GFAP values with longitudinal increase in UMSARS values. In first [¹⁸F]D2-Deprenyl-PETs, we detected phenotype-specific differences in standardized uptake value ratios (SUVr), with MSA-P showing higher putaminal and MSA-C showing higher cerebellar tracer binding.

Conclusions

This data indicate that both plasma and CSF based GFAP values might be suitable fluid-based biomarkers for disease severity in MSA. Preliminary [¹⁸F]D2-Deprenyl-PET results indicate the potential to detect phenotype-specific regional differences of reactive astrocytosis in MSA and highlight the importance of neuroinflammation for the pathological disease process in MSA.

Aims

Methods

Results

Conclusions

Aims

Perivascular space (PVS) alteration, as captured by MRI, is one of the pathological findings in Alzheimer’s disease (AD). Validation of PVS against neuropathology and histopathology is missing. Therefore, the utility of the PVS imaging as a specific marker of AD pathology has been hindered. Here, we investigate the association of PVS morphology with neurofilament light (NfL) level in CSF and various AD-related postmortem histopathological findings.

Methods

ADNI data was used for this validation study. Two sub-groups were analyzed: 1) participants with MRI and CSF NfL data, 2) participants with premortem MRI and postmortem histology (including Amyloid-B, Tau, neuronal loss, and CAA). White matter and Basal ganglia (BG) PVS were automatically mapped. We used linear regression to assess if PVS morphology is a predictor of CSF-NfL or postmortem AD pathology, correcting of age, sex, and postmortem interval.

Results

PVS morphology was a predictor of CSF-NfL (t=-2.008, p=0.048). BG PVS morphology was a predictor of glial Tau pathology in the superior and middle temporal gyri (t=4.1, p=0.00003) and the parahippocampal gyrus (t=3.5, p=0.0005) and Entorhinal Cortex (t=3.14, p=0.002). PVS volume fraction in white matter was a predictor of vascular pathology, including CAA in the Amygdala (t=2.6, p=0.008) and Entorhinal cortex (t=2.9, p=0.003).

Conclusions

We found that PVS morphology is a predictor of glial Tau aggregation, but not neuronal Tau aggregation, suggesting that PVS alteration is an indicative of the disruption of brain homeostasis. We also observed that individuals with higher PVS volume fraction in BG have lower NfL load, an observation that demands further investigation.

Aims

To evaluate the prognostic value of QyPredict(R), a tunable machine learning model for clinical trial enrichment, in amyloid-positive (A+) and all-comer mild cognitive impairment (MCI) populations.

Methods

QyPredict® incorporates multiple inputs (QyScore® vMRI results, demographic, clinical, genetic and biological markers) and generates a score (0-1) representing the probability of an individual demonstrating a specific outcome (here, CDR-SOB increase of 0.5+ over 12 months). We used ADNI subjects with ages (55-85), MMSE (24-30), CDR=0.5 and available amyloid status.

We evaluated performance using probability cut-off scores of 0.1, 0.2, 0.3 and 0.4. For both all-comer and A+ populations we calculated the mean, standard deviation and Cohen’s d for change in CDR-SOB values over 12, 24 and 36 months, and Pearson’s correlation between the probability score and observed change in CDR-SOB.

Results

For the full sample without QyPredict(R) enrichment, change in CDR-SOB was 0.33 (±1.02) with d=0.32. Change in CDR-SOB increased with increasing cut-off values (0.46(±1.04) d=0.44 for cut-off 0.1, to 0.73 (±1.01) d=0.72 for cut-off 0.4).

For the A+ population without QyPredict(R) enrichment, change in CDR-SOB was 2.06 (±2.89) with d=0.71. Increasing cut-off values again led to increased CDR-SOB change (2.26 (±2.27) d=0.76 for cut-off 0.1, to 3.23 (±3.32) d=0.97 for cut-off 0.4).

Correlation values ranged from r=0.39-0.5. Higher cut-off values, longer follow-up time, and combining QyPredict(R) enrichment with amyloid positivity were all associated with higher correlations.

Conclusions

Subsets of MCI populations selected using QyPredict® exhibit faster cognitive decline, whether or not amyloid positivity is also enforced.

Aims

Early Alzheimer’s disease (AD) is characterised in cerebrospinal fluid (CSF) by a decreased concentration of amyloid beta 1-42 and and an increase in tau. Aim of this study was to identify processes associated with abeta and tau pathology in cognitively normal monozygotic twins.

Methods

We included 126 twins (54 pairs) from the PreclinAD study. We assessed 690 proteins by OLINK multiplex panels and total-tau (t-tau), abeta42, abeta40 by ELISA. The abeta42/40 ratio was used as measure of amyloid pathology. We correlated the abeta42/40 ratio and t-tau levels with all proteins. For proteins that showed an association with abeta42/40 or t-tau we performed Cross-Twin Cross-Trait (CTCT) analysis by correlating the concentration of abeta42/40 or t-tau in one twin with the concentration of a protein in the co-twin. Enrichment analysis was performed using Gene Ontology.

Results

Average age was 70 years. The Abeta42/40 ratio correlated positively with 3 proteins of which one correlated with abeta42/40 in CTCT analysis. The abeta 42/40 ratio correlated negatively with 114 proteins, which were enriched for apoptosis (p=7.8*10-11) and cytokine production (p=3.7*10-9). Three proteins correlated with abeta42/40 in CTCT analysis. T-tau correlated positively with 414 proteins which were enriched for nervous system development (p=9.7*10-21). 335 of these proteins correlated with t-tau in CTCT analysis. T-tau correlated negatively with 21 proteins which were enriched for leukocyte migration (p=9.7*10-3). Seven proteins correlated with t-tau in CTCT analysis.

Conclusions

Increased amyloid pathology was associated apoptosis and cytokine production. Increases in t-tau were associated with neuronal plasticity and these associations had a shared genetic background.

Aims

Alzheimer's disease (AD) is a neurodegenerative disorder responsible for more than 80% of cases of senile dementia. Despite the presence of tau protein aggregates is an established hallmark of the AD pathology, the limited scientific evidence on the timing of the molecular cascade leading to AD-related neurodegeneration has made difficult the development of both early diagnostic strategies and effective therapies. The actual challenges are to define new biomarkers and non-invasive technologies to measure neuropathological changes in vivo at pre-symptomatic stages, and to develop humanized AD models to understand the molecular cascade and thus accelerate the screening process for diagnostic and therapeutic candidate molecules. Recent evidences indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non-invasive rapid detection of AD biomarkers. Considering the retina as a window on the brain provides a platform from which to study diseases of the nervous system.

Methods

Rational design, in silico evaluation of a small-size focused library of fluorescent probes, consisting of a BODIPY core (electron acceptor) featuring highly conjugated systems (electron donor).

Synthesis and characterization of BT1 BODIPY.

Confocal imaging of BT1 on iPSCs derived neuronal, retinal cultures and retinal slices from AD patients

Results

BT1, has tested on in vitro onto human iPSC-derived NGN2-induced neuronal cell cultures after 30 days in culture. The probes showed high selectivity allowing in vitro imaging of hyperphosphorylated tau protein filaments with minimal background noise.

Conclusions

This study provides a new tau selective fluorophores to be used in retinal tissues of AD patients.

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