CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB

BACKGROUND: Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. OBJECTIVE: The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. METHODS: We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. RESULTS: (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. CONCLUSION: CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF. These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use.I recieved an honorarium from Roche Diagnostics for my participation in the advisory panel meeting leading to this pape

A novel deep-intronic de novo WDR45/WIPI4 mutation causes impaired selective autophagy in BPAN

Here we report the first deep-intronic de novo mutation in WDR45 (splice, c.235+159C>G) which was found by a phenotypically driven sequencing approach leveraging the unique MRI features of BPAN. mRNA analysis of the splice effect revealed an aberrant WDR45 transcript resulting in a frameshift with significantly reduced WDR45 mRNA levels. We next studied this loss-of-function mutation in patient derived fibroblasts as a paradigmatic model to elucidate the process of autophagy underlying BPAN. Altered LC3-I and LC3-II levels confirmed a block in autophagic flux. Automated image-based analysis unravelled a decrease of WIPI2-positive autophagosomal membranes. Likewise, despite overall increased p62 levels, less WIPI2 colocalized with the autophagy cargo receptor p62, suggesting that selective autophagy is compromised in BPAN fibroblasts. In sum, our results indicate that (i) identifying de novo variations in the deep-intronic space might allow molecular diagnosis in so far unsolved BPAN/NBIA patients, and (ii) that deficits in particular in selective autophagy may present a key mechanism causative for BPAN

The Need for a Neutron Source at the Rare Isotope Accelerator

An intense neutron source facility with radiochemical processing capability is necessary at the Rare Isotope Accelerator to fully realize its potential benefit to stockpile stewardship and astrophysics. While many of the important physics missions of RIA can be addressed with radioactive ion beams, direct neutron cross-section measurements of interest to stockpile stewardship and astrophysics cannot because one cannot make a neutron target. Thus, one must collect a sufficient amount of the appropriate short-lived isotope, quickly chemically process the material into a target, and promptly radiate the sample with an intense ''beam'' of neutrons. The unprecedented production rates expected at RIA enables many of these direct neutron cross-section measurements, but only if the proper infrastructure is in place. This document not only describes the major piece of this required infrastructure, a neutron source facility with radiochemical processing capabilities, but also the motivation for measuring such direct neutron cross-sections

Struktureller Ultraschall des medialen Temporallappens bei Alzheimer-Demenz

Abstract Purpose One of the anatomical hallmarks of Alzheimer’s disease (AD) is the atrophy of the medial temporal lobe (MTL), yet cost-effective and broadly available methodological alternatives to the current imaging tools for screening of this brain area are not currently available. Materials and Methods Using structural transcranial ultrasound (TCS), we attempted to visualize and measure the MTL, and compared the results of 32 AD patients and 84 healthy controls (HC). The MTL and the surrounding space were defined in the coronal plane on TCS. A ratio of the height of the MTL/height of the choroidal fissure (M/F) was calculated in order to obtain a regional proportion. Results An insufficient temporal bone window was identified in 22 % of the AD patients and 12 % of the HCs. The results showed that the ratio of M/F was significantly smaller in the AD group on both sides (p = 0.004 right, p = 0.007 left side). Furthermore, the M/F ratio made it possible to discriminate AD patients from HCs with a sensitivity of 83 % (right)/73 % (left) and a specificity of 76 % (right)/72 % (left) which is basically comparable to results published for magnetic resonance imaging. The measurements showed substantial intra/interrater reliability (ICC:0.79/0.69). Conclusion These results suggest that utilization of structural TCS may possibly constitute a cheap and easy-to-use supplement to other techniques for the diagnosis of AD. It may be especially useful as a screening tool in the large population of individuals with cognitive decline. Further studies are needed to validate this novel method.</jats:p

Effects of exergaming on attentional deficits and dual-tasking in Parkinson's disease

Introduction: Impairment of dual-tasking, as an attention-based primary cognitive dysfunction, is frequently observed in Parkinson's Disease (PD). The Training-PD study investigated the efficiency of exergaming, as a novel cognitive-motor training approach, to improve attention-based deficits and dual-tasking in PD when compared to healthy controls. Methods: Eighteen PD patients and 17 matched healthy controls received a 6-week home-based training period of exergaming. Treatment effects were monitored using quantitative motor assessment of gait and cognitive testing as baseline and after 6 weeks of training. Results: At baseline PD patients showed a significantly worse performance in several quantitative motor assessment parameters and in two items of cognitive testing. After 6 weeks of exergames training, the comparison of normal gait vs. dual-tasking in general showed an improvement of stride length in the PD group, without a gait-condition specific improvement. In the direct comparison of three different gait conditions (normal gait vs. dual-tasking calculating while walking vs. dual-tasking crossing while walking) PD patients showed a significant improvement of stride length under the dual-tasking calculating condition. This corresponded to a significant improvement in one parameter of the D2 attention test. Conclusions: We conclude, that exergaming, as an easy to apply, safe technique, can improve deficits in cognitive-motor dual-tasking and attention in PD