Publications by authors named "Walter J Schulz-Schaeffer"

74 Publications

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.

Nat Neurosci 2021 02 30;24(2):168-175. Epub 2020 Nov 30.

Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.
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http://dx.doi.org/10.1038/s41593-020-00758-5DOI Listing
February 2021

Correction to: Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle.

Vet Res 2020 Oct 15;51(1):130. Epub 2020 Oct 15.

Institute of Neuropathology, Medical Faculty of the Saarland University, Homburg, Germany.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13567-020-00855-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559756PMC
October 2020

Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle.

Vet Res 2020 Jun 17;51(1):82. Epub 2020 Jun 17.

Institute of Neuropathology, Medical Faculty of the Saarland University, Homburg, Germany.

In a study originally designed to find potential risk factors for bovine spongiform encephalopathy (BSE) we examined tissues from 403 Holstein Frisian cattle in total. These included 20 BSE cattle and their 236 birth- and feeding cohort animals plus 32 offspring, 103 age, breed and district-matched control cattle and further twelve cattle with neurological signs. In addition to the obex, we examined the celiac ganglion, cervical cranial ganglion, trigeminal ganglion and proximal ganglion of the vagus nerve using histological techniques. Unexpectedly, we found a high number of neurofibroma, a benign peripheral nerve sheath tumor consisting of Schwann cells, fibroblasts and perineural cells. The neurofibroma were present only in the celiac ganglion and found during histologic examination. With a frequency of 9.91% in BSE cattle and their cohorts (case animals) and 9.09% in the age, breed and district matched control animals there seems to be no correlation between the occurrence of BSE and neurofibroma. Benign peripheral nerve sheath tumors have been described more often in cattle than in other domestic animals. Usually, they are incidental macroscopic findings in the thoracic ganglia during meat inspection. To our knowledge, there are no previous systematic histologic studies including bovine celiac ganglia at all. The high incidence of celiac ganglia neurofibroma may play a role in the frequently occurring abomasal displacements in Holstein Frisian cattle as the tumors might cause a gastrointestinal motility disorder. At present a genetic predisposition for these neoplasms cannot be ruled out.
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http://dx.doi.org/10.1186/s13567-020-00800-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301510PMC
June 2020

Acid Sphingomyelinase Deficiency Ameliorates Farber Disease.

Int J Mol Sci 2019 Dec 11;20(24). Epub 2019 Dec 11.

Department of Molecular Biology, University of Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.

Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can't achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
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http://dx.doi.org/10.3390/ijms20246253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941101PMC
December 2019

Targeting Chemokine Receptor CXCR4 and Translocator Protein for Characterization of High-Risk Plaque in Carotid Stenosis Ex Vivo.

Stroke 2018 08;49(8):1988-1991

From the Department of Neurology (G.M.G., H.W., K.W.).

Background and Purpose- This pilot study aims to demonstrate the feasibility of targeting molecular characteristics of high-risk atherosclerotic plaque in symptomatic and asymptomatic carotid stenosis (CS), that is, upregulation of the translocator protein (TSPO) and the chemokine receptor type 4 (CXCR4), by means of molecular imaging. Methods- In a translational setting, specimens of carotid plaques of patients with symptomatic and asymptomatic CS obtained by carotid endarterectomy were analyzed for the presence of TSPO and CXCR4 by autoradiography, using the positron emission tomography tracers F-GE180 and Ga-Pentixafor and evaluated by histopathology. In addition, Ga-Pentixafor positron emission tomography/computed tomography was performed in a patient with high-grade CS. Results- Distinct patterns of upregulation of TSPO (F-GE180 uptake) and CXCR4 (Ga-Pentixafor uptake) were identified in carotid plaque by autoradiography. The spatial distribution was associated with specific histological hallmarks that are established features of high-risk plaque: TSPO upregulation correlated with activated macrophages infiltration, whereas CXCR4 upregulation also corresponded to areas of intraplaque hemorrhage. Ga-Pentixafor uptake was significantly higher in plaques of symptomatic compared with asymptomatic CS. Clinical positron emission tomography revealed marked Ga-Pentixafor uptake in carotid plaque of a patient with high-grade CS. Conclusions- Clinical imaging of molecular signatures of high-risk atherosclerotic plaque is feasible and may become a promising diagnostic tool for comprehensive characterization of carotid disease. This methodology provides a platform for future studies targeting carotid plaque.
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http://dx.doi.org/10.1161/STROKEAHA.118.021070DOI Listing
August 2018

Pathological manifestations of Farber disease in a new mouse model.

Biol Chem 2018 09;399(10):1183-1202

Department of Molecular Biology, University of Duisburg-Essen, Hufelandstraße 55, D-45147 Essen, Germany.

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.
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http://dx.doi.org/10.1515/hsz-2018-0170DOI Listing
September 2018

Analysis of the vasculature by immunohistochemistry in paraffin-embedded brains.

Brain Struct Funct 2018 Mar 19;223(2):1001-1015. Epub 2017 Dec 19.

Department of Neurology, University of the Saarland, Kirrberger Strasse, 66421, Homburg/Saar, Germany.

The brain vasculature can be investigated in different ways ranging from in vivo to biochemical analysis. Immunohistochemistry is a simple and powerful technique that can also be applied to archival tissues. However, staining of brain vessels on paraffin sections has been challenging. In this study, we developed an optimized method that can be used in paraffin-embedded mouse and human brain tissues derived from healthy controls and neurological disorders such as Alzheimer's disease. We subsequently showed that this method is fully compatible with the detection of glial cells and key markers of Alzheimer's disease including amyloid beta and phosphorylated Tau protein. Furthermore, we observed that the length of microvasculature in hippocampus of TgCRND8 Alzheimer's disease mouse model is reduced, which is correlated with the decreased blood flow in hippocampus as determined by arterial spin labeling perfusion magnetic resonance imaging. Finally, we determined that the microvasculature length in two other Alzheimer's disease mouse models, APP and PS1 double-transgenic mice and P301S Tau-transgenic mice, is also shortened in the dentate gyrus. Thus, we have established a new, simple and robust method to characterize the brain vasculature in the mouse and human brain.
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http://dx.doi.org/10.1007/s00429-017-1595-8DOI Listing
March 2018

Morgagnian cataract resulting from a naturally occurring nonsense mutation elucidates a role of CPAMD8 in mammalian lens development.

PLoS One 2017 6;12(7):e0180665. Epub 2017 Jul 6.

University of Goettingen, Institute of Veterinary Medicine, Goettingen, Germany.

To investigate the genetic basis of hereditary lens opacities we analyzed 31 cases of bilateral congenital cataract in Red Holstein Friesian cattle. A genome-wide association study revealed a significant association on bovine chromosome 7 at positions 6,166,179 and 12,429,691. Whole genome re-sequencing of one case and four relatives showed a nonsense mutation (g.5995966C>T) in the PZP-like, alpha-2-macroglobulin domain containing 8 (CPAMD8) gene leading to a premature stop codon (CPAMD8 p.Gln74*) associated with cataract development in cattle. With immunohistochemistry we confirmed a physiological expression of CPAMD8 in the ciliary body epithelium of the eye in unaffected cattle, while the protein was not detectable in the ciliary body of cattle with cataracts. RNA expression of CPAMD8 was detected in healthy adult, fetal and cataractous lenses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500361PMC
October 2017

Types and Strains: Their Essential Role in Understanding Protein Aggregation in Neurodegenerative Diseases.

Front Aging Neurosci 2017 16;9:187. Epub 2017 Jun 16.

Institute of Neuropathology, Saarland University Medical CenterHomburg, Germany.

Protein misfolding and aggregation is a key event in diseases like Alzheimer's disease (AD) or Parkinson's disease (PD) and is associated with neurodegeneration. Factors that initiate protein misfolding and the role of protein aggregation in the pathophysiology of disease pose major challenges to the neuroscientific community. Interestingly, although the accumulation of the same misfolded protein, e.g., α-synuclein is detectable in all idiopathic PD patients, the disease spectrum covers a variety of different clinical presentations and disease courses. In a more recent attempt this clinical variance is being explained in analogy to prion diseases by different protein aggregate conformations. In prion diseases a relationship between protein aggregate conformation properties and the clinical disease course was shown by relating different prion types to a dementia and an ataxic disease course in Creutzfeldt-Jakob patients. This principle is currently transferred to AD, PD and other neurodegenerative diseases with protein aggregation. However, differences in protein aggregate conformation are frequently addressed as disease strains. The term "strain" also derives from prion research and evolved by adopting the virus terminology at a time when transmissible spongiform encephalopathies (TSEs; later called prion diseases) were assumed to be caused by a virus. The problem is that in virus taxonomy the term "type" refers to properties of the disease agent itself and the term "strain" refers to host associated factors that interact with the disease agent and may moderately modify the clinical disease presentation. Strain factors can be discovered only after transmission and passaging of the agent in a host of a different species. The incorrect use of the terminology confuses disease agent and host factors and hampers the understanding of the pathophysiology of protein aggregate-associated neurodegenerative diseases. In this review article the discoveries are reviewed that explain how the terms "type" and "strain" emerged for unconventional disease agents. This may help to avoid confusion in the terminology of protein aggregation diseases and to reflect correctly the impact of protein aggregate conformation as well as host factor contribution on different clinical variations of AD, PD and other neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnagi.2017.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472693PMC
June 2017

Neuropsychological Symptoms in Sporadic Creutzfeldt-Jakob Disease Patients in Germany.

J Alzheimers Dis 2017 ;59(1):329-337

Department of Neurology, University Medical School, Georg-August University Göttingen, Germany.

Background: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD.

Objective: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype.

Methods: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129 V polymorphism of PRNP and prion protein type.

Results: Neuropsychological symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes.

Conclusion: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129 V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes.
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http://dx.doi.org/10.3233/JAD-161129DOI Listing
April 2018

Cellular prion protein mediates early apoptotic proteome alternation and phospho-modification in human neuroblastoma cells.

Cell Death Dis 2017 01 19;8(1):e2557. Epub 2017 Jan 19.

Institute for Clinical Chemistry / UMG-Laboratories, University Medical Center Goettingen, Georg-August University, Goettingen, Germany.

Anti-apoptotic properties of physiological and elevated levels of the cellular prion protein (PrP) under stress conditions are well documented. Yet, detrimental effects of elevated PrP levels under stress conditions, such as exposure to staurosporine (STS) have also been described. In the present study, we focused on discerning early apoptotic STS-induced proteome and phospho-proteome changes in SH-SY5Y human neuroblastoma cells stably transfected either with an empty or PRNP-containing vector, expressing physiological or supraphysiological levels of PrP, respectively. PrP-overexpression per se appears to stress the cells under STS-free conditions as indicated by diminished cell viability of PrP-overexpressing versus control cells. However, PrP-overexpression becomes advantageous following exposure to STS. Thus, only a short exposure (2 h) to 1 μM STS results in lower survival rates and significantly higher caspase-3 activity in control versus PrP-overexpressing cells. Hence, by exposing both experimental groups to the same apoptotic conditions we were able to induce apoptosis in control, but not in PrP-overexpressing cells (as assessed by caspase-3 activity), which allowed for filtering out proteins possibly contributing to protection against STS-induced apoptosis in PrP-overexpressing cells. Among other proteins regulated by different PrP levels following exposure to STS, those involved in maintenance of cytoskeleton integrity caught our attention. In particular, the finding that elevated PrP levels significantly reduce profilin-1 (PFN-1) expression. PFN-1 is known to facilitate STS-induced apoptosis. Silencing of PFN-1 expression by siRNA significantly increased viability of PrP-overexpressing versus control cells, under STS treatment. In addition, PrP-overexpressing cells depleted of PFN-1 exhibited increased viability versus PrP-overexpressing cells with preserved PFN-1 expression, both subjected to STS. Concomitant increase in caspase-3 activity was observed in control versus PrP-overexpressing cells after treatment with siRNA- PFN-1 and STS. We suggest that reduction of PFN-1 expression by elevated levels of PrP may contribute to protective effects PrP-overexpressing SH-SY5Y cells confer against STS-induced apoptosis.
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http://dx.doi.org/10.1038/cddis.2016.384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386350PMC
January 2017

Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease.

J Alzheimers Dis 2017 ;56(2):441-446

Molecular Neuroimaging, New Haven, CT, USA.

Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.
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http://dx.doi.org/10.3233/JAD-160821DOI Listing
February 2018

Doxycycline in early CJD: a double-blinded randomised phase II and observational study.

J Neurol Neurosurg Psychiatry 2017 Feb 2;88(2):119-125. Epub 2016 Nov 2.

Department of Neurology, National Reference Center for TSE Surveillance, University Medical Center Goettingen, Göttingen, Germany.

Objectives: The main objective of the present study is to study the therapeutic efficiency of doxycycline in a double-blinded randomised phase II study in a cohort of patients with sporadic Creutzfeldt-Jakob disease (sCJD).

Methods: From the National Reference Center of TSE Surveillance in Germany, patients with probable or definite sCJD were recruited for a double-blinded randomised study with oral doxycycline (EudraCT 2006-003934-14). In addition, we analysed the data from patients with CJD who received compassionate treatment with doxycycline in a separate group. Potential factors which influence survival such as age at onset, gender, codon 129 polymorphism and cognitive functions were evaluated. The primary outcome measure was survival.

Results: Group 1: in the double-blinded randomised phase II study, 7 patients in the treatment group were compared with 5 controls. Group 2: 55 patients with sCJD treated with oral doxycycline were analysed and compared with 33 controls by a stratified propensity score applied to a Cox proportional hazard analysis. The results of both studies were combined by means of a random-effects meta-analysis. A slight increase in survival time in the doxycycline treatment group was observed (p=0.049, HR=0.63 (95% CI 0.402 to 0.999)).

Conclusions: On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD.

Trial Registration Number: EudraCT 2006-003934-14; Results.
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http://dx.doi.org/10.1136/jnnp-2016-313541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5284486PMC
February 2017

Cerebellar Amyloid-β Plaques: How Frequent Are They, and Do They Influence 18F-Florbetaben SUV Ratios?

J Nucl Med 2016 Nov 30;57(11):1740-1745. Epub 2016 Jun 30.

University of Leipzig, Leipzig, Germany.

SUV ratios (SUVRs) are used for relative quantification of F-florbetaben scans. The cerebellar cortex can be used as a reference region for quantification. However, cerebellar amyloid-β (Aβ) plaques may be present in Alzheimer disease (AD). The aim of this study was to assess the influence of Aβ pathology, including neuritic plaques, diffuse plaques, and vascular deposits, in F-florbetaben SUVR when cerebellum is used as the reference.

Methods: Using immunohistochemistry to demonstrate Aβ plaques and vascular deposits, and using the Bielschowsky method to demonstrate neuritic plaques, we performed a neuropathologic assessment of the frontal, occipital, anterior cingulate, and posterior cingulate cerebral cortices and the cerebellar cortex of 87 end-of-life patients (64 with AD, 14 with other types of dementia, and 9 nondemented aged volunteers; mean age ± SD, 80.4 ± 10.2 y) who had undergone F-florbetaben PET before death. The lesions were rated as absent (none or sparse) or present (moderate or frequent). Mean cortical SUVRs were compared among cases with different cerebellar Aβ loads.

Results: None of the 83 evaluable cerebellar samples showed frequent diffuse Aβ or neuritic plaques; 8 samples showed frequent vascular Aβ deposits. Diffuse Aβ plaques were rated as absent in 78 samples (94%) and present in 5 samples (6%). Vascular Aβ was rated as absent in 62 samples (74.7%) and present in 21 samples (25.3%). No significant differences in cerebellar SUVs were found among cases with different amounts or types of Aβ deposits in the cerebral cortex. Both diffuse and neuritic plaques were found in the cerebral cortex of 26-44 cases. No significant SUVR differences were found between these brains with different cerebellar Aβ loads.

Conclusion: The effect of cerebellar plaques on cortical F-florbetaben SUVRs appears to be negligible even in advanced stages of AD with a higher cerebellar Aβ load.
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http://dx.doi.org/10.2967/jnumed.115.171652DOI Listing
November 2016

The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases.

Nat Protoc 2016 Nov 13;11(11):2233-2242. Epub 2016 Oct 13.

Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

The development and adaption of in vitro misfolded protein amplification systems has been a major innovation in the detection of abnormally folded prion protein scrapie (PrP) in human brain and cerebrospinal fluid (CSF) samples. Herein, we describe a fast and efficient protein amplification technique, real-time quaking-induced conversion (RT-QuIC), for the detection of a PrP seed in human brain and CSF. In contrast to other in vitro misfolded protein amplification assays-such as protein misfolding cyclic amplification (PMCA)-which are based on sonication, the RT-QuIC technique is based on prion seed-induced misfolding and aggregation of recombinant prion protein substrate, accelerated by alternating cycles of shaking and rest in fluorescence plate readers. A single RT-QuIC assay typically analyzes up to 32 samples in triplicate, using a 96-well-plate format. From sample preparation to analysis of results, the protocol takes ∼87 h to complete. In addition to diagnostics, this technique has substantial generic analytical applications, including drug screening, prion strain discrimination, biohazard screening (e.g., to reduce transmission risk related to prion diseases) and the study of protein misfolding; in addition, it can potentially be used for the investigation of other protein misfolding diseases such as Alzheimer's and Parkinson's disease.
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http://dx.doi.org/10.1038/nprot.2016.120DOI Listing
November 2016

Clinical Definition of Camptocormia in Parkinson's Disease.

Mov Disord Clin Pract 2017 May-Jun;4(3):349-357. Epub 2016 Oct 11.

Department of Neurology University Hospital Schleswig-Holstein Kiel Germany.

Background: Clinical key aspects of camptocormia in patients with idiopathic Parkinson's disease (PD) await further definition.

Methods: Based on a self-assessment of PD patients, we performed an observational study, asking patients with subjectively felt involuntary forward bending to return a questionnaire and provide photographs showing their axial disorder. Forty-two matched PD patients without subjective signs of camptocormia were recruited as controls.

Results: The stooped posture of patients with advanced PD without camptocormia is characterized by a forward bending angle of always less than 30 degrees. Of the 145 camptocormia patients in our study, 70% had an angle ≥30 degrees. The patients with a more-severe forward bending angle were more severely affected in daily life than those with an angle of less than 30 degrees. Back pain was more frequent (81% vs. 43%) and more severe in PD patients with camptocormia than in controls. Back diseases in camptocormia PD patients were also significantly more frequent than in the PD control patients (55% vs. 26%). Camptocormia is a relevant burden in everyday life. Seventy-seven percent of patients needed walking aids and 85% reported specific disabilities attributed to camptocormia (e.g. increased risk of falling, dyspnea, problems in eating or swallowing).

Conclusions: Camptocormia cannot be clinically defined based on the forward bending angle alone, but an angle larger than 30 degrees is only found in camptocormia. Back pain is an essential aspect of camptocormia in PD. Back diseases can be seen as a risk factor in these patients.
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http://dx.doi.org/10.1002/mdc3.12437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174367PMC
October 2016

Camptocormia in Parkinson's Disease: A Muscle Disease Due to Dysregulated Proprioceptive Polysynaptic Reflex Arch.

Front Aging Neurosci 2016 21;8:128. Epub 2016 Jun 21.

Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center Göttingen Göttingen, Germany.

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http://dx.doi.org/10.3389/fnagi.2016.00128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914504PMC
July 2016

Application of an in vitro-amplification assay as a novel pre-screening test for compounds inhibiting the aggregation of prion protein scrapie.

Sci Rep 2016 07 7;6:28711. Epub 2016 Jul 7.

Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE)-Göttingen campus, Göttingen, Germany.

In vitro amplification assays, such as real-time quaking-induced conversion (RT-QuIC) are used to detect aggregation activity of misfolded prion protein (PrP) in brain, cerebrospinal fluid (CSF) and urine samples from patients with a prion disease. We believe that the method also has a much broader application spectrum. In the present study, we applied RT-QuIC as a pre-screening test for substances that potentially inhibit the aggregation process of the cellular PrP (PrP(C)) to proteinase (PK)-resistant PrP(res). We chose doxycycline as the test substance as it has been tested successfully in animal models and proposed in clinical studies as a therapeutic for prion diseases. The RT-QuIC-reaction was seeded with brain tissue or CSF from sCJD patients and doxycycline was then added in different concentrations as well as at different time points. In both experiments, we observed a dose- and time-dependent inhibition of the RT-QuIC seeding response and a decrease of PK resistant PrP(res) when doxycycline was added. In contrast, ampicillin or sucrose had no effect on the RT-QuIC seeding response. Our study is the first to apply RT-QuIC as a pre-screening assay for compounds inhibiting the PrP aggregation in vitro and confirms that doxycycline is an efficient inhibitor of the PrP aggregation process in RT-QuIC analysis.
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http://dx.doi.org/10.1038/srep28711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935936PMC
July 2016

Hereditary Human Prion Diseases: an Update.

Mol Neurobiol 2017 08 20;54(6):4138-4149. Epub 2016 Jun 20.

Department of Neurology, University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

Prion diseases in humans are neurodegenerative diseases which are caused by an accumulation of abnormal, misfolded cellular prion protein known as scrapie prion protein (PrP). Genetic, acquired, or spontaneous (sporadic) forms are known. Pathogenic mutations in the human prion protein gene (PRNP) have been identified in 10-15 % of CJD patients. These mutations may be single point mutations, STOP codon mutations, or insertions or deletions of octa-peptide repeats. Some non-coding mutations and new mutations in the PrP gene have been identified without clear evidence for their pathogenic significance. In the present review, we provide an updated overview of PRNP mutations, which have been documented in the literature until now, describe the change in the DNA, the family history, the pathogenicity, and the number of described cases, which has not been published in this complexity before. We also provide a description of each genetic prion disease type, present characteristic histopathological features, and the PrP isoform expression pattern of various familial/genetic prion diseases.
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http://dx.doi.org/10.1007/s12035-016-9918-yDOI Listing
August 2017

A First Tetraplex Assay for the Simultaneous Quantification of Total α-Synuclein, Tau, β-Amyloid42 and DJ-1 in Human Cerebrospinal Fluid.

PLoS One 2016 26;11(4):e0153564. Epub 2016 Apr 26.

Paracelsus-Elena-Klinik, Kassel, Germany and University Medical Center, Göttingen, Germany.

The quantification of four distinct proteins (α-synuclein, β-amyloid1-42, DJ-1, and total tau) in cerebrospinal fluid (CSF) has been proposed as a laboratory-based platform for the diagnosis of Parkinson's disease (PD) and Alzheimer's disease (AD). While there is some clinical utility in measuring these markers individually, their usage in routine clinical testing remains challenging, in part due to substantial overlap of concentrations between healthy controls and diseased subjects. In contrast, measurement of different analytes in a single sample from individual patients in parallel appears to considerably improve the accuracy of AD or PD diagnosis. Here, we report the development and initial characterization of a first, electrochemiluminescence-based multiplex immunoassay for the simultaneous quantification of all four proteins ('tetraplex') in as little as 50 μl of CSF. In analytical performance experiments, we assessed its sensitivity, spike-recovery rate, parallelism and dilution linearity as well as the intra- and inter-assay variability. Using our in-house calibrators, we recorded a lower limit of detection for α-synuclein, β-amyloid42, DJ-1, and t-tau of 1.95, 1.24, 5.63, and 4.05 pg/ml, respectively. The corresponding, linear concentration range covered >3 orders of magnitude. In diluted CSF samples (up to 1:4), spike-recovery rates ranged from a low of 55% for β-amyloid42 to a high of 98% for DJ-1. Hillslopes ranged from 1.03 to 1.30, and inter-assay variability demonstrated very high reproducibility. Our newly established tetraplex assay represents a significant technical advance for fluid-based biomarker studies in neurodegenerative disorders allowing the simultaneous measurement of four pivotal makers in single CSF specimens. It provides exceptional sensitivity, accuracy and speed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153564PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846093PMC
February 2017

Monocyte Subsets and Related Chemokines in Carotid Artery Stenosis and Ischemic Stroke.

Int J Mol Sci 2016 Mar 23;17(4):433. Epub 2016 Mar 23.

Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.

Carotid stenosis (CS) is an important cause of ischemic stroke. However, reliable markers for the purpose of identification of high-risk, so-called vulnerable carotid plaques, are still lacking. Monocyte subsets are crucial players in atherosclerosis and might also contribute to plaque rupture. In this study we, therefore, aimed to investigate the potential role of monocyte subsets and associated chemokines as clinical biomarkers for vulnerability of CS. Patients with symptomatic and asymptomatic CS (n = 21), patients with cardioembolic ischemic strokes (n = 11), and controls without any cardiovascular disorder (n = 11) were examined. Cardiovascular risk was quantified using the Essen Stroke Risk Score (ESRS). Monocyte subsets in peripheral blood were measured by quantitative flow cytometry. Plaque specimens were histologically analyzed. Furthermore, plasma levels of monocyte chemotactic protein 1 (MCP-1) and fractalkine were measured. Intermediate monocytes (Mon2) were significantly elevated in symptomatic and asymptomatic CS-patients compared to controls. Mon2 counts positively correlated with the ESRS. Moreover, stroke patients showed an elevation of Mon2 compared to controls, independent of the ESRS. MCP-1 levels were significantly higher in patients with symptomatic than in those with asymptomatic CS. Several histological criteria significantly differed between symptomatic and asymptomatic plaques. However, there was no association of monocyte subsets or chemokines with histological features of plaque vulnerability. Due to the multifactorial influence on monocyte subsets, the usability as clinical markers for plaque vulnerability seems to be limited. However, monocyte subsets may be critically involved in the pathology of CS.
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http://dx.doi.org/10.3390/ijms17040433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848889PMC
March 2016

Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study.

J Nucl Med 2016 Jun 28;57(6):900-6. Epub 2016 Jan 28.

Leipzig University, Leipzig, Germany.

Unlabelled: Training for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT).

Methods: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques.

Results: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person-trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person-trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person-trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person-trained interpreters and in 87.7% of scans for e-trained interpreters.

Conclusion: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.
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http://dx.doi.org/10.2967/jnumed.115.161927DOI Listing
June 2016

Partial-Volume Effect Correction Improves Quantitative Analysis of 18F-Florbetaben β-Amyloid PET Scans.

J Nucl Med 2016 Feb 5;57(2):198-203. Epub 2015 Nov 5.

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Unlabelled: Neocortical atrophy reduces PET signal intensity, potentially affecting the diagnostic efficacy of β-amyloid (Aβ) brain PET imaging. This study investigated whether partial-volume effect correction (PVEC), adjusting for this atrophy bias, improves the accuracy of (18)F-florbetaben Aβ PET.

Methods: We analyzed (18)F-florbetaben PET and MRI data obtained from 3 cohorts. The first was 10 patients with probable Alzheimer disease (AD) and 10 age-matched healthy controls (HCs), the second was 31 subjects who underwent in vivo imaging and postmortem histopathology for Aβ plaques, and the third was 5 subjects who underwent PET and MRI at baseline and 1 y later. The imaging data were coregistered and segmented. PVEC was performed using the voxel-based modified Müller-Gärtner method (PVELab, SPM8). From the PET data, regional and composite SUV ratios (SUVRs) with and without PVEC were obtained. In the MRI data, mesial temporal lobe atrophy was determined by the Scheltens mesial temporal atrophy scale and gray matter volumes by voxel-based morphometry.

Results: In cohort 1, PVEC increased the effect on AD-versus-HC discrimination from a Cohen d value of 1.68 to 2.0 for composite SUVRs and from 0.04 to 1.04 for mesial temporal cortex SUVRs. The PVEC-related increase in mesial temporal cortex SUVR correlated with the Scheltens score (r = 0.84, P < 0.001), and that of composite SUVR correlated with the composite gray matter volume (r = -0.75, P < 0.001). In cohort 2, PVEC increased the correlation coefficient between mesial temporal cortex SUVR and histopathology score for Aβ plaque load from 0.28 (P = 0.09) to 0.37 (P = 0.03). In cohort 3, PVEC did not affect the composite SUVR dynamics over time for the Aβ-negative subject. This finding was in contrast to the 4 Aβ-positive subjects, in 2 of whom PVEC changed the composite SUVR dynamics.

Conclusion: The influence of PVEC on (18)F-florbetaben PET data is associated with the degree of brain atrophy. Thus, PVEC increases the ability of (18)F-florbetaben PET to discriminate between AD patients and HCs, to detect Aβ plaques in the atrophic mesial temporal cortex, and potentially to evaluate changes in brain Aβ load over time. As such, the use of PVEC should be considered for quantitative (18)F-florbetaben PET scans, especially in assessing patients with brain atrophy.
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http://dx.doi.org/10.2967/jnumed.115.161893DOI Listing
February 2016

Biological confounders for the values of cerebrospinal fluid proteins in Parkinson's disease and related disorders.

J Neurochem 2016 10 10;139 Suppl 1:290-317. Epub 2016 Feb 10.

Program in Neuroscience and Division of Neurology, The Ottawa Hospital, University of Ottawa Brain & Mind Research Institute, Ottawa, Ontario, Canada.

Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and decreased levels of β-amyloid 1-42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α-synuclein (α-syn) represent a pathological hallmark of Parkinson's disease (PD). In most - but not all - studies published to date total CSF α-syn concentrations have been found to be decreased in disorders related to α-syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice. To investigate potential biological (i.e., non-technical) confounders of reported CSF levels for α-syn, Aβ42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory-based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease. Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α-synuclein (α-Syn), amyloid-β 1-42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested. This article is part of a special issue on Parkinson disease.
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http://dx.doi.org/10.1111/jnc.13390DOI Listing
October 2016

Is Cell Death Primary or Secondary in the Pathophysiology of Idiopathic Parkinson's Disease?

Biomolecules 2015 Jul 16;5(3):1467-79. Epub 2015 Jul 16.

Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Str. 40, Göttingen 37075, Germany.

Currently, the pathophysiology of idiopathic Parkinson's disease is explained by a loss of mainly dopaminergic nerve cells that causes a neurotransmitter deficiency. In the final stage of the disease, there is a marked loss of neurons in the substantia nigra. In addition, Lewy bodies can be found in some of the remaining neurons, which serve as the pathological hallmark of the disease. These Lewy bodies are composed mainly of aggregated α-synuclein, a physiological presynaptic protein. Lewy bodies were thought to be the pathophysiologically relevant form of α-synuclein because their appearance coincided with neuron loss in the substantia nigra. In consequence, neuron loss was thought to be the primary step in the neurodegeneration in Parkinson's disease. On the other hand, the clinical syndrome suggests a synaptic disorder. If α-synuclein aggregation was causally linked to the pathophysiology of disease, α-synuclein pathology should be found at the synapse. As recently demonstrated, one to two orders of magnitude more α-synuclein aggregates are present in presynaptic terminals than in Lewy bodies or Lewy neurites. Degeneration of dendritic spines associated with synaptic α-synuclein aggregates has been shown to occur in human disease. In experiments, using transgenic mice or cell cultures, mild (two- to three-fold) overexpression of α-synuclein caused an altered vesicle turnover and led to a reduction in neurotransmitter release. Different approaches linked these alterations to presynaptic aggregation of α-synuclein. These findings may fundamentally change the pathophysiological concept of Parkinson's disease: not nerve cell loss, but the synaptic dysfunction of still existing nerve cells should become the focus of attention. From recent findings, it is quite evident that the death of dopaminergic neurons is a secondary event in the pathophysiology of Parkinson's disease.
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http://dx.doi.org/10.3390/biom5031467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598759PMC
July 2015

Clinical findings and diagnosis in genetic prion diseases in Germany.

Eur J Epidemiol 2016 Feb 16;31(2):187-96. Epub 2015 Jun 16.

Department of Neurology, National Reference Center for TSE Surveillance, University Medical School, Georg-August University Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.

To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG.
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http://dx.doi.org/10.1007/s10654-015-0049-yDOI Listing
February 2016

Cellular prion protein directly interacts with and enhances lactate dehydrogenase expression under hypoxic conditions.

Exp Neurol 2015 Sep 27;271:155-67. Epub 2015 May 27.

Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany.

Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clarified, a PrP(c)-mediated neuroprotection against hypoxic/ischemic insult is intriguing. After ischemic stroke prion protein knockout mice (Prnp(0/0)) display significantly greater lesions as compared to wild-type (WT) mice. Earlier reports suggested an interaction between the glycolytic enzyme lactate dehydrogenase (LDH) and PrP(c). Since hypoxic environment enhances LDH expression levels and compels neurons to rely on lactate as an additional oxidative substrate for energy metabolism, we examined possible differences in LDH protein expression in WT and Prnp(0/0) knockout models under normoxic/hypoxic conditions in vitro and in vivo, as well as in a HEK293 cell line. While no differences are observed under normoxic conditions, LDH expression is markedly increased after 60-min and 90-min of hypoxia in WT vs. Prnp(0/0) primary cortical neurons with concurrent less hypoxia-induced damage in the former group. Likewise, cerebral ischemia significantly increases LDH levels in WT vs. Prnp(0/0) mice with accompanying smaller lesions in the WT group. HEK293 cells overexpressing PrP(c) show significantly higher LDH expression/activity following 90-min of hypoxia as compared to control cells. Moreover, a cytoplasmic co-localization of LDH and PrP(c) was recorded under both normoxic and hypoxic conditions. Interestingly, an expression of monocarboxylate transporter 1, responsible for cellular lactate uptake, increases with PrP(c)-overexpression under normoxic conditions. Our data suggest LDH as a direct PrP(c) interactor with possible physiological relevance under low oxygen conditions.
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http://dx.doi.org/10.1016/j.expneurol.2015.04.025DOI Listing
September 2015

Alpha-synuclein is associated with the synaptic vesicle apparatus in the human and rat enteric nervous system.

Brain Res 2015 Jul 18;1614:51-9. Epub 2015 Apr 18.

Department of Anatomy, Christian Albrecht´s University, Kiel, Germany.

Background And Aims: Aggregation of alpha-synuclein (a-syn) has been implicated in the development of neurodegenerative diseases including its spread from the enteric nervous system (ENS) to the brain. Physiologically, a-syn is located at the presynapse and might be involved in regulating of neurotransmission. Therefore, the aim of the study was to characterize the physiological ontogenetic and locoregional expression pattern of a-syn in the ENS and its association with the synaptic vesicle apparatus.

Material And Methods: Ontogenetic mRNA expression of a-syn and synaptophysin was determined in the rat intestine. Myenteric plexus cultures treated with glial cell line-derived neurotrophic factor (GDNF) were assessed for mRNA expression of a-syn, co-localization of a-syn with the pan-neuronal marker PGP 9.5 and the synaptic vesicle marker synaptophysin and studied by scanning electron microscopy (SEM). Human colonic specimens were subjected to co-localization studies of a-syn with synaptophysin.

Results: a-syn and synaptophysin intestinal gene expression levels were highest during early postnatal life and also detectable at adult age. a-syn was co-localized with PGP 9.5 and synaptophysin in myenteric plexus cultures and up-regulated after GDNF treatment. SEM confirmed the presence of neuronal varicosities to which a-syn was associated. Consistently, a-syn and synaptophysin showed partial co-localization in the human ENS.

Conclusions: The ontogenetic and cellular expression pattern as well as the regulation by GNDF give evidence that a-syn is physiologically associated to the synaptic vesicle apparatus. The data suggest that a-syn is involved in the regulation of synaptic plasticity in the ENS during early postnatal life and adult age.
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http://dx.doi.org/10.1016/j.brainres.2015.04.015DOI Listing
July 2015

Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: phase 3 study.

Alzheimers Dement 2015 Aug 28;11(8):964-74. Epub 2015 Mar 28.

Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.

Background: Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias.

Methods: Open-label, nonrandomized, multicenter, phase 3 study to validate the (18)F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology.

Results: Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8-100%], specificity 88.9% [95% CI 77.0-100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively.

Conclusions: Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD.

Trial Registration: ClinicalTrials.govNCT01020838.
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http://dx.doi.org/10.1016/j.jalz.2015.02.004DOI Listing
August 2015

Effect of neurostimulation on camptocormia in Parkinson's disease depends on symptom duration.

Mov Disord 2015 Mar 12;30(3):368-72. Epub 2015 Feb 12.

Prion and Dementia Research Unit, Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.

Although some reports on neurostimulation are positive, no effective treatment method for camptocormia in Parkinson's disease (PD) is known to date. We aim to identify prognostic factors for a beneficial DBS effect on camptocormia. In an observational cohort study, we investigated 25 idiopathic PD patients, who suffered additionally from camptocormia, and underwent bilateral neurostimulation of the subthalamic nucleus (STN) to improve classical PD symptoms. Using an established questionnaire, we examined deep brain stimulation (DBS) effects on camptocormia in addition to general neurostimulation effects. A beneficial neurostimulation effect on camptocormia was defined as an improvement in the bending angle of a least 50%. In 13 patients, the bending angle of camptocormia improved, in 12 patients it did not. A multifactorial analysis revealed a short duration between onset of camptocormia and start of neurostimulation to be the relevant factor for outcome. All patients with duration of camptocormia up to 1.5 years showed a beneficial effect; patients between 1.5 and ∼3 years showed mixed results, but none with a duration of more than 40 months improved except for 1 patient whose camptocormia was levodopa responsive. The bending angle was not a prognostic factor. Our data indicate that the main prognostic factor for a beneficial DBS effect on camptocormia is its short duration. As an explanation, we suggest that neurostimulation may improve camptocormia only as long as muscle pathology is limited. Our findings may help to elucidate the mode of action of neurostimulation. A prospective study is necessary.
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http://dx.doi.org/10.1002/mds.26081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132064PMC
March 2015