Publications by authors named "Peter Riederer"

212 Publications

Is Galactose a Hormetic Sugar? An Exploratory Study of the Rat Hippocampal Redox Regulatory Network.

Mol Nutr Food Res 2021 Nov 9;65(21):e2100400. Epub 2021 Sep 9.

Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.

Scope: Galactose, a ubiquitous monosaccharide with incompletely understood physiology is often exploited for inducing oxidative-stress mediated aging in animals. Recent research demonstrates that galactose can conserve cellular function during periods of starvation and prevent/alleviate cognitive deficits in a rat model of sporadic Alzheimer's disease. The present aim is to examine the acute effects of oral galactose on the redox regulatory network (RRN).

Methods And Results: Rat plasma and hippocampal RRNs are analyzed upon acute orogastric gavage of galactose (200 mg kg ). No systemic RRN disbalance is observed; however, a mild pro-oxidative shift accompanied by a paradoxical increment in tissue reductive capacity suggesting overcompensation of endogenous antioxidant systems is observed in the hippocampus. Galactose-induced increment of reductive capacity is accompanied by inflation of the hippocampal pool of nicotinamide adenine dinucleotide phosphates indicating ROS detoxification through disinhibition of the oxidative pentose phosphate pathway flux, reduced neuronal activity, and upregulation of Leloir pathway gatekeeper enzyme galactokinase-1.

Conclusion: Based on the observed findings, and in the context of previous work on galactose, a hormetic hypothesis of galactose is proposed suggesting that the protective effects may be inseparable from its pro-oxidative action at the biochemical level.
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http://dx.doi.org/10.1002/mnfr.202100400DOI Listing
November 2021

No Metagenomic Evidence of Causative Viral Pathogens in Postencephalitic Parkinsonism Following Encephalitis Lethargica.

Microorganisms 2021 Aug 12;9(8). Epub 2021 Aug 12.

Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.

Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.
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http://dx.doi.org/10.3390/microorganisms9081716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398509PMC
August 2021

Kurt Jellinger, Doyen of international neuropathology.

J Neural Transm (Vienna) 2021 10 22;128(10):1479-1480. Epub 2021 Aug 22.

Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Margarete Hoeppel-Platz 1, 97080, Wuerzburg, Germany.

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http://dx.doi.org/10.1007/s00702-021-02397-xDOI Listing
October 2021

Correction to: Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses.

J Neural Transm (Vienna) 2021 Jun 19. Epub 2021 Jun 19.

Institut für Virologie und Immunbiologie, Universität Würzburg, Versbacherstraße Straße 7, 97078, Würzburg, Germany.

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http://dx.doi.org/10.1007/s00702-021-02356-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214065PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration.

Cells 2021 04 12;10(4). Epub 2021 Apr 12.

Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Margarete-Höppel-Platz 1, 97080 Würzburg, Germany.

Symptomatic treatments are available for Parkinson's disease and Alzheimer's disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.
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http://dx.doi.org/10.3390/cells10040873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069143PMC
April 2021

The Nigral Coup in Parkinson's Disease by α-Synuclein and Its Associated Rebels.

Cells 2021 03 9;10(3). Epub 2021 Mar 9.

Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy Margarete-Hoeppel-Platz 1, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.

The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.
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http://dx.doi.org/10.3390/cells10030598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000327PMC
March 2021

Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials.

J Neural Transm (Vienna) 2021 02 23;128(2):127-169. Epub 2021 Feb 23.

Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.

The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington's disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine's therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.
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http://dx.doi.org/10.1007/s00702-021-02306-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901515PMC
February 2021

Proteomic Characterization of Synaptosomes from Human Substantia Nigra Indicates Altered Mitochondrial Translation in Parkinson's Disease.

Cells 2020 12 2;9(12). Epub 2020 Dec 2.

Medizinisches Proteom-Center, Medical Faculty, Ruhr-University Bochum, 44801 Bochum, Germany.

The pathological hallmark of Parkinson's disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was performed. Therefore, synaptosomes were isolated by density gradient centrifugation from SNpc tissue of individuals at advanced PD stages (N = 5) as well as control subjects free of pathology (N = 5) followed by mass spectrometry-based analysis. In total, 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome comprised all proteins expressed within the synapses without regard to data analysis software, gender, age, or disease. The differential analysis between control subjects and PD cases revealed that CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, neurolysin, and Methionine-tRNA ligase (MARS2) were underrepresented in PD suggesting an alteration in mitochondrial translation within synaptosomes.
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http://dx.doi.org/10.3390/cells9122580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761546PMC
December 2020

Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses.

J Neural Transm (Vienna) 2020 09 28;127(9):1217-1228. Epub 2020 Jul 28.

Institut für Virologie und Immunbiologie, Universität Würzburg, Versbacherstraße Straße 7, 97078, Würzburg, Germany.

While there is abounding literature on virus-induced pathology in general and coronavirus in particular, recent evidence accumulates showing distinct and deleterious brain affection. As the respiratory tract connects to the brain without protection of the blood-brain barrier, SARS-CoV-2 might in the early invasive phase attack the cardiorespiratory centres located in the medulla/pons areas, giving rise to disturbances of respiration and cardiac problems. Furthermore, brainstem regions are at risk to lose their functional integrity. Therefore, long-term neurological as well as psychiatric symptomatology and eventual respective disorders cannot be excluded as evidenced from influenza-A triggered post-encephalitic Parkinsonism and HIV-1 triggered AIDS-dementia complex. From the available evidences for coronavirus-induced brain pathology, this review concludes a number of unmet needs for further research strategies like human postmortem brain analyses. SARS-CoV-2 mirroring experimental animal brain studies, characterization of time-dependent and region-dependent spreading behaviours of coronaviruses, enlightening of pathological mechanisms after coronavirus infection using long-term animal models and clinical observations of patients having had COVID-19 infection are calling to develop both protective strategies and drug discoveries to avoid early and late coronavirus-induced functional brain disturbances, symptoms and eventually disorders. To fight SARS-CoV-2, it is an urgent need to enforce clinical, molecular biological, neurochemical and genetic research including brain-related studies on a worldwide harmonized basis.
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http://dx.doi.org/10.1007/s00702-020-02230-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386201PMC
September 2020

[Structure and efferences of the substantia nigra pars compacta in Parkinson's disease].

Fortschr Neurol Psychiatr 2020 Sep 12;88(9):591-599. Epub 2020 May 12.

Krankenhaus Lindenbrunn, Coppenbrügge.

There is consensus that the neuropathological characteristic of Parkinson's disease (PD) is the neuronal cell loss of the substantia nigra pars compacta (SNc) in connection with a Lewy pathology. The transsynaptic spread of Lewy pathology is considered essential in PD pathogenesis. Therefore, the knowledge of pre-existing neuroanatomical connections of the SNc is essential. We describe recent animal experiments on the afferent and efferent projections of the SNc and discuss the evidence for and against the sequential transsynaptic spread of Lewy pathology in the pathogenesis of PD.
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http://dx.doi.org/10.1055/a-1149-9280DOI Listing
September 2020

Creation of a gene expression classifier for predicting Parkinson's disease rate of progression.

J Neural Transm (Vienna) 2020 05 8;127(5):755-762. Epub 2020 May 8.

BioShai Ltd., 1 Ha-Tsmikha St., Yokneam, Israel.

Parkinson's disease (PD) etiology is heterogeneous, genetic, and multi-factorial, resulting in a varied disease from a mild slow progression to a more severe rapid progression. Prognostic information on the nature of the patient's disease at diagnosis aids the physician in counseling patients on treatment options and life planning. In a cohort of PD patients from the PPMI study, the relative gene expression levels of SKP1A, UBE2K, ALDH1A1, PSMC4, HSPA8 and LAMB2 were measured in baseline blood samples by real-time quantitative PCR. At baseline PD patients were up to 2 years from diagnosis, H&Y scale ≤ 2 and PD treatment naïve. PD-Prediction algorithm comprised of ALDH1A1, LAMB2, UBE2K, SKP1A and age was created by logistic regression for predicting progression to ≤ 70% Modified Schwab and England Activities of Daily Living (S&E-ADL). In relation to patients negative for PD-Prediction (n = 180), patients positive (n = 30) for Cutoff-1 (at 82% specificity, 80.0% sensitivity) had positive hazard ratio (HR+) of 10.6 (95% CI, 2.2-50.1), and positive (n = 23) for Cutoff-2 (at 93% specificity, 47% sensitivity) had HR+ of 17.1 (95% CI, 3.2-89.9) to progress to ≤ 70% S&E-ADL within 3 years (P value < 0.0001). Likewise, patients positive for PD-Prediction Cutoff-1 (n = 49) had HR+ 4.3 (95% CI, 1.6-11.6) for faster time to H&Y 3 in relation to patients negative (n = 170) for PD-Prediction (P value = 0.0002). Our findings show an algorithm that seems to predict fast PD progression and may potentially be used as a tool to assist the physician in choosing an optimal treatment plan, improving the patient's quality of life and overall health outcome.
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http://dx.doi.org/10.1007/s00702-020-02194-yDOI Listing
May 2020

The role of alpha-synuclein as ferrireductase in neurodegeneration associated with Parkinson's disease.

J Neural Transm (Vienna) 2020 05 21;127(5):749-754. Epub 2020 Apr 21.

University Hospital Wuerzburg, Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy Margarete-Hoeppel-Platz 1, 97080, Wuerzburg, Germany.

Misfolding of the protein α-synuclein contributes to the formation of the intracellular inclusion, Lewy bodies. Although these structures are not exclusive to Parkinson's disease, nevertheless, their presence in the substantia nigra is mandatory for the pathological diagnosis of the disorder. Therefore, there must be a focus on the pathological mechanisms responsible for Lewy body generation. Recent studies have suggested that α-synuclein has the potential to operate as the enzyme ferrireductase. Perhaps in the early diseased state, overexpression or mutation of alpha-synuclein/ferrireductase invokes the dyshomeostasis of iron (III)/(II) only, while in advanced stages, accumulation of iron in particular areas of the brain follows. Furthermore, the loss of an important iron chelator, neuromelanin (due to dopaminergic neuronal death), may then result in the release and increase in unbound free iron. Iron could generate reactive oxygen species, which could instigate a torrent of cellular deleterious processes. In addition, loss of energy supply may contribute to the alteration in activity of enzymes involved in the mitochondrial respiratory chain and would, therefore, confer a vulnerability to the dopaminergic neurons in the substantia nigra. Therefore, the ferrireductase alpha-synuclein may hold the key for major pathology of Parkinson's disease. In conclusion, we hypothesize that environmentally or genetically overexpressed and/or mutated α-synuclein/ferrireductase causes iron dyshomeostasis without increase of free iron concentration in the early phases of PD, while increased iron concentration accompanied by iron dyshomeostasis is a marker for progressed PD stages. It is essential to elucidate these degenerative mechanisms, so as to provide effective therapeutic treatment to halt or delay the progression of the illness already in the early phase of PD. The development of iron chelators seems to be a reasonable approach.
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http://dx.doi.org/10.1007/s00702-020-02192-0DOI Listing
May 2020

Gerald Stern (1930-2018).

Authors:
Peter Riederer

J Neural Transm (Vienna) 2020 May;127(5):699

Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Margarete Hoeppel‑Platz 1, 97080, Wuerzburg, Germany.

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http://dx.doi.org/10.1007/s00702-020-02176-0DOI Listing
May 2020

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease.

J Neural Transm (Vienna) 2020 02 6;127(2):231-250. Epub 2020 Feb 6.

Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common chronic neurodegenerative disorders, characterized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and co-expression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder.
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http://dx.doi.org/10.1007/s00702-020-02152-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035309PMC
February 2020

Prof. Dr. Moussa B.H. Youdim: an appreciation on the occasion of his 80th birthday.

Authors:
Peter Riederer

J Neural Transm (Vienna) 2020 02;127(2):117-118

University Hospital Wuerzburg, Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, Margarete Hoeppel-Platz 1, 97080, Wuerzburg, Germany.

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http://dx.doi.org/10.1007/s00702-020-02153-7DOI Listing
February 2020

Selegiline: a molecule with innovative potential.

J Neural Transm (Vienna) 2020 05 27;127(5):831-842. Epub 2019 Sep 27.

Department of Pharmacodynamics, Semmelweis University, Nagyvárad tér 4, 1089, Budapest, Hungary.

Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on-off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson's disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors.
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http://dx.doi.org/10.1007/s00702-019-02082-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242272PMC
May 2020

Anxiety and Stress - Translational Perspectives.

Authors:
Peter Riederer

J Neural Transm (Vienna) 2019 Sep;126(9):1115

Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie, Würzburg, Germany.

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http://dx.doi.org/10.1007/s00702-019-02063-3DOI Listing
September 2019

α-Synuclein in Parkinson's disease: causal or bystander?

J Neural Transm (Vienna) 2019 07 25;126(7):815-840. Epub 2019 Jun 25.

Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.

Parkinson's disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.
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http://dx.doi.org/10.1007/s00702-019-02025-9DOI Listing
July 2019

Melanin and Neuromelanin Fluorescence Studies Focusing on Parkinson's Disease and Its Inherent Risk for Melanoma.

Cells 2019 06 15;8(6). Epub 2019 Jun 15.

Institute of Pathology, Department of Neuropathology, University of Wuerzburg, Comprehensive Cancer Center (CCC) Mainfranken Wuerzburg, 97080 Wuerzburg, Germany.

Parkinson's disease is associated with an increased risk of melanoma (and vice versa). Several hypotheses underline this link, such as pathways affecting both melanin and neuromelanin. For the first time, the fluorescence of melanin and neuromelanin is selectively accessible using a new method of nonlinear spectroscopy, based on a stepwise two-photon excitation. Cutaneous pigmentation and postmortem neuromelanin of Parkinson patients were characterized by fluorescence spectra and compared with controls. Spectral differences could not be documented, implying that there is neither a Parkinson fingerprint in cutaneous melanin spectra nor a melanin-associated fingerprint indicating an increased melanoma risk. Our measurements suggest that Parkinson's disease occurs without a configuration change of neuromelanin. However, Parkinson patients displayed the same dermatofluorescence spectroscopic fingerprint of a local malignant transformation as controls. This is the first comparative retrospective fluorescence analysis of cutaneous melanin and postmortem neuromelanin based on nonlinear spectroscopy in patients with Parkinson's disease and controls, and this method is a very suitable diagnostic tool for melanoma screening and early detection in Parkinson patients. Our results suggest a non-pigmentary pathway as the main link between Parkinson's disease and melanoma, and they do not rule out the melanocortin-1-receptor gene as an additional bridge between both diseases.
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http://dx.doi.org/10.3390/cells8060592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627191PMC
June 2019

Guidelines for the standardized collection of blood-based biomarkers in psychiatry: Steps for laboratory validity - a consensus of the Biomarkers Task Force from the WFSBP.

World J Biol Psychiatry 2019 06 25;20(5):340-351. Epub 2019 Mar 25.

s Department of Psychiatry , Melbourne Medical School, University of Melbourne , Melbourne , VIC , Australia.

Recently, there has been a major shift in the field of psychiatry towards the exploration of complex relationships between blood-based biomarkers and the pathophysiology of psychiatric and neuropsychiatric disorders. However, issues with study reproducibility, validity and reliability have hindered progress towards the identification of clinically relevant biomarkers for psychiatry. The achievement of laboratory validity is a crucial first step for the posterior development of clinical validity. There is evidence that the variability observed in blood-based research studies may be minimised with the implementation of standardised pre-analytical methods and uniform clinical protocols (i.e., pre-venipuncture). It has been documented that errors made in the pre-analytical phase account for 46-68.2% of laboratory testing errors. Thus, standardising clinical assessment, ethical procedures and pre-analytical phase of clinical research is essential for the reproducibility, validity and reliability of blood marker assessment, and reducing the risk of invalid test results. Various other areas of research have already moved towards guidelines for the standardised collection of blood-based biomarkers. Here we aim to provide a set of guidelines that we believe would improve biomarker research: (1) pre-venipuncture information and documentation, (2) ethics of participant consent and (3) pre-analytical methods. Ultimately, we hope this will assist study planning and will improve data comparison across studies allowing for the discovery of biomarkers in psychiatry with both laboratorial and clinical validity.
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http://dx.doi.org/10.1080/15622975.2019.1574024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728424PMC
June 2019

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice.

Neuropharmacology 2019 04 17;148:50-67. Epub 2018 Dec 17.

Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, HR-10 000, Zagreb, Croatia; Research Centre of Excellence of Fundamental, Clinical and Translational Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 12, HR-10 000, Zagreb, Croatia. Electronic address:

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5- (5M) and 10- (10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid β1-42 (sAβ1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAβ1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.
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http://dx.doi.org/10.1016/j.neuropharm.2018.12.018DOI Listing
April 2019

Astrocyte- and Microglia-Specific Mitochondrial DNA Deletions Levels in Sporadic Alzheimer's Disease.

J Alzheimers Dis 2019 ;67(1):149-157

Institute of Pathology, Department of Neuropathology, University of Wuerzburg, Germany.

Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage with an age-dependent accumulation. In a previous study, we analyzed mtDNA levels in diverse neuronal cell types in order to unravel the impact of oxidative stress in brains of AD patients. The aim of this study was to identify possible correlations between mtDNA deletion levels of selected astrocytes and microglia from three brain regions with different vulnerability to AD pathology and different stages of disease compared to controls. Our results reflect a higher vulnerability of hippocampal astrocytes and microglia to oxidative stress compared to other brain regions, such as cerebellum and brainstem.
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http://dx.doi.org/10.3233/JAD-180661DOI Listing
March 2020

[Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP].

Nervenarzt 2019 May;90(5):463-471

Klinische Pharmakologie, Institut AGATE, Pentling, und Klinische Pharmakologie am Lehrstuhl für Pharmakologie und Toxikologie, Universität Regensburg, Regensburg, Deutschland.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology.
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http://dx.doi.org/10.1007/s00115-018-0643-9DOI Listing
May 2019

Introduction to the special issue on monoamine oxidase A and B: eternally enigmatic isoenzymes.

J Neural Transm (Vienna) 2018 11 26;125(11):1517-1518. Epub 2018 Sep 26.

Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi, 320-0195, Japan.

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http://dx.doi.org/10.1007/s00702-018-1920-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467517PMC
November 2018

Streptozotocin Impairs Proliferation and Differentiation of Adult Hippocampal Neural Stem Cells -Correlation With Alterations in the Expression of Proteins Associated With the Insulin System.

Front Aging Neurosci 2018 18;10:145. Epub 2018 May 18.

Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.

Rats intracerebroventricularily (icv) treated with streptozotocin (STZ), shown to generate an insulin resistant brain state, were used as an animal model for the sporadic form of Alzheimer's disease (sAD). Previously, we showed in an study that 3 months after STZ icv treatment hippocampal adult neurogenesis (AN) is impaired. In the present study, we examined the effects of STZ on isolated adult hippocampal neural stem cells (NSCs) using an approach. We revealed that 2.5 mM STZ inhibits the proliferation of NSCs as indicated by reduced number and size of neurospheres as well as by less BrdU-immunoreactive NSCs. Double immunofluorescence stainings of NSCs already being triggered to start with their differentiation showed that STZ primarily impairs the generation of new neurons, but not of astrocytes. For revealing mechanisms possibly involved in mediating STZ effects we analyzed expression levels of insulin/glucose system-related molecules such as the glucose transporter (GLUT) 1 and 3, the insulin receptor (IR) and the insulin-like growth factor (IGF) 1 receptor. Applying quantitative Real time-PCR (qRT-PCR) and immunofluorescence stainings we showed that STZ exerts its strongest effects on GLUT3 expression, as GLUT3 mRNA levels were found to be reduced in NSCs, and less GLUT3-immunoreactive NSCs as well as differentiating cells were detected after STZ treatment. These findings suggest that cultured NSCs are a good model for developing new strategies to treat nerve cell loss in AD and other degenerative disorders.
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http://dx.doi.org/10.3389/fnagi.2018.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968103PMC
May 2018

Monoamine oxidase-B inhibitors in the treatment of Parkinson's disease: clinical-pharmacological aspects.

J Neural Transm (Vienna) 2018 11 22;125(11):1751-1757. Epub 2018 Mar 22.

Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Berlin, Germany.

This invited narrative review emphasizes the role of MAO-B inhibition in the drug portfolio for dopamine substitution in patients with Parkinson's disease. Neuronal and glial MAO-B inhibition contributes to more stable levels of dopamine and other biogenic amines in the synaptic cleft. Accordingly, symptomatic effects of MAO-B inhibition for a limited amelioration of impaired motor behaviour and wearing-off phenomena in patients with Parkinson's disease are well proven, even when MAO-B inhibitors are only applied together with dopamine agonists. Delay of disease progression by MAO-B inhibition is under debate despite positive experimental findings. This discussion does not consider, that levodopa, respectively, dopamine agonists, are substrates, respectively, inhibitors of the ABCB1 (P-gp, MDR1, and CD243) transporter system. It supports toxin efflux over the blood-brain barrier. ABCB1 transporters have a limited capacity. MAO-B inhibitors do not weaken it. Treatment with MAO-B inhibitors is advantageous as it enables sparing of dopamine agonist and levodopa dosing.
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http://dx.doi.org/10.1007/s00702-018-1876-2DOI Listing
November 2018

Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimer's disease.

Neuropharmacology 2018 06 28;135:48-62. Epub 2018 Feb 28.

Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, HR-10 000 Zagreb, Croatia; Research Centre of Excellence for Fundamental Clinical and Translational Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 12, HR-10 000 Zagreb, Croatia. Electronic address:

Insulin resistance and metabolic dysfunction in the brain are considered to be the pathophysiological core of sporadic Alzheimer's disease (sAD). In line with that fact, nutrients that could have therapeutic effects at this level have been investigated as possible targets in AD therapy. Galactose, an epimer of glucose, may serve as an alternative source of energy, and given orally may stimulate secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Our preliminary research indicated that oral galactose might prevent development of memory impairment in a rat model of sAD generated by intracerebroventricular administration of streptozotocin (STZ-icv). Here, we explored whether chronic oral galactose treatment could have beneficial effects on cognitive deficits already manifested at the time of initiation of galactose treatment in adult STZ-icv rats (treatment initiated 1 month after STZ-icv injection). The results clearly show that a 2-month exposure to oral galactose (200 mg/kg/day administered in a drink ad libitum) normalises impaired learning and memory functions. Memory improvement was accompanied by an improvement in brain glucose hypometabolism measured by fluorodeoxyglucose-positron emission tomography neuroimaging and by increments in active GLP-1 plasma levels as well as by an increased expression of GLP-1 receptors in the hippocampus and hypothalamus. Our findings provide strong evidence of beneficial effects of oral galactose treatment in the STZ-icv rat model of sAD and present possible underlying mechanisms including both direct effects of galactose within the brain and indirect GLP-1-induced neuroprotective effects that might open a new, dietary-based strategy in sAD treatment.
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http://dx.doi.org/10.1016/j.neuropharm.2018.02.027DOI Listing
June 2018
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