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Background: With the increasing development of disease-modifying causative treatment, the importance of early diagnosis and detection of asymptomatic or oligosymptomatic early stages of neurodegenerative diseases is increasing. Objective: Presentation of early stages of neurodegenerative diseases, diagnostic procedures for the early detection and possible treatment consequences. Material and methods: Selective literature search, discussion of basic research and expert recommendations. Results: Many neurodegenerative diseases have a prodromal phase preceding the manifest disease that can be diagnosed with current criteria. In this prodromal phase, those affected are often oligosymptomatic but in some cases can already be identified using biomarkers. These developments are already taken into account in diagnostic criteria for some of these prodromal phases. The prodromal phase, in turn, is preceded by an asymptomatic phase which, however, already shows molecular changes and can be identified by biomarkers in some diseases. The early identification and stratification of patients is particularly important when planning studies for disease-modifying treatment, and biomarkers are already being used in clinical trials for this purpose. Discussion: Biomarker-based identification of individuals in the prodromal phase of neurodegenerative diseases is already possible for some entities. People who show the first signs of a neurodegenerative disease can be referred to centers for clinical trials and observational studies. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson's disease (PD) leads to cognitive impairment. Widely used methods to assess cognition are the Clock Drawing Test (CDT) and the Mini-Mental State Examination (MMSE). Another option is the Vienna Visuo-Constructional Test 3.0 Screening (VVT-3.0). We studied the neuropsychological and demographic data of 45 healthy controls (HC) and 64 individuals diagnosed with PD (total N = 109) and compared the validity of each test by using receiver-operator characteristic (ROC) curves and logistic regression analyses. The ROC analyses of PD yielded areas under the curve (AUC) of 0.68 using VVT-3.0, 0.74 using MMSE, and 0.72 using CDT as predictors, respectively. The VVT-3.0 shows comparable validity to the more established measurement tools and MMSE und CDT and is easy to administer in a clinical setting. [ABSTRACT FROM AUTHOR]

Background: Visual hallucinations (VH) have mainly been considered as late symptoms of Parkinson's disease (PD); however, minor forms of VH also occur in early stages of the disease. Initially dopaminergic overstimulation was discussed as the cause and later on VH have been considered as an early red flag of dementia in PD. Objective: The present study analyzed whether the pathophysiological concept of VH has been enlarged in recent years. Material and methods: Clinical, pharmacological, neuropathological as well as functional magnetic resonance imaging studies dealing with VH were reviewed. A systematic classification in monomodal and multimodal models of VH is proposed. The applicability to various forms of VH and various triggering situations is critically examined. Results: Reduction of the visual information input, erroneous visual processing, attention deficits, and dysfunctional connectivity between various cerebral networks have been shown. There is partial overlapping with the Lhermitte syndrome and the Charles Bonnet syndrome. No model is able to fully explain all VH variants. Not all VH have the same pathogenesis and the same poor prognosis. Conclusion: The chain of causes underlying VH is complex and can vary from patient to patient. So far the therapeutic applications are largely unexplored; however, there is preliminary evidence that beside adjustment of the medication, improvement of visual acuity, active involvement of the partner, and possibly, individually adaptable coping strategies could be successfully implemented. [ABSTRACT FROM AUTHOR]

The key aspect of the classification of neurodegenerative diseases is the histopathological detection of certain proteins in the brain. The various disease entities are distinguished with respect to the type of detected protein and with respect to the configuration and localization of the corresponding protein aggregates. Aggregates of alpha-synuclein (ASYN) are the defining hallmark of several neurodegenerative disorders termed synucleinopathies. The most well-known diseases in this spectrum are Parkinson's disease (PD) with neuronal detection of Lewy bodies, dementia with Lewy bodies (DLB), with additional detection of beta-amyloid and multiple system atrophy (MSA), where ASYN aggregates are found in glia cells in the form of Papp-Lantos inclusions. ASYN has been identified as a key target for the development of therapeutic approaches to synucleinopathies given its central role in the pathophysiology of these diseases. Current treatment strategies can be roughly classified into six groups: 1) lowering ASYN expression (antisense therapy), 2) inhibition of formation of toxic ASYN aggregates (aggregation inhibitors, chelators), 3) dissolving or removal of intracellular or extracellular toxic AYSN aggregates (active and passive immunotherapy, aggregation inhibitors), 4) enhancement of cellular clearance mechanisms (autophagy, lysosomal microphagy) for removal of toxic forms of alpha-synuclein, 5) modulation of neuroinflammatory processes and 6) neuroprotective strategies. This article summarizes the current therapeutic approaches and sheds light on promising future treatment approaches. [ABSTRACT FROM AUTHOR]

Dopamin (DA) ist das wichtigste und häufigste Catecholamin im Gehirn und zugleich Vorläufer anderer Neurotransmitter. Die Degeneration von Neuronen des Nigrostriatums (Substantia nigra, Pars compacta) bei Parkinson‐Kranken ist die am besten untersuchte Verknüpfung zwischen Neurotransmission und Neuropathologie durch DA. Catecholamine sind reaktive Moleküle, für die es komplexe Kontroll‐ und Transportsysteme gibt. Unter normalen Bedingungen werden kleine Mengen cytosolischen Dopamins unter Melanisierung von Peptiden und Proteinen schrittweise zu Neuromelanin umgewandelt. Überschießendes cytosolisches oder extraneuronales DA kann allerdings unselektive Proteinmodifikationen auslösen. Die dabei ablaufende Oxidation von DA zu Chinonverbindungen hängt von der Gegenwart redoxaktiver Übergangsmetallionen wie Eisen und Kupfer ab. Auch andere oxidierte DA‐Metaboliten sind wahrscheinlich an posttranslationalen Proteinmodifikationen beteiligt. Die Protein‐Chinonmodifikation ist also ein heterogener Vorgang mit verschiedenen DA‐Abkömmlingen, die Struktur‐ und Konformationsänderungen von Proteinen hervorrufen; dies kann zur Aggregation und Inaktivierung der modifizierten Proteine führen. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress induced by reactive oxygen species (ROS) is one of the critical factors that involves in the pathogenesis and progression of many diseases. However, lack of proper techniques to scavenge ROS depending on their cellular localization limits a thorough understanding of the pathological effects of ROS. Here, we demonstrate the selective scavenging of mitochondrial, intracellular, and extracellular ROS using three different types of ceria nanoparticles (NPs), and its application to treat Parkinson's disease (PD). Our data show that scavenging intracellular or mitochondrial ROS inhibits the microglial activation and lipid peroxidation, while protecting the tyrosine hydroxylase (TH) in the striata of PD model mice. These results indicate the essential roles of intracellular and mitochondrial ROS in the progression of PD. We anticipate that our ceria NP systems will serve as a useful tool for elucidating the functions of various ROS in diseases. [ABSTRACT FROM AUTHOR]

Abstract: Small aggregates of misfolded proteins play a key role in neurodegenerative disorders. Such species have proved difficult to study due to the lack of suitable methods capable of resolving these heterogeneous aggregates, which are smaller than the optical diffraction limit. We demonstrate here an all‐optical fluorescence microscopy method to characterise the structure of individual protein aggregates based on the fluorescence anisotropy of dyes such as thioflavin‐T, and show that this technology is capable of studying oligomers in human biofluids such as cerebrospinal fluid. We first investigated in vitro the structural changes in individual oligomers formed during the aggregation of recombinant α‐synuclein. By studying the diffraction‐limited aggregates we directly evaluated their structural conversion and correlated this with the potential of aggregates to disrupt lipid bilayers. We finally characterised the structural features of aggregates present in cerebrospinal fluid of Parkinson's disease patients and age‐matched healthy controls. [ABSTRACT FROM AUTHOR]

Abstract: Structural variation of α‐synuclein (αSyn) fibrils has been linked to the diverse etiologies of synucleinopathies. However, little is known about what specific mechanism provides αSyn fibrils with pathologic features. Herein, we demonstrate Cu(II)‐based supramolecular approach for unraveling the formation process of pathogenic αSyn fibrils and its application in a neurotoxic mechanism study. The conformation of αSyn monomer was strained by macrochelation with Cu(II), thereby disrupting the fibril elongation while promoting its nucleation. This non‐canonical process formed shortened, β‐sheet enriched αSyn fibrils (<0.2 μm) that were rapidly transmitted and accumulated to neuronal cells, causing neuronal cell death, in sharp contrast to typical αSyn fibrils (ca. 1 μm). Our approach provided the supramolecular basis for the formation of pathogenic fibrils through physiological factors, such as brain Cu(II). [ABSTRACT FROM AUTHOR]

Systemic amyloidosis is caused by the misfolding of a circulating amyloid precursor protein and the deposition of amyloid fibrils in multiple organs. Chemical and biophysical analysis of amyloid fibrils from human AL and murine AA amyloidosis reveal the same fibril morphologies in different tissues or organs of one patient or diseased animal. The observed structural similarities concerned the fibril morphology, the fibril protein primary and secondary structures, the presence of post-translational modifications and, in case of the AL fibrils, the partially folded characteristics of the polypeptide chain within the fibril. Our data imply for both analyzed forms of amyloidosis that the pathways of protein misfolding are systemically conserved; that is, they follow the same rules irrespective of where inside one body fibrils are formed or accumulated. [ABSTRACT FROM AUTHOR]

Parkinson's disease has long been known to involve the loss of dopaminergic neurons in the substantia nigra and the coincidental appearance of Lewy bodies containing oligomerized forms of α-synuclein. The 'catecholaldehyde hypothesis' posits a causal link between these two central pathologies mediated by 3,4-dihydroxyphenylacetaldehyde (DOPAL), the most toxic dopamine metabolite. Here we determine the structure of the dominant product in reactions between DOPAL and α-synuclein, a dicatechol pyrrole lysine adduct. This novel modification results from the addition of two DOPAL molecules to the Lys sidechain amine through their aldehyde moieties and the formation of a new carbon-carbon bond between their alkyl chains to generate a pyrrole ring. The product is detectable at low concentrations of DOPAL and its discovery should provide a valuable chemical basis for future studies of DOPAL-induced crosslinking of α-synuclein. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic neurodegenerative disease which is characterized by the cardinal symptoms akinesia, rigidity, rest tremor and postural instability. Besides PD features also a wide range of non-motor symptoms. Physical activity is recommended for all stages of PD and may hypothetically even have a positive influence on the course of the disease. Rehabilitative treatments become increasingly important in the advanced stage of the disease and include mainly physiotherapy, occupational therapy and speech therapy. Neurorehabilitation is arguably most important for the treatment of axial symptoms such as freezing, hypophonia, dysphagia, postural instability and postural disturbances that respond poorly to drug therapy. This article provides an overview of current developments in the field of neurorehabilitation in PD. [ABSTRACT FROM AUTHOR]

The design of the first dual-purpose activity-based probe of monoamine oxidase B (MAO-B) is reported. This probe is highly selective towards MAO-B, even at high MAO-A expression levels, and could sensitively report endogenous MAO-B activities by both in situ proteome profiling and live-cell bioimaging. With a built-in imaging module as part of the probe design, the probe was able to accomplish what all previously reported MAO-B imaging probes failed to do thus far: the live-cell imaging of MAO-B activities without encountering diffusion problems. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation has become an established therapy for various movement disorders but questions regarding its long-term effectiveness remain. Objectives: This study was designed to evaluate the long-term effectiveness of deep brain stimulation for movement disorders refractory to current medical therapy based on published long-term studies. Methods: A review was carried out of all available studies with a minimum follow-up of 5 years of patients with deep brain stimulation for Parkinson's disease, essential tremor and dystonia. Results: A total of 23 studies of deep brain stimulation for Parkinson's disease, 7 studies for essential tremor and 14 studies for dystonia were included. After a follow-up of at least 5 years, improvement of current motor scores could be observed in Parkinson's disease (subthalamic stimulation) by approximately 40 %, by approximately 50 % for essential tremor and by 60 % for dystonia (mostly generalized forms). In Parkinson's disease, motor improvements tend to diminish over time due to progression of dysarthria, axial symptoms and other motor features less responsive to deep brain stimulation. Non-dopaminergic symptoms tend to progress and lessen the positive effects on the quality of life. There appears to be a subgroup of patients with essential tremor who show decreasing effectiveness of deep brain stimulation, probably related to disease progression. Currently, no single prognostic marker has been established to identify this subgroup. Most forms of secondary dystonia seem to respond more variably than primary generalized dystonia. Conclusion: Deep brain stimulation remains a relatively safe and effective therapy in carefully selected patients after long-term follow-up according to published data, although disease progression and other disease-specific factors seem to modify its effectiveness over time. [ABSTRACT FROM AUTHOR]

Rapid eye movement (REM) sleep behavior disorder (RBD) is defined as a parasomnia characterized by loss of REM sleep-associated atonia and the presence of motor activity during dreaming typically presenting with an aggressive dream content. Epidemiological data on the prevalence of RBD are insufficient but it can be idiopathic or symptomatic. A video-audio polysomnography is essential for diagnosis. Clonazepam and melatonin are available as pharmaceutical treatment. Recent studies demonstrated that individuals suffering from idiopathic RBD carry a high specific risk (up to 80 %) for developing a neurodegenerative disorder of the α-synucleinopathy type (e.g. Parkinson's disease, dementia with Lewy bodies and multiple system atrophy) within 10-20 years. The current article provides a short overview of symptoms, epidemiology, pathophysiology, diagnosis and therapy of RBD. [ABSTRACT FROM AUTHOR]

lthough the mechanisms which cause Parkinson's disease (PD) are still poorly understood, research on monogenic forms of PD have demonstrated a significant genetic contribution to its etiology. Monogenic forms of PD only account for a minority of cases but offer a unique avenue of research into the pathogenesis of PD. In this article the potential of structural and functional neuroimaging in monogenic forms to provide general insights into the pathophysiology of PD, including the more common idiopathic disease is reviewed. The review has a particular focus on neuroimaging of non-manifesting mutation carriers to study functional and structural changes in the brain at the asymptomatic stage of PD. This line of research has started to provide valuable insights into how the brain can cope with a latent nigrostriatal dopaminergic deficit and thereby delay the clinical onset of PD. [ABSTRACT FROM AUTHOR]

Immunotherapeutic approaches for treating Alzheimer's disease were first described in 1999. A clinical trial using an active immunization with Aβ1-42 was initiated shortly thereafter, but it was halted early because of serious safety issues (acute meningoencephalitis in 6% of the treated patients). Despite this drawback, encouraging data from preclinical and clinical data were available, prompting researchers to seek alternative approaches for safer active and passive immunization. Currently, several passive and active immunotherapeutic approaches are being tested in clinical trials. However, our understanding of the mechanisms behind immunization in neurodegenerative disorders is still incomplete. In this review we present the current status of the different approaches in relation to Alzheimer's disease as well as to other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]