Role of dopamine agonists in Parkinson's disease therapy.

Dopamine agonists are an important component of Parkinson's therapy. When weighing up the various therapy options, therapy with levodopa has recently been increasingly preferred due to its stronger efficacy and the ostensibly lower rate of side effects. The advantage of the lower incidence of motor complications during therapy with dopamine agonists was neglected. The occurrence of side effects can be explained by the different receptor affinity to the individual dopaminergic and non-dopaminergic receptors of the individual dopamine agonists. However, the different affinity to individual receptors also explains the different effect on individual Parkinson symptoms and can, therefore, contribute to a targeted use of the different dopamine agonists. Since comparative studies on the differential effect of dopamine agonists have only been conducted for individual substances, empirical knowledge of the differential effect is of great importance. Therefore, the guidelines for the treatment of Parkinson's disease do not consider the differential effect of the dopamine agonists. The historical consideration of dopamine agonists within Parkinson's therapy deserves special attention to be able to classify the current discussion about the significance of dopamine agonists.

Disease modification in Parkinsonism: obstacles and ways forward.

To date, the diagnoses of Parkinson syndromes are based on clinical examination. Therefore, these specific diagnoses are made, when the neuropathological process is already advanced. However, disease modification or neuroprotection, is considered to be most effective before marked neurodegeneration has occurred. In recent years, early clinical or prodromal stages of Parkinson syndromes came into focus. Moreover, subtypes of distinct diseases will allow predictions of the individual course of the diseases more precisely. Thereby, patients will be enrolled into clinical trials with more specific disease entities and endpoints. Furthermore, novel fluid and imaging biomarkers that allow biochemical diagnoses are under development. These will lead to earlier diagnoses and earlier therapy in the future as consequence. Furthermore, therapeutic approaches will take the underlying neuropathological process of neurodegenerative Parkinson syndromes more specific into account. Specifically, future therapies will target the aggregation of aggregation-prone proteins such as alpha-synuclein and tau, the degradation of pathological aggregates, and the spreading of pathological protein aggregates throughout the brain. Many of these approaches are already in (pre)clinical development. In addition, anti-inflammatory approaches are in development. Furthermore, drug-repurposing is a feasible approach to shorten the developmental process of new drugs.

Drug safety profiles in geriatric patients with Parkinson's disease using the FORTA (Fit fOR The Aged) classification: results from a mono-centric retrospective analysis.

To reduce potentially inappropriate medications, the FORTA (Fit fOR The Aged) concept classifies drugs in terms of their suitability for geriatric patients with different labels, namely A (indispensable), B (beneficial), C (questionable), and D (avoid). The aims of our study were to assess the medication appropriateness in PD inpatients applying the FORTA list and drug-drug interaction software, further to assess the adequacy of FORTA list for patients with PD. We retrospectively collected demographic data, comorbidities, laboratory values, and the medication from the discharge letters of 123 geriatric inpatients with PD at the university hospital of Hannover Medical School. Patients suffered on average from 8.2 comorbidities. The majority of the medication was labeled A (60.6% of PD-specific and 40.9% of other medication) or B (22.3% of PD-specific and 26.9% of other medication). Administered drugs labeled with D were amantadine, clozapine, oxazepam, lorazepam, amitriptyline, and clonidine. Overall, 545 interactions were identified, thereof 11.9% severe interactions, and 1.7% contraindicated combinations. 81.3% of patients had at least one moderate or severe interaction. The FORTA list gives rational recommendations for PD-specific and other medication, especially for general practitioners. Considering the demographic characteristics and the common multimorbidity of geriatric PD patients, this study underlines the importance of awareness, education, and preventive interventions to increase drug safety.

[Severe epigastric pain in a 59-year-old patient]. / Massivste epigastrische Schmerzen bei einem 59-jährigen Patienten.

Abdominal pain is a frequent cause of consultation to doctors' offices and emergency rooms. The most common differential diagnoses can be confirmed with readily available, cost-effective, and low-risk diagnostic tools such as laboratory tests, ultrasound, or gastroscopy. Additional diagnostic tests are required to exclude rare causes such as small, solid, or hematological malignancies, metabolic disorders, or polyneuropathies of varying origin. In the following, we present the case of a patient with severe epigastric pain due to neuroborreliosis, and recapitulate the diagnostic steps for clarifying abdominal pain using this example.

Association of Motor and Cognitive Symptoms with Health-Related Quality of Life and Caregiver Burden in a German Cohort of Advanced Parkinson's Disease Patients.

Parkinson's disease (PD) is a chronic progressive movement disorder with severe reduction in patients' health-related quality of life (HR-QoL). Motor and cognitive symptoms are especially linked with decreased PD patients' HR-QoL. However, the relationship of these symptoms to caregiver burden is relatively unclear. Influence of the Montreal Cognitive Assessment scale (MoCA) as a cognitive screening tool and Movement Disorders Society Unified Parkinson's disease Rating Scale MDS-UPDRS symptoms in relation to patients' HR-QoL and caregivers` burden was analyzed. PD patients (n = 124) completed MDS-UPDRS, MoCA, and the PD questionnaire 8 (PDQ-8) as a measure of quality of life. Caregivers (n = 78) were assessed by the PD caregiver burden inventory (PDCB). PDQ-8 and PDCB scores were regressed on MDS-UPDRS subscales and MoCA subscores. PDQ-8 correlated with attention (R 2 0.1282; p < 0.001) and executive (R 2 0.0882; p 0.001) MoCA subscores and all parts of the MDS-UPDRS. PDCB correlated most strongly with MDS-UPDRS part III motor symptoms (R 2 0.2070; p < 0.001) and the MoCA attention subscore (R 2 0.1815; p < 0.001). While all facets of PD symptoms assessed by the MDS-UPDRS relate to PD patients' quality of life, motor symptoms are the most relevant factor for the prediction of caregiver burden. In addition, patients' attentional symptoms seem to affect not only them, but also their caregivers. These findings show the potential of a detailed analysis of MDS-UPDRS and MoCA performance in PD patients.

[Tauopathies : From molecule to therapy]. / Tauopathien : Vom Molekül zur Therapie.

BACKGROUND: The microtubule-associated tau protein is the defining denominator of a group of neurodegenerative diseases termed tauopathies. OBJECTIVE: Provide a timely state of the art review on recent scientific advances in the field of tauopathies. MATERIAL AND METHODS: Systematic review of the literature from the past 10 years. RESULTS: Tau proteins are increasingly being recognized as a highly variable protein, underlying and defining a spectrum of molecularly defined diseases, with a clinical spectrum ranging from dementia to hypokinetic movement disorders. Genetic variation at the tau locus can trigger disease or modify disease risk. Tau protein alterations can damage nerve cells and propagate pathologies through the brain. Thus, tau proteins may serve both as a serological and imaging biomarker. Tau proteins also provide a broad spectrum of rational therapeutic interventions to prevent disease progression. This knowledge has led to modern clinical trials. CONCLUSION: The field of tauopathies is in a state of dynamic and rapid progress, requiring close interdisciplinary collaboration.

New classification of tauopathies.

Tauopathies are a group of neurodegenerative diseases characterized by pathological intracellular deposits of the protein tau. Isoform composition, morphology and anatomical distribution of cellular tau-immunoreactivities are defining distinct tauopathies as molecular pathological disease entities. The clinical spectrum of tauopathies includes syndromes with primary motor symptoms and with primary cognitive dysfunction. The traditional syndrome-based classification is currently being complemented by a molecular-pathological classification. While the syndrome-based classification is helpful to select symptomatic therapies, and to generate clinical working hypotheses about underlying etiologies, the molecular-pathological classification is most important for the development and application of molecularly tailored disease-modifying therapies.

[Pharmacotherapy of Parkinson's disease : Aspects of drug safety]. / Pharmakotherapie des Morbus Parkinson : Aspekte der Arzneimitteltherapiesicherheit.

BACKGROUND: This overview focuses on the aspects of the pharmacotherapy of Parkinson's disease, which is one of the most common disorders of the nervous system. This article presents the complexity of the pharmacotherapy of geriatric patients with neurological diseases. OBJECTIVES: Information about the potential risk factors and aspects of drug safety in the pharmacotherapy of Parkinson's disease. MATERIALS AND METHODS: Selective literature search using PubMed and the scientific-clinical experience of the authors. RESULTS: Patients with Parkinson's disease are usually geriatric patients with concomitant diseases. As a result they are often treated with comedication which leads to a complex medication regime with more than five drugs. Such polypharmacy increases the risk of adverse drug events due to the rising number of possible interactions and contraindications. To control this risk and maintain a safe therapy, certain measures should be considered. This implies additional need for educational work in order to create awareness regarding potential adverse drug events. In certain cases of diagnosed comorbidities or relevant drug prescriptions in the medication regime, follow-up examinations should be conducted. CONCLUSION: Specific parameters of Parkinson's disease, the health-related quality of life of affected patients and the quality of pharmacotherapeutic drug safety can be improved by targeted monitoring of the medication regime. As a result, the overall drug safety can be increased.

The phenotypic spectrum of progressive supranuclear palsy.

Traditionally, the clinical picture of progressive supranuclear palsy (PSP) was defined by early postural instability with falls, supranuclear vertical gaze palsy, symmetric akinesia and rigidity, frontal and subcortical dementia, and pseudobulbar palsy, leading to death after a mean disease duration of approximately six years. A definite diagnosis of PSP depends on neuropathological confirmation. In recent years, clinico-pathological studies have drawn attention to various "atypical" clinical manifestations of PSP. In these, a clinical diagnosis of PSP is delayed or never accomplished. Comprehensive understanding of the natural history of PSP is required to permit an early and accurate diagnosis. Based on current evidence, this review provides an update on the clinical spectrum of PSP.

The frontal assessment battery is not useful to discriminate progressive supranuclear palsy from frontotemporal dementias.

BACKGROUND: The frontal assessment battery (FAB) has been suggested as a useful tool in the differential diagnosis of progressive supranuclear palsy (PSP) from Parkinson's disease (PD) and multiple system atrophy with parkinsonism (MSA-P). However, the utility of the FAB in the differential diagnosis of PSP from frontotemporal dementia (FTD) phenotypes is still under research. METHODS: We performed the FAB, in a multi-centre cohort of 70 PSP, 103 FTD (N = 84 behavioral variant FTD, N = 10 semantic dementia, N = 9 progressive non-fluent aphasia), 26 PD and 11 MSA-P patients, diagnosed according to established criteria. Patients were also rated with the mini mental state examination and motor scales. RESULTS: The FAB total score showed a poor discriminatory power between PSP and FTD as a group [area under the curve (AUC) = 0.523]. Moreover, the FAB score showed no correlation with disease duration in PSP (r = 0.05) or FTD group (r = 0.04). In contrast, we confirmed that the FAB is clinically useful to differentiate PSP from PD and MSA-P (AUC = 0.927). In fact, the sum of two FAB subscores together (verbal fluency and Luria motor series) were as good as the total score in differentiating PSP from PD and MSA-P (AUC = 0.957). CONCLUSIONS: The FAB may not be a useful tool to differentiate PSP from FTDs, and shows no correlation with disease duration in these disorders. On the other hand, the essential information to differentiate PSP from PD and MSA-P is contained in the sum of only two FAB subscores. This should be taken into consideration in both clinical practice and the planning of clinical trials.

Striatal tyrosine hydroxylase-positive neurons are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the therapeutic gold standard in Parkinson's disease. However, long-term treatment is complicated by the induction of debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesias (LIDs). Until today the underlying mechanisms of LID pathogenesis are not fully understood. The aim of this study was to reveal new factors, which may be involved in the induction of LID. We have focused on the expression of striatal tyrosine hydroxylase-positive (TH+) neurons, which are capable of producing either L-DOPA or dopamine (DA) in target areas of ventral midbrain DAergic neurons. To address this issue, a daily L-DOPA dose was administered over the course of 15 days to mice with unilateral 6-hydroxydopamine-induced lesions of the medial forebrain bundle and LIDs were evaluated. Remarkably, the number of striatal TH+ neurons strongly correlated with both induction and severity of LID as well as ΔFosB expression as an established molecular marker for LID. Furthermore, dyskinetic mice showed a marked augmentation of serotonergic fiber innervation in the striatum, enabling the decarboxylation of L-DOPA to DA. Axial, limb and orolingual dyskinesias were predominantly associated with TH+ neurons in the lateral striatum, whereas medially located TH+ neurons triggered locomotive rotations. In contrast, identified accumbal and cortical TH+ cells did not contribute to the generation of LID. Thus, striatal TH+ cells and serotonergic terminals may cooperatively synthesize DA and subsequently contribute to supraphysiological synaptic DA concentrations, an accepted cause in LID pathogenesis.

Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease.

Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.

Brain energy metabolism in early MSA-P: A phosphorus and proton magnetic resonance spectroscopy study.

INTRODUCTION: Recently, mutations in the COQ2 gene, encoding for an enzyme involved in coenzyme Q10 biosynthesis, have been suggested to confer susceptibility risk for multiple system atrophy (MSA). Thus, the possible role of mitochondrial dysfunction in the pathophysiology of MSA has emerged. Here, we studied brain energy metabolism in vivo in early MSA-parkinsonism (MSA-P) patients and compared to healthy controls. METHODS: We have used combined phosphorus and proton magnetic resonance spectroscopy to measure high- and low-energy phosphates in the basal ganglia of early (Hoehn and Yahr stage I-III), probable MSA-P patients (N = 9) compared to healthy controls (N = 9). RESULTS: No significant changes in the high energy phosphates and other parameters reflecting the energy status of the cells were found in the basal ganglia of MSA-P patients compared to healthy controls. N-acetylaspartate was significantly reduced in MSA-P compared to healthy controls and correlated with the Unified Multiple System Atrophy Rating Scale. CONCLUSION: Brain energy metabolism in early MSA-P is not impaired, despite the presence of impaired neuronal integrity. This may imply that mitochondrial dysfunction may not play a primary role in the pathophysiology of MSA, at least in European populations.

Subcellular expression and neuroprotective effects of SK channels in human dopaminergic neurons.

Small-conductance Ca(2+)-activated K(+) channel activation is an emerging therapeutic approach for treatment of neurological diseases, including stroke, amyotrophic lateral sclerosis and schizophrenia. Our previous studies showed that activation of SK channels exerted neuroprotective effects through inhibition of NMDAR-mediated excitotoxicity. In this study, we tested the therapeutic potential of SK channel activation of NS309 (25 µM) in cultured human postmitotic dopaminergic neurons in vitro conditionally immortalized and differentiated from human fetal mesencephalic cells. Quantitative RT-PCR and western blotting analysis showed that differentiated dopaminergic neurons expressed low levels of SK2 channels and high levels of SK1 and SK3 channels. Further, protein analysis of subcellular fractions revealed expression of SK2 channel subtype in mitochondrial-enriched fraction. Mitochondrial complex I inhibitor rotenone (0.5 µM) disrupted the dendritic network of human dopaminergic neurons and induced neuronal death. SK channel activation reduced mitochondrial membrane potential, while it preserved the dendritic network, cell viability and ATP levels after rotenone challenge. Mitochondrial dysfunction and delayed dopaminergic cell death were prevented by increasing and/or stabilizing SK channel activity. Overall, our findings show that activation of SK channels provides protective effects in human dopaminergic neurons, likely via activation of both membrane and mitochondrial SK channels. Thus, SK channels are promising therapeutic targets for neurodegenerative disorders such as Parkinson's disease, where dopaminergic cell loss is associated with progression of the disease.

Kaurenoic acid from pulp of Annona cherimolia in regard to Annonaceae-induced Parkinsonism.

Guadeloupean Parkinsonism has been linked epidemiologically to the consumption of Annonaceae fruits. These were proposed to be etiological agents for sporadic atypical Parkinsonism worldwide, because of their content of neurotoxins such as isoquinolinic alkaloids and Annonaceous acetogenins. The pulp of Annona cherimolia Mill. from Spain was screened for these toxic molecules using Matrix-Assisted Laser Desorption Ionisation - Time of Flight mass spectrometry (MALDI-TOF MS) and it was found not to be a source of exposure. However, kaurenoic acid, a diterpene considered to be cytotoxic, was detected in high amounts (66 mg/fresh fruit). Treatment of rat embryonic striatal primary cultures, up to a high concentration (50 µM), did not cause neuronal death nor astrogliosis, suggesting that this molecule is not at risk of implication in human neurodegenerative diseases.

Magnetic resonance imaging in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a tauopathy, presenting clinically most often with a symmetrical akinetic-rigid syndrome, postural instability, supranuclear gaze palsy and frontal dementia. In the absence of reliably validated biomarkers, the diagnosis of PSP in vivo is presently based on clinical criteria, which to date do not include supporting imaging findings, as is accepted for other neurodegenerative diseases. However, data from conventional magnetic resonance imaging (MRI) and various advanced MRI techniques including magnetic resonance volumetry, voxel-based morphometry, diffusion-weighted and diffusion-tensor imaging, magnetization transfer imaging and proton resonance spectroscopy suggest that MRI can contribute valuable information for the differential diagnosis of PSP. We review here the presently published literature concerning MRI in PSP and discuss the potential role of MRI in differentiating PSP from other parkinsonian syndromes.

[Differential diagnosis of Parkinson's disease: current consensus criteria and outlook]. / Differenzialdiagnosen der Parkinson-Krankheit: aktuelle Konsensuskriterien und Ausblicke.

Parkinsonian-syndrome, clinically based on the combination of cardinal symptoms, could be the clinical manifestation of different, neuropathological defined entities. Because of the different prognostic, therapeutical and scientific implications a reliable differential diagnostic of the entities in early course of disease is desirable. For this purpose standardized clinical diagnostic criteria with sufficient validation against the gold standard of the neuropathological diagnostic are important. In this article, the clinical diagnostic criteria of atypical Parkinsonian-syndrome and their validity were discussed.