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.

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.

Caregiver burden and health-related quality of life in idiopathic dystonia patients under botulinum toxin treatment: a cross-sectional study.

Dystonia is a chronic movement disorder that is associated with a reduction in health-related quality of life (HR-QoL) and restriction of activities of daily living. Botulinum neurotoxin (BT) improves disease-specific HR-QoL by reducing abnormal movements, postures, and pain. We examined the burden of the corresponding primary caregiver as a potential important factor for disease management and HR-QoL of dystonia patients under treatment with BT. 114 patients with focal, segmental, or generalized dystonia were recruited, together with 93 corresponding caregivers, whose burden was investigated using the Caregiver Burden Inventory. In addition, all participants were assessed for cognitive impairment, depression, anxiety, alexithymia, and HR-QoL. Only a small proportion of caregivers suffered from caregiver burden. Despite BT therapy, patients' HR-QoL was decreased compared to the age-matched general German population. Psychological symptoms, notably anxiety, and depression correlated significantly with reduced HR-QoL. Our data imply that caregiver burden emerged to be an issue in subgroups of dystonia patients. Furthermore, HR-QoL of dystonia patients is reduced even under optimized BT treatment in a specialized center.

Validating the Parkinson's disease caregiver burden questionnaire (PDCB) in German caregivers of advanced Parkinson's disease patients.

BACKGROUND: Advanced Parkinson's disease (PD) may place a high burden on patients and their caregivers. Understanding the determinants of caregiver burden is of critical importance. This understanding requires the availability of adequate assessment tools. Recently, the Parkinson's disease caregiver burden questionnaire (PDCB) has been developed as a PD-specific measure of caregiver burden. However, the PDCB has only been evaluated in a sample of Australian caregivers of patients at a less advanced stage of the disease. OBJECTIVE: We tested whether a German translation of the PDCB qualifies as an adequate measure of caregiver burden in a German sample of caregivers of advanced patients with PD. METHODS: We collected PDCB data from 65 caregivers of advanced patients with PD. Reliability of the scale was assessed and compared against the original version. To validate the German version of the PDCB, we examined the correlations with the caregiver burden inventory (CBI), the short form 36 health survey (SF-36), the Parkinson's disease quality of life questionnaire 39 (PDQ-39), disease duration, and the amount of caregiving time. RESULTS: The total PDCB score proved to be reliable and to be significantly related to CBI and SF-36 scores. PDCB scores also increased with increasing amounts of caregiving time. CONCLUSIONS: The German version of the PDCB appears to be an adequate measure of caregiver burden in caregivers of advanced PD patients.

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.

Species-specific vesicular monoamine transporter 2 (VMAT2) expression in mammalian pancreatic beta cells: implications for optimising radioligand-based human beta cell mass (BCM) imaging in animal models.

AIMS/HYPOTHESIS: Imaging of beta cell mass (BCM) is a major challenge in diabetes research. The vesicular monoamine transporter 2 (VMAT2) is abundantly expressed in human beta cells. Radiolabelled analogues of tetrabenazine (TBZ; a low-molecular-weight, cell-permeant VMAT2-selective ligand) have been employed for pancreatic islet imaging in humans. Since reports on TBZ-based VMAT2 imaging in rodent pancreas have been fraught with confusion, we compared VMAT2 gene expression patterns in the mouse, rat, pig and human pancreas, to identify appropriate animal models with which to further validate and optimise TBZ imaging in humans. METHODS: We used a panel of highly sensitive VMAT2 antibodies developed against equivalently antigenic regions of the transporter from each species in combination with immunostaining for insulin and species-specific in situ hybridisation probes. Individual pancreatic islets were obtained by laser-capture microdissection and subjected to analysis of mRNA expression of VMAT2. RESULTS: The VMAT2 protein was not expressed in beta cells in the adult pancreas of common mouse or rat laboratory strains, in contrast to its expression in beta cells (but not other pancreatic endocrine cell types) in the pancreas of pigs and humans. VMAT2- and tyrosine hydroxylase co-positive (catecholaminergic) innervation was less abundant in humans than in rodents. VMAT2-positive mast cells were identified in the pancreas of all species. CONCLUSIONS/INTERPRETATION: Primates and pigs are suitable models for TBZ imaging of beta cells. Rodents, because of a complete lack of VMAT2 expression in the endocrine pancreas, are a 'null' model for assessing interference with BCM measurements by VMAT2-positive mast cells and sympathetic innervation in the pancreas.