[How the implementation of a school for people with Parkinson's disease can succeed-Results of a consensus study and a formative evaluation]. / Wie die Umsetzung einer Schule für Menschen mit Parkinson-Krankheit gelingen kann ­ Ergebnisse eines Konsensusverfahrens und einer formativen Evaluation.

BACKGROUND: As the most rapidly increasing neurodegenerative disease worldwide, Parkinson's disease is highly relevant to society. Successful treatment requires active patient participation. Patient education has been successfully implemented for many chronic diseases, such as diabetes and could also provide people with Parkinson's disease with skills to manage the disease better and to participate in shared decision making. MATERIAL AND METHODS: To prepare the implementation of a concept for patient education for people with Parkinson's disease, a structured consensus study was conducted and a pilot project formatively evaluated. The structured consensus study included experts from all over Germany. It consisted of two online surveys and an online consensus conference. The formative evaluation was conducted as three focus groups. Transcripts were evaluated using content-structuring qualitative content analysis. RESULTS: From the consensus procedure 59 consented statements emerged, mainly regarding the contents of a patient school and a group size of 6-8 persons. Only two statements could not be consented. The formative evaluation detected a tendency towards a positive attitude for a digital training format and a very positive evaluation of the contents. DISCUSSION: Overall, important recommendations for a patient school can be drawn from this study. The following subjects require further investigation: format, inclusion criteria, group composition and inclusion of caregivers.

Systematic review-based guideline "Parkinson's disease" of the German Society of Neurology: diagnostic use of transcranial sonography.

BACKGROUND AND OBJECTIVE: Transcranial brain parenchyma sonography (TCS) has been recommended as a tool for the early and differential diagnosis of Parkinson's disease (PD) in German and European clinical guidelines. Still, the brain structures to be examined for the diagnostic questions and the requirements for being a qualified investigator were not specified in detail. These issues have now been addressed in the 2023 update of the clinical guideline on PD by the German Society of Neurology (DGN). METHODS: The recommendations were based on a systematic literature review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three diagnostic questions were defined: (1) What is the accuracy of TCS in the differential diagnosis of PD versus atypical and secondary Parkinsonian syndromes? (2) What is the accuracy of TCS in the differential diagnosis of PD versus essential tremor? (3) What is the accuracy of TCS in the diagnosis of PD in persons with typical early symptoms, compared with the diagnosis established by clinical follow-up? The brain structures to be assessed and the level of recommendation were formulated for these questions. The training requirements for being regarded as qualified TCS investigator were stipulated by the responsible medical societies (German Society of Ultrasound in Medicine, DEGUM; German Society for Clinical Neurophysiology and Functional Imaging, DGKN). Finally, the recommendations for these diagnostic questions reached strong consensus (each ≥ 97%) of the guideline committee. Here, the details of review and recommendations are presented. CONCLUSION: The updated guideline clarifies the diagnostic uses and limitations of TCS in PD.

Measuring the Usability of eHealth Solutions for Patients With Parkinson Disease: Observational Study.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disorder with a variety of motor and nonmotor symptoms. Many of these symptoms can be monitored by eHealth solutions, including smartphone apps, wearable sensors, and camera systems. The usability of such systems is a key factor in long-term use, but not much is known about the predictors of successful use and preferable methods to assess usability in patients with PD. OBJECTIVE: This study tested methods to assess usability and determined prerequisites for successful use in patients with PD. METHODS: We performed comprehensive usability assessments with 18 patients with PD using a mixed methods usability battery containing the System Usability Scale, a rater-based evaluation of device-specific tasks, and qualitative interviews. Each patient performed the usability battery with 2 of 3 randomly assigned devices: a tablet app, wearable sensors, and a camera system. The usability battery was administered at the beginning and at the end of a 4-day testing period. Between usability batteries, the systems were used by the patients during 3 sessions of motor assessments (wearable sensors and camera system) and at the movement disorder ward (tablet app). RESULTS: In this study, the rater-based evaluation of tasks discriminated the best between the 3 eHealth solutions, whereas subjective modalities such as the System Usability Scale were not able to distinguish between the systems. Successful use was associated with different clinical characteristics for each system: eHealth literacy and cognitive function predicted successful use of the tablet app, and better motor function and lower age correlated with the independent use of the camera system. The successful use of the wearable sensors was independent of clinical characteristics. Unfortunately, patients who were not able to use the devices well provided few improvement suggestions in qualitative interviews. CONCLUSIONS: eHealth solutions should be developed with a specific set of patients in mind and subsequently tested in this cohort. For a complete picture, usability assessments should include a rater-based evaluation of task performance, and there is a need to develop strategies to circumvent the underrepresentation of poorly performing patients in qualitative usability research.

Feasibility of a Multimodal Telemedical Intervention for Patients with Parkinson's Disease-A Pilot Study.

Symptoms of Parkinson's disease (PD) can be controlled well, but treatment often requires expert judgment. Telemedicine and sensor-based assessments can allow physicians to better observe the evolvement of symptoms over time, in particular with motor fluctuations. In addition, they potentially allow less frequent visits to the expert's office and facilitate care in rural areas. A variety of systems with different strengths and shortcomings has been investigated in recent years. We designed a multimodal telehealth intervention (TelePark) to mitigate the shortcomings of individual systems and assessed the feasibility of our approach in 12 patients with PD over 12 weeks in preparation for a larger randomized controlled trial. TelePark uses video visits, a smartphone app, a camera system, and wearable sensors. Structured training included setting up the equipment in patients' homes and group-based online training. Usability was assessed by questionnaires and semi-standardized telephone interviews. Overall, 11 out of 12 patients completed the trial (5 female, 6 male). Mean age was 65 years, mean disease duration 7 years, mean MoCA score 27. Adherence was stable throughout the study and 79% for a short questionnaire administered every second day, 62% for medication confirmation, and 33% for an electronic Hauser diary. Quality of life did not change in the course of the study, and a larger cohort will be required to determine the effect on motor symptoms. Interviews with trial participants identified motivations to use such systems and areas for improvements. These insights can be helpful in designing similar trials.

Adult Neural Stem Cells from Midbrain Periventricular Regions Show Limited Neurogenic Potential after Transplantation into the Hippocampal Neurogenic Niche.

The regulation of adult neural stem or progenitor cell (aNSC) proliferation and differentiation as an interplay of cell-intrinsic and local environmental cues remains in part unclear, impeding their role in putative regenerative therapies. aNSCs with all major properties of NSCs in vitro have been identified in a variety of brain regions beyond the classic neurogenic niches, including the caudal periventricular regions (PVRs) of the midbrain, though active neurogenesis is either limited or merely absent in these regions. To elucidate cell-intrinsic properties of aNSCs from various PVRs, we here examined the proliferation and early differentiation capacity of murine aNSCs from non-neurogenic midbrain PVRs (PVRMB) compared to aNSCs from the neurogenic ventricular-subventricular zone (PVRV-SVZ) 7 days after transplantation into the permissive pro-neurogenic niche of the dentate gyrus (DG) of the hippocampus in mice. An initial in vitro characterization of the transplants displayed very similar characteristics of both aNSC grafts after in vitro expansion with equal capacities of terminal differentiation into astrocytes and Tuj1+ neurons. Upon the allogenic transplantation of the respective aNSCs into the DG, PVRMB grafts showed a significantly lower graft survival and proliferative capacity compared to PVRV-SVZ transplants, whereby the latter are exclusively capable of generating new neurons. Although these differences might be-in part-related to the transplantation procedure and the short-term study design, our data strongly imply important cell-intrinsic differences between aNSCs from neurogenic compared to non-neurogenic PVRs with respect to their neurogenic potential and/or their sensitivity to neurogenic cues.

One nerve suffices: A clinically guided nerve ultrasound protocol for the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS).

OBJECTIVE: To investigate diagnostic accuracy of a nerve ultrasound (US) protocol that is individualized to a patient's clinical deficits for the differentiation of amyotrophic lateral sclerosis with predominant lower motoneuron disease (ALS/LMND) and multifocal motor neuropathy (MMN). METHODS: Single-center, prospective, examiner-blinded, diagnostic study in two cohorts. Cohort I (model development): Convenience sample of subjects with ALS/LMND or MMN according to revised El-Escorial or EFNS guidelines. Cohort II (model validation): Consecutively recruited treatment-naïve subjects with suspected diagnosis of ALS/LMND or MMN. Cutoffs for 28 different US values were determined by Receiver Operating Curve (ROC) in cohort I. Area Under The Curve (AUC) of US was compared to nerve conduction studies (NCS). Diagnostic accuracy of US protocols, individualized according to clinical deficits, was compared to former rigid non-individualized protocols and to random examination site selection in cohort II. RESULTS: 48 patients were recruited. In cohort I (28 patients), US had higher ROC AUCs than NCS, US 0.82 (0.12) (mean (standard deviation)), NCS (compound muscle action potential (CMAP) 0.60 (0.09), p < .001; two-sided t-test). US models based on the nerve innervating the clinically most affected muscles had higher correct classification rates (CCRs, 93%) in cohort II than former rigid protocols (85% and 80%), or models with random measurement site selection (66% and 80%). CONCLUSIONS: Clinically guided US protocols for differentiation of ALS/LMND from MMN increase diagnostic accuracy when compared to clinically unguided protocols. They also require less measurements sites to achieve this accuracy.

"Silenced" polydendrocytes: a new cell type within the oligodendrocyte progenitor cell population?

Oligodendrocyte progenitor cells (OPCs) were first described more than two decades ago. Novel labeling techniques have shown them to be cells with more than just progenitor functions, with their classification as a fourth glial cell type in addition to astrocytes, oligodendrocytes, and microglial cells. Another term used for this cell type is polydendrocytes, owing to both their morphology and to the evolving knowledge about their diverse functions. Recently, an exclusive hallmark of neurons--the generation of action potentials--became debatable, because a subset of polydendrocytes was reported to generate action potentials in response to adequate stimuli. The new technique of inducible reporter gene expression has brought new insights into the fate and function of polydendrocytes. In recent studies, so-called "silenced" OPCs were detected in cortical tissue, and which underwent proliferation with subsequent cell cycle exit, but without any signs of differentiation. Within this review, we focus on the identification of this new subset of polydendrocytes and their possible functions within cortical networks.

Building a Parkinson-Network-Experiences from Germany.

Parkinson's disease is a complex neurodegenerative disease that can be best treated with a multi-disciplinary care approach. Building care networks has been shown as a useful tool to facilitate the integration of care services and improve outcomes for patients and care providers. However, experiences and practices relating to building a network are very limited in the field of Parkinson's disease. This paper portrays existing Parkinson networks in Germany. With the help of a standardized template, description of networks and their building-blocks, so-called modules, were collected from all over Germany. Modules were rated in terms of their expected benefit and the required effort when implementing them, with the help of an expert survey. The rating showed that some modules were perceived as more important than others, but all modules were recognized as beneficial for patients and care providers. Overall, the German experience shows that building a Parkinson network facilitates the integration of care and provides a benefit to all stakeholders involved.

Structured Care and Self-Management Education for Persons with Parkinson's Disease: Why the First Does Not Go without the Second-Systematic Review, Experiences and Implementation Concepts from Sweden and Germany.

Integrated care is regarded as a key for care delivery to persons with chronic long-term conditions such as Parkinson's disease. For persons with Parkinson's disease, obtaining self-management support is a top priority in the context of integrated care. Self-management is regarded as a crucial competence in chronic diseases since the affected persons and their caregivers inevitably take up the main responsibility when it comes to day-to-day management. Formal self-management education programs with the focus on behavioral skills relevant to the induction and maintenance of behavioral change have been implemented as a standard in many chronic long-term conditions. However, besides the example of the Swedish National Parkinson School, the offers for persons with Parkinson's disease remain fragmented and limited in availability. Today, no such program is implemented as a nationwide standard in Germany. This paper provides (1) a systematic review on structured self-management education programs specifically designed or adopted for persons with Parkinson's disease, (2) presents the Swedish National Parkinson School as an example for a successfully implemented nationwide program and (3) presents a concept for the design, evaluation and long-term implementation of a future-orientated self-management education program for persons with Parkinson's disease in Germany.

Parkinson Network Eastern Saxony (PANOS): Reaching Consensus for a Regional Intersectoral Integrated Care Concept for Patients with Parkinson's Disease in the Region of Eastern Saxony, Germany.

As integrated care is recognized as crucial to meet the challenges of chronic conditions such as Parkinson's disease (PD), integrated care networks have emerged internationally and throughout Germany. One of these networks is the Parkinson Network Eastern Saxony (PANOS). PANOS aims to deliver timely and equal care to PD patients with a collaborative intersectoral structured care pathway. Additional components encompass personalized case management, an electronic health record, and communicative and educative measures. To reach an intersectoral consensus of the future collaboration in PANOS, a structured consensus process was conducted in three sequential workshops. Community-based physicians, PD specialists, therapists, scientists and representatives of regulatory authorities and statutory health insurances were asked to rate core pathway-elements and supporting technological, personal and communicative measures. For the majority of core elements/planned measures, a consensus was reached, defined as an agreement by >75% of participants. Additionally, six representatives from all partners involved in the network-design independently assessed PANOS based on the Development Model for Integrated Care (DMIC), a validated model addressing the comprehensiveness and maturity of integrated care concepts. The results show that PANOS is currently in an early maturation state but has the potential to comprehensively represent the DMIC if all planned activities are implemented successfully. Despite the favorable high level of consensus regarding the PANOS concept and despite its potential to become a balanced integrated care concept according to the DMIC, its full implementation remains a considerable challenge.

Practically applicable nerve ultrasound models for the diagnosis of axonal and demyelinating hereditary motor and sensory neuropathies (HMSN).

PURPOSE: To develop specific diagnostic ultrasound (US) models for hereditary motor and sensory neuropathies (HMSN) in patients with primarily demyelinating or axonal polyneuropathies (PNP) according to standard nerve conduction studies (NCS) criteria. METHODS: Single-centre, examiner-blinded cross-sectional study in acquired PNP (consecutive recruitment strategy) and HMSN patients (convenience sample). Allocation into demyelinating or axonal phenotype via easily applicable NCS criteria. Assessment of single measurements by receiver-operating curve (ROC) analysis, development of diagnostic models based on the best measurement values in ROC. RESULTS: Of 85 enrolled subjects, 53 (62%) had HMSN and 32 (38%) acquired PNPs, and 60 subjects (71%) had demyelinating and 25 (29%) axonal PNP. ROC area under the curve of means of the z-transformed 5 best measurement values was 0.87 for demyelinating and 0.99 for axonal HMSN. Diagnostic models showed high accuracy for both demyelinating (84% sensitivity, 86% specificity) and axonal HMSN (100% sensitivity and specificity). As a measure of variability of morphologic changes, standard deviations of z-transformed measurements were compared for acquired PNP and HMSN. In contrast to previous reports of more homogenous nerve enlargements in HMSN, standard deviations were higher in HMSN than in acquired PNP. Additionally, the performance of previously published models for the diagnosis of HMSN in demyelinating PNP was compared. Previously published models showed lower sensitivities (50-58%), but comparable specificities (91-100%) when applied to NCS-criteria defined demyelinating PNP group. CONCLUSION: Diagnostic ultrasound models for HMSN in patients with demyelinating or axonal neuropathies show high accuracy and can contribute to differential diagnosis in clinical routine.

Diagnostic accuracy of nerve ultrasound in hereditary and sporadic non-entrapment neuropathies.

The objective of this study is to compare the diagnostic accuracy of nerve ultrasound (US) and nerve conduction studies (NCS) for acquired non-entrapment peripheral neuropathies (PNP) and hereditary motor and sensory neuropathies (HMSN) in a routine clinical setting. The methods are based on a single-center, prospective, examiner-blinded cross-sectional study on three subject groups of healthy controls, PNP (both enrolled by a consecutive recruitment strategy), and HMSN patients (convenience sample). A clinical reference standard based on the neuropathy impairment (NIS) and neuropathy symptoms scores (NSS) was used for PNP as the external validation criterion. Diagnostic accuracy was assessed by receiver-operating curve (ROC) analyses of single-nerve measurements and logit models. Of a total of 676 consecutively screened subjects, 107 (15.8 %) were recruited, of which 36 (33.6 %) had a PNP. HMSN group consisted of 53 subjects (30 subjects (56.6 %) with genetic confirmation). AUCs of best diagnostic logit models to distinguish between controls and PNP patients were 0.86 for US and 0.97 for NCS corresponding to an equivalent specificity [US 93 % (95 % CI: 83-98 %), NCS 89 % (95 % CI: 78-95 %)], but inferior sensitivity of US [US 56 % (95 % CI: 35-74 %), NCS 97 % (95 % CI: 84-100 %)]. For differentiation between PNP and HMSN, both methods had equivalent AUCs of 0.95 corresponding to similar sensitivities/specificities. Simpler diagnostic models based on measurement protocols feasible for clinical routine revealed similar diagnostic accuracies. US has an inferior sensitivity than NCS for acquired PNP, but comparable specificity. For identification of HMSN in a PNP population, US and NCS show comparable performance.

Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND).

The objective of the study was to investigate nerve ultrasound (US) in comparison to nerve conduction studies (NCS) for differential diagnosis of amyotrophic lateral sclerosis with predominant lower motoneuron disease(ALS/LMND) and multifocal motor neuropathy(MMN). A single-center, prospective, examiner-blinded cross-sectional diagnostic study in two cohorts was carried out. Cohort I: convenience sample of subjects diagnosed with ALS/LMND or MMN (minimal diagnostic criteria:possible ALS (revised EL-Escorial criteria), possible MMN (European Federation of Neurosciences guidelines).Cohort II: consecutive subjects with suspected diagnosis of either ALS/LMND or MMN. Diagnostic US and NCS models were developed based on ROC analysis of 28 different US and 32 different NCS values measured in cohort I. Main outcome criterion was sensitivity/specificity of these models between ALS/LMND and MMN in cohort II.Cohort I consisted of 16 patients with ALS/LMND and 8 patients with MMN. For cohort II, 30 patients were recruited, 8 with ALS/LMND, 5 with MMN, and 17 with other diseases. In cohort I, the three best US measures showed higher mean ± SD areas under the curve than the respective NCS measures (0.99 ± 0.01 vs. 0.79 ± 0.03, p<0.001; two-sided t test). The US model with highest measurement efficacy (8 values) and diagnostic quality reached 100 % sensitivity and 92 % specificity for MMN in cohort II, while the respective NCS model (6 values, including presence of conduction blocks) reached 100 and 52 %. Nerve US is of high diagnostic accuracy for differential diagnosis of ALS/LMND and MMN. It might be superior to NCS in the diagnosis of MMN in hospital-admitted patients with this differential diagnosis.

Preventive brain radio-chemotherapy alters plasticity associated metabolite profile in the hippocampus but seems to not affect spatial memory in young leukemia patients.

BACKGROUND: Neuronal plasticity leading to evolving reorganization of the neuronal network during entire lifespan plays an important role for brain function especially memory performance. Adult neurogenesis occurring in the dentate gyrus of the hippocampus represents the maximal way of network reorganization. Brain radio-chemotherapy strongly inhibits adult hippocampal neurogenesis in mice leading to impaired spatial memory. METHODS: To elucidate the effects of CNS radio-chemotherapy on hippocampal plasticity and function in humans, we performed a longitudinal pilot study using 3T proton magnetic resonance spectroscopy ((1)H-MRS) and virtual water-maze-tests in 10 de-novo patients with acute lymphoblastic leukemia undergoing preventive whole brain radio-chemotherapy. Patients were examined before, during and after treatment. RESULTS: CNS radio-chemotherapy did neither affect recall performance in probe trails nor flexible (reversal) relearning of a new target position over a time frame of 10 weeks measured by longitudinal virtual water-maze-testing, but provoked hippocampus-specific decrease in choline as a metabolite associated with cellular plasticity in (1)H-MRS. CONCLUSION: Albeit this pilot study needs to be followed up to definitely resolve the question about the functional role of adult human neurogenesis, the presented data suggest that (1)H-MRS allows the detection of neurogenesis-associated plasticity in the human brain.

Lack of vascular endothelial growth factor receptor-2/Flk1 signaling does not affect substantia nigra development.

Oxygen tension is critical for proliferation of human and murine midbrain-derived neural precursor cells (mNPCs). Lack of hypoxia-inducible factor-1α (HIF1α) impairs midbrain dopaminergic neurogenesis which could be rescued by vascular endothelial growth factor (VEGF) via VEGFR-2 signaling. Here, we conditionally inactivated the VEGFR-2, encoded by the fetal liver kinase 1 (Flk1) gene, in murine NPCs to determine its role in proliferation and survival in vitro as well as survival of dopaminergic neurons in vivo. Flk1 conditional knock-out (Flk1 CKO) mice showed no general brain phenotype. There was no midbrain-specific impairment of NPC proliferation as seen in HIF1α CKO mice. In the substantia nigra (SN) of adult Flk1 CKO mice, nonbiased stereological cell counts revealed no reduction of TH-positive neurons of Flk1 CKO mice compared with control Cre/wt mice (in which the wild-type Flk1 allele is expressed in parallel with the Cre recombinase allele). In conclusion, VEGF receptor signaling seems not to be relevant to the development and survival of substantia nigra dopaminergic neurons within the hypoxia-HIF1α signaling pathway.

Stem cell-based therapies in Parkinson's disease: future hope or current treatment option?

Parkinson's disease (PD) is one of the most frequent neurodegenerative diseases and represents a major therapeutic challenge because of the so far missing therapeutic means to influence the ongoing loss of dopaminergic innervation to the striatum. Cell replacement has raised hope to offer the first restorative treatment option. Clinical trials have provided "proof of principle" that transplantation of dopamine-producing neurons into the striatum of PD patients can achieve symptomatic relief given that the striatum is sufficiently re-innervated. Various cell sources have been tested, including fetal ventral midbrain tissue, embryonic stem cells, fetal and adult neural stem cells and, after a ground-breaking discovery, induced pluripotent stem cells. Although embryonic and induced pluripotent stem cells have emerged as the most promising candidates to overcome most of the obstacles to clinical successful cell replacement, each cell source has its unique drawbacks. This review does not only provide a comprehensive overview of the different cellular candidates, including their assets and drawbacks, but also of the various additional issues that need to be addressed in order to convert cellular replacement therapies from an experimental to a clinically relevant therapeutic alternative.

Proton MR spectroscopy of neural stem cells: does the proton-NMR peak at 1.28 ppm function as a biomarker for cell type or state?

Recently, a peak at 1.28 ppm in proton magnetic resonance spectroscopy ((1)H-MRS) of neural stem cells (NSCs) was introduced as a noninterventional biomarker for neurogenesis in vivo. This would be an urgently needed requisite for translational studies in humans regarding the beneficial role of adult neurogenesis for the structural and functional integrity of the brain. However, many concerns have risen about the validity of the proposed signal as a specific marker for NSCs. The peak has also been related to cell-type-independent phenomena such as apoptosis or necrosis. Thus, we compared the 1.28-ppm peak in various immature stem cell populations, including embryonic stem cells, mouse embryonic fibroblasts, embryonic stem cell- and induced pluripotent stem cell-derived NSCs, ex vivo isolated embryonic NSCs, as well as mature and tumor cell types from different germ layers. To correlate the integral peak intensity with cell death, we induced both apoptosis with camptothecin and necrosis with sodium azide. A peak at 1.28 ppm was found in most cell types, and in most, but not all, NSCH cultures, demonstrating no specificity for NSCs. The intensities of the 1.28-ppm resonance significantly correlated with the rate of apoptosis, but not with the rate of necrosis, cell cycle phase distribution, cell size, or type. Multiple regression analysis displayed a significant predictive value of the peak intensity for apoptosis only. In this context, its specificity for apoptosis as a major selection process during neurogenesis may suggest this resonance as an indirect marker for neurogenesis in vivo.