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See detailLeveraging the Potential of Digital Technology for Better Individualized Treatment of Parkinson's Disease.
Fröhlich, Holger; Bontridder, Noémi; Petrovska-Delacréta, Dijana et al

in Frontiers in neurology (2022), 13

Recent years have witnessed a strongly increasing interest in digital technology within medicine (sensor devices, specific smartphone apps) and specifically also neurology. Quantitative measures derived ... [more ▼]

Recent years have witnessed a strongly increasing interest in digital technology within medicine (sensor devices, specific smartphone apps) and specifically also neurology. Quantitative measures derived from digital technology could provide Digital Biomarkers (DMs) enabling a quantitative and continuous monitoring of disease symptoms, also outside clinics. This includes the possibility to continuously and sensitively monitor the response to treatment, hence opening the opportunity to adapt medication pathways quickly. In addition, DMs may in the future allow early diagnosis, stratification of patient subgroups and prediction of clinical outcomes. Thus, DMs could complement or in certain cases even replace classical examiner-based outcome measures and molecular biomarkers measured in cerebral spinal fluid, blood, urine, saliva, or other body liquids. Altogether, DMs could play a prominent role in the emerging field of precision medicine. However, realizing this vision requires dedicated research. First, advanced data analytical methods need to be developed and applied, which extract candidate DMs from raw signals. Second, these candidate DMs need to be validated by (a) showing their correlation to established clinical outcome measures, and (b) demonstrating their diagnostic and/or prognostic value compared to established biomarkers. These points again require the use of advanced data analytical methods, including machine learning. In addition, the arising ethical, legal and social questions associated with the collection and processing of sensitive patient data and the use of machine learning methods to analyze these data for better individualized treatment of the disease, must be considered thoroughly. Using Parkinson's Disease (PD) as a prime example of a complex multifactorial disorder, the purpose of this article is to critically review the current state of research regarding the use of DMs, discuss open challenges and highlight emerging new directions. [less ▲]

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See detailDie Geschichte des ‚Freezing-of-gait‘ beim Parkinson-Syndrom – vom Phänomen zum Symptom.
Klucken, Jochen; Winkler, Juergen; Krüger, Rejko UL et al

in Fortschritte der Neurologie-Psychiatrie (2020), 88(9), 573-581

The background of the freezing-of-gait (FOG) phenomenon in Parkinson's syndrome is presented in this review. The following issues are addressed: characterization of the symptom freezing and its subtypes ... [more ▼]

The background of the freezing-of-gait (FOG) phenomenon in Parkinson's syndrome is presented in this review. The following issues are addressed: characterization of the symptom freezing and its subtypes that challenge standardized diagnostic procedures; available assessment methods generating freezing-related parameters that not only support clinical studies but can also be applied in everyday care, and current therapy options. FOG exists in different subtypes, and clinical and diagnostic definitions are limited by subjective characterization and semi-standardized tests. FOG-specific drug options are not existing, apart from the optimization of dopaminergic medication, which may also be due to the poor discriminatory power of standardized diagnostics. This is also true for deep brain stimulation. Both of these therapeutic options may be due not only to the complex neural network alterations as a motor-control correlate of FOG, but also because of challenging diagnostic assessments methodologies. Innovative, wearable, sensor-based diagnostic strategies are currently being developed, and supportive therapies using tools and technologies focusing on 'cueing' are becoming increasingly well accepted. Even though high level evidence is missing, they provide a helpful treatment option for individualized therapy. It can be assumed that these options will become particularly popular due to technological progress and likely alter the everyday treatment challenges faced by doctors and therapists. [less ▲]

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See detailManagement of Parkinson’s Disease 20 Years from Now: Towards Digital Health Pathways
Krüger, Rejko UL; Klucken, Jochen; Bloem, Bastiaan et al

in Journal of Parkinson's Disease (2018)

[en] Current best medical treatment for patients with Parkinson’s disease (PD) involves a medical professional who applies state-of-the-art knowledge of diagnostics and treatment— as derived from cohort ... [more ▼]

[en] Current best medical treatment for patients with Parkinson’s disease (PD) involves a medical professional who applies state-of-the-art knowledge of diagnostics and treatment— as derived from cohort studies and clinical trials— to the healthcare process of individual patients. Thus, the much-needed personalization of medicine depends on the abilities, experience and intuition of medical professionals to adjust group-based knowledge to individual decision making. Within 20 years from now, such personal clinical decisions will be largely supported by digital means, also defining a new ecosystem of healthcare often referred to as “digital medicine”. We expect that the next phase of digitalization will include new “digital health pathways”: data-driven personalized decision support that is based on a combination of multimodal data sources, including evidence-based medical knowledge (e.g., clinical guidelines), personal disease profiles (including genetic determinants of disease progression and treatment response), insights into individual disease trajectories (thereby defining subgroups of patients) and individual patients’ needs. Here, we illustrate the potential of this development by sketching the contours of a digitally supported care pathway for gait disability and falls. Such digital health pathways will support the introduction of personalized medicine for PD patients, allowing patients to benefit optimally from individually tailored treatments. This should result in a better quality of life for patients and lower costs for society. [less ▲]

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See detailThe Luxembourg Parkinson’s Study: A Comprehensive Approach for Stratification and Early Diagnosis
Hipp Epouse D'amico, Géraldine UL; Vaillant, Michel; Diederich, Nico J. et al

in Frontiers in Aging Neuroscience (2018), 10

While genetic advances have successfully defined part of the complexity in Parkinson’s disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies ... [more ▼]

While genetic advances have successfully defined part of the complexity in Parkinson’s disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson’s study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches. [less ▲]

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See detailClassification of advanced stages of Parkinson's disease: translation into stratified treatments.
Krüger, Rejko UL; Klucken, Jochen; Weiss, Daniel et al

in Journal of Neural Transmission (2017), 124(124), 1015-1027

Advanced stages of Parkinson's disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain ... [more ▼]

Advanced stages of Parkinson's disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain milestones of motor disability apparently fall short in addressing the increasingly recognized complexity of motor and non-motor symptoms and do not allow to account for the clinical heterogeneity that require more personalized approaches. Therefore, deep phenotyping approaches are required to characterize the broad-scaled, continuous and multidimensional spectrum of disease-related motor and non-motor symptoms and their progression under real-life conditions. This will also facilitate the reasoning for clinical care and therapeutic decisions, as neurologists currently have to refer to clinical trials that provide guidance on a group level; however, this does not always account for the individual needs of patients. Here, we provide an overview on different classifications for advPD that translate into critical phenotypic patterns requiring the differential therapeutic adjustments. New concepts refer to precision medicine approaches also in PD and first studies on genetic stratification for therapeutic outcomes provide a potential for more objective treatment recommendations. We define novel treatment targets that align with this concept and make use of emerging device-based assessments of real-life information on PD symptoms. As these approaches require empowerment of patients and integration into treatment decisions, we present communication strategies and decision support based on new technologies to adjust treatment of advPD according to patient demands and safety. [less ▲]

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See detailOverexpression of synphilin-1 promotes clearance of soluble and misfolded alpha-synuclein without restoring the motor phenotype in aged A30P transgenic mice.
Casadei, Nicolas; Pohler, Anne-Maria; Tomas-Zapico, Cristina et al

in Human molecular genetics (2014), 23(3), 767-81

Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures are composed of fibrillized and ubiquitinated alpha-synuclein suggesting that impaired protein clearance is ... [more ▼]

Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures are composed of fibrillized and ubiquitinated alpha-synuclein suggesting that impaired protein clearance is an important event in aggregate formation. The A30P mutation is known for its fast oligomerization, but slow fibrillization rate. Despite its toxicity to neurons, mechanisms involved in either clearance or conversion of A30P alpha-synuclein from its soluble state into insoluble fibrils and their effects in vivo are poorly understood. Synphilin-1 is present in Lewy bodies, interacting with alpha-synuclein in vivo and in vitro and promotes its sequestration into aggresomes, which are thought to act as cytoprotective agents facilitating protein degradation. We therefore crossed animals overexpressing A30P alpha-synuclein with synphilin-1 transgenic mice to analyze its impact on aggregation, protein clearance and phenotype progression. We observed that co-expression of synphilin-1 mildly delayed the motor phenotype caused by A30P alpha-synuclein. Additionally, the presence of N- and C-terminal truncated alpha-synuclein species and fibrils were strongly reduced in double-transgenic mice when compared with single-transgenic A30P mice. Insolubility of mutant A30P and formation of aggresomes was still detectable in aged double-transgenic mice, paralleled by an increase of ubiquitinated proteins and high autophagic activity. Hence, this study supports the notion that co-expression of synphilin-1 promotes formation of autophagic-susceptible aggresomes and consecutively the degradation of human A30P alpha-synuclein. Notably, although synphilin-1 overexpression significantly reduced formation of fibrils and astrogliosis in aged animals, a similar phenotype is present in single- and double-transgenic mice suggesting additional neurotoxic processes in disease progression. [less ▲]

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See detailGuidelines for the use and interpretation of assays for monitoring autophagy.
Klionsky, Daniel J.; Abdalla, Fabio C.; Abeliovich, Hagai et al

in Autophagy (2012), 8(4), 445-544

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field ... [more ▼]

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field. [less ▲]

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