Pathophysiological mechanisms in Parkinson`s Disease and Dystonia – converging aetiologies

In this thesis I used a range of experimental approaches including genetics, enzyme activity measurements, histology and imaging to explore converging pathophysiological mechanisms of Parkinson`s disease and dystonia, two conditions with frequent clinical overlap. First, based on a combined retro- and prospective cohort of patients, using a combination of lysosomal enzyme activity measurements in peripheral blood and brain samples, as well as a target gene approach, I provide first evidence of reduced levels of enzyme activity in Glucocerebrosidase and the presence of GBA mutations, indicating lysosomal abnormality, in a relevant proportion of patients with dystonia of previously unknown origin. Second, based on a retrospective cohort of patients, I detail that a relevant proportion of genetically confirmed mitochondrial disease patients present with a movement disorder phenotype - predominantly dystonia and parkinsonism. Analysing volumetric MRI data, I describe a patterned cerebellar atrophy in these particular patients. This also includes the first cases of isolated dystonia due to mitochondrial disease, adding the latter as a potential aetiology for dystonia of unknown origin. Third, I used a combination of post-GWAS population genetic approaches and tissue-based experiments to explore in how far the strong association between advancing age and Parkinson ́s disease is mediated via telomere length. Although the initial finding of an association between genetically determined telomere length and PD risk did not replicate in independent cohorts, I provide evidence that telomere length in human putamen physiologically shortens with advancing age and 3 is regulated differently than in other brain regions. This is unique in the human brain, implying a particular age-related vulnerability of the striatum, part of the nigro-striatal network, crucially involved in PD pathophysiology. I conclude by discussing the above findings in light of the current literature, expand on their relevance and possible direction of future experiments

Ortaöğretim Bilgisayar Bilimi Ders Kitabındaki Analojilerin İncelenmesi

Bu araştırmanın temel amacı Türkiye'de ortaöğretim düzeyinde okutulan bilgisayar bilimi adlı dersin resmi ders kitabını, analojilerin nicelikleri ve nitelikleri açısından analiz etmektir. Bu araştırma nitel bir çalışmadır ve nitel araştırma yöntemlerinden içerik analizi tekniği uygulanmıştır. İçerik analizi bir alanda var olan literatürü değerlendirmeye yardımcı olan bir yöntem olduğundan bu teknikte “dokümanlar” araştırmanın amacına uygun olarak, Milli Eğitim Bakanlığı tarafından 2017 yılında yayınlanan ortaöğretim düzeyine ait "Bilgisayar Bilimi" Ders kitabıdır. Bu bağlamda bilgisayar bilimi ders kitabı, eleştirel bir göz ile literatürde yer alan bir analoji sınıflandırılması kapsamında incelenmiştir. Ayrıca bu sınıflamaya ek olarak “kişisel analoji” kategorisi de dahil edilmiştir. Yapılan incelemeler sonucunda İlişkilerine Göre, Sunum Formatına Göre, Durumuna Göre, Görevine Göre, Zenginlik Düzeyine Göre ayrılan analojilerin kitapta yer aldığı fakat Kişisel olarak kategorize edilen analojilerin kitapta hiç yer almadığı görülmüştür. Son olarak araştırma sonuçlarına göre toplamda analoji sayılarının oldukça yetersiz olduğundan dolayı genel olarak tüm sınıflandırma tiplerinde analojileri arttırma yoluna gidilmesi gerektiği önerilir

Der Einfluss humanen Wildtyp-Alpha-Synucleins auf die Adulte Neurogenese am Beispiel der transgenen mThy1-Alpha-Synuclein-Maus

Einleitung: Das pathologische Charakteristikum des Parkinson-Syndroms ist die Akkumulation und Aggregation von α-Synuclein in Neuronen des Gehirns. Transgene (tg) humanes Wildtyp (h-wt) α-Synuclein-Tiere simulieren bestimmte Aspekte des Parkinson-Syndroms. Die adulte Neurogenese, die Neubildung neuer Neurone im adulten hippocampalen Gyrus dentatus und im System Subventrikularzone – Bulbus olfactorius ist in Modelltieren zum Parkinson-Syndrom verändert. Bei tg hPDGFβ h-wt α-Synuclein-Mäusen ist die Zahl neu gebildeter Neurone durch eine vermehrte Apoptose neu geborener Zellen in Hippocamps und Blubus olfactorius vermindert. Ziel der vorliegenden Studie war es, die adulte Neurogenese in Tieren zu analysieren, die h-wt α-Synuclein unter der regulatorischen Kontrolle von mThy1 exprimieren, da diese eine höhere Synuclein-Expression als hPDGFβ h-wt α-Synuclein-Tiere zeigen. Darüberhinaus wurden beide tg Mausstämme bezüglich der Pathologie an Dendriten und synaptischen spines analysiert und mit Kontrollen verglichen. Methoden: Standard Immunhistochemie, Immunfluoreszenz, Konfokalmikroskopie; Hippocampale retrovirale Injektionen mit einem CAG-GFP Konstrukt mit nachfolgender Analyse der Dendriten und synaptischen Spines markierter neu geborener hippocampaler Neurone; Ergebnisse: 1) Im Vergleich zu Kontrollen weisen tg h-wt mThy1 Tiere eine um 38% signifikant verminderte Anzahl reifer hippocampaler Neuroblasten (p=0,04) auf, ohne sich darüber hinaus in Proliferation, Überleben, Differenzierung oder Apoptose neu geborener Neurone von Kontrollen zu unterscheiden. 2) Während Neuroblasten bei hPDGFβ tg Tieren α-Synuclein ab den frühesten Stadien der neuronalen Differenzierung exprimieren, ist dies in mThy1 Tieren erst später - nach dem Stadium Doublecortin-positiver Neuroblasten - der Fall. 3) Tg mThy1 α-Synuclein Tiere weisen aufgrund einer verminderten dopaminergen Differenzierung um 61% weniger dopaminerge neugeborene Neuronen in der Glomerulärzellschicht des Bulbus olfactorius auf (p=0,04). 4) Neu geborene mThy1 und hPDGFβ Neurone weisen signifikant kürzere Dendriten, mThy1 Neurone zusätzlich eine verminderrte Dichte synaptischer spines auf. Zusammenfassung: Die adulte Neurogenese ist bei der tg hPDGFβ α-Synuclein Maus deutlicher vermindert als bei der tg mThy1 Maus – wahrscheinlich aufgrund einer Promotor-abhängig früheren Expression von α-Synuclein. Daher spekulieren wir, dass der Effekt von α-Synuclein auf die adulte hippocampale Neurogenese nicht nur vom quantitativen sondern auch temporalen Expressionsmuster abhängt. Die bekannten Verhaltensdefizite der mThy1 Maus sind wahrscheinlich mit dem durch eine verminderte dopaminerge Differenzierung bedingten signifikanten Unterschied in der Neurogenese im Bulbus olfactorius assoziiert. Die quantifizierten Unterschiede im dendritischen Verzweigungsmuster und Bildung synaptischer spines an neu geborenen Neuronen zwischen mThy1, hPDGFβ und Kontrolltieren spiegelt nicht nur die unterschiedlichen Expressionsmuster der verschiedenen Promotoren wieder, sondern ähnelt auch den neuronalen Dendritenpathologien bei Patienten mit Parkinson-Syndrom

Functional lesional neurosurgery for tremor - a protocol for a systematic review and meta-analysis

Introduction: The recent introduction of incision-less lesional neurosurgery using Gamma Knife and MRI-guided focused ultrasound has revived interest in lesional treatment options for tremor disorders. Preliminary literature researches reveal that the consistency of treatment effects after lesional neurosurgery for tremor has not formally been assessed yet. Similarly, the efficacy of different targets for lesional treatment and incidence of persistent side effects of lesional neurosurgical interventions has not been comprehensively assessed. This work therefore aims to describe a suitable process how to review the existing literature on efficacy and persistent side effects of lesional neurosurgical treatment for tremor due to Parkinson’s disease, essential tremor, multiple sclerosis and midbrain/rubral tremor. Methods and analysis: We will search electronic databases (Medline, Cochrane) and reference lists of included articles for studies reporting lesional interventions for tremor in cohorts homogeneous for tremor aetiology and intervention (technique and target). We will include cohorts with a minimum number of five subjects and follow-up of 2 months. One investigator will perform the initial literature search and two investigators then independently decide which references to include for final efficacy and safety analysis. After settling of disagreement, data will be extracted from articles using a standardised template. We will perform a random-effect meta-analysis calculating standardised mean differences (Hedge’s g) for comparison in Forest plots and subgroup analysis after assessment of heterogeneity using I2 statistics. Ethics and dissemination: This study will summarise the available evidence on the efficacy of lesional interventions for the most frequent tremor disorders, as well as for the incidence rate of persisting side effects after unilateral lesional treatment. This data will be useful to guide future work on incision-less lesional interventions for tremor. Systematic review registration: This study has been registered with the PROSPERO database (no. CRD42016048049)

Machine Learning in Tremor Analysis: Critique and Directions

Tremor is the most frequent human movement disorder, and its diagnosis is based on clinical assessment. Yet finding the accurate clinical diagnosis is not always straightforward. Fine-tuning of clinical diagnostic criteria over the past few decades, as well as device-based qualitative analysis, has resulted in incremental improvements to diagnostic accuracy. Accelerometric assessments are commonplace, enabling clinicians to capture high-resolution oscillatory properties of tremor, which recently have been the focus of various machine-learning (ML) studies. In this context, the application of ML models to accelerometric recordings provides the potential for less-biased classification and quantification of tremor disorders. However, if implemented incorrectly, ML can result in spurious or nongeneralizable results and misguided conclusions. This work summarizes and highlights recent developments in ML tools for tremor research, with a focus on supervised ML. We aim to highlight the opportunities and limitations of such approaches and provide future directions while simultaneously guiding the reader through the process of applying ML to analyze tremor data. We identify the need for the movement disorder community to take a more proactive role in the application of these novel analytical technologies, which so far have been predominantly pursued by the engineering and data analysis field. Ultimately, big-data approaches offer the possibility to identify generalizable patterns but warrant meaningful translation into clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

İlahiyat fakültesi öğrencilerinin mobil öğrenmeye yönelik tutumları

Bu araştırma, İlahiyat Fakültesi’nde okuyan öğrencilerin mobil öğrenme teknolojilerine yönelik tutumlarını incelemeyi amaçlanmıştır. Bu temel amaç doğrultusunda katılımcıların “Mobil Öğrenmeye Yönelik Tutum Ölçeğinden” aldıklarıpuanların cinsiyet/sınıf değişkenine göre anlamlı bir farklılık gösterip göstermediğine bakılmıştır. Araştırma yöntemi olarak nicel araştırma yöntemlerinden nedensel karşılaştırma tercih edilmiştir. Araştırmanın örneklemini; Hatay MustafaKemal Üniversitesi (MKÜ) İlahiyat Fakültesi’nde 1. Sınıfta (55) ve 2. Sınıfta (46)okuyan ve yaşları 18-30 arasında değişen toplam 101 gönüllü öğrenci oluşturmaktadır. Araştırmaya katılan öğrencilerin mobil öğrenmeye yönelik tutumlarına ait veriler nicel olarak Demir ve Akpınar tarafından 2016 yılında geliştirilen“Mobil Öğrenmeye Yönelik Tutum Ölçeği” ile toplanmıştır. Araştırmada eldeedilen nicel veriler SPSS 20.0 veri analizi programı ile çözümlenmiş ve bağımsızgruplar t-testi ile analiz edilmiştir. Araştırmanın ilk sonucuna göre çalışmaya katılan İlahiyat Fakültesi öğrencilerinin cinsiyet değişkenine göre ölçek alt faktörlerinde (memnuniyet, öğrenmeye etki, motivasyon, kullanışlılık) ve ölçek toplampuanlarının anlamlı bir şekilde farklılaşmadığı sonucuna ulaşılmıştır. İkinci olarak katılımcılar arasında sınıf değişkenine göre kullanışlılık alt ölçeğinde anlamlıbir farklılık olmadığı; fakat memnuniyet, öğrenmeye etki, motivasyon ve ölçektoplam puanı açısından anlamlı bir farklılık olduğu ortaya çıkmıştır.In this study, it is aimed to examine the attitudes of students studying at Hatay Mustafa Kemal University, Faculty of Theology towards mobile learning technologies. In line with this basic purpose, it was examined whether the scores the participants got from the “Attitude Scale towards Mobile Learning” differed significantly by gender / class variables. Quantitative research method was preferred as the research method. The study group of the research; A total of 101 volunteer students, aged between 18-30 and studying at the 1st grade (55) and 2nd grade (46) of the Faculty of Theology at Hatay Mustafa Kemal University (MKU). The data related to the attitudes of the students who participated in the research towards mobile learning were collected quantitatively with the “Attitude Scale towards Mobile Learning” developed by Demir and Akpınar in 2016. Quantitative data obtained in the study were analyzed with SPSS 20.0 data analysis program and independent groups were analyzed by t-test. According to the first result of the research, it was concluded that the students of the Faculty of Theology who participated in the study differed from the scale sub-factors (satisfaction, effect on learning, motivation, usefulness) and scale total scores, but this difference was not significant. Secondly, there was no significant difference in the usefulness subscale according to the class variable among the participants; but there was a significant difference in satisfaction, learning effect, motivation and scale total score

İlahiyat Fakültesi öğrencilerinin mobil öğrenmeye yönelik tutumları

Bu araştırma, İlahiyat Fakültesi’nde okuyan öğrencilerin mobil öğrenme teknolojilerine yönelik tutumlarını incelemeyi amaçlanmıştır. Bu temel amaç doğrultusunda katılımcıların “Mobil Öğrenmeye Yönelik Tutum Ölçeğinden” aldıkları puanların cinsiyet/sınıf değişkenine göre anlamlı bir farklılık gösterip göstermediğine bakılmıştır. Araştırma yöntemi olarak nicel araştırma yöntemlerinden nedensel karşılaştırma tercih edilmiştir. Araştırmanın örneklemi; Hatay Mustafa Kemal Üniversitesi (MKÜ) İlahiyat Fakültesi’nde 1. Sınıfta (55) ve 2. Sınıfta (46) okuyan ve yaşları 18-30 arasında değişen toplam 101 gönüllü öğrenci oluşturmaktadır. Araştırmaya katılan öğrencilerin mobil öğrenmeye yönelik tutumlarına ait veriler nicel olarak Demir ve Akpınar tarafından 2016 yılında geliştirilen “Mobil Öğrenmeye Yönelik Tutum Ölçeği” ile toplanmıştır. Araştırmada elde edilen nicel veriler SPSS 20.0 veri analizi programı ile çözümlenmiş ve bağımsız gruplar t-testi ile analiz edilmiştir. Araştırmanın ilk sonucuna göre çalışmaya katılan İlahiyat Fakültesi öğrencilerinin cinsiyet değişkenine göre ölçek alt faktörlerinde (memnuniyet, öğrenmeye etki, motivasyon, kullanışlılık) ve ölçek toplam puanlarının anlamlı bir şekilde farklılaşmadığı sonucuna ulaşılmıştır. İkinci olarak katılımcılar arasında sınıf değişkenine göre kullanışlılık alt ölçeğinde anlamlı bir farklılık olmadığı; fakat memnuniyet, öğrenmeye etki, motivasyon ve ölçek toplam puanı açısından anlamlı bir farklılık olduğu ortaya çıkmıştır

Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal

Delayed gastric emptying (GE) is a frequent non-motor feature in Parkinson´s disease (PD). This prospective study (clinicaltrials.gov Identifier NCT01518751) investigated GE and visceral perception in early motor phase PD patients in comparison to age-matched and younger controls. In addition, the effect of Levodopa on GE was assessed in healthy aged controls. 16 PD patients (Hoehn & Yahr 2), 11 sex-/age-matched Ctrl1 and 10 young, male Ctrl2 subjects were subjected to a high caloric (428 kcal) (13)C-Sodium Octanoate breath test strictly OFF dopaminergic medication. Visceral appetite sensation was monitored using visual analogue scales (VAS). GE was similarly studied in 7 controls ON/OFF oral Levodopa. GE was not altered in PD patients compared to age-/sex-matched and younger controls (p = 0.76). Subjective appetite perception was not altered in the PD group in comparison to Ctrl1, but was significantly higher in Ctrl2 subjects (p = 0.02). 100 mg oral Levodopa/25 mg Benserazide significantly slowed GE by 18% among healthy controls (p = 0.04). In early motor stage PD OFF dopaminergic medication, there was no GE slowing after a high caloric test meal. Levodopa, however, caused a robust GE slowing in healthy aged individuals. Our data indicate that clinically relevant GE slowing in early PD is related to the iatrogenic effect of dopamine treatment. Subjective appetite perception is not affected in this disease stage. This data add to the understanding of gastrointestinal symptoms in early motor stage PD and highlight the influence of dopaminergic medication

Functional lesional neurosurgery for tremor: back to the future?

For nearly a century, functional neurosurgery has been applied in the treatment of tremor. While deep brain stimulation has been in the focus of academic interest in recent years, the establishment of incisionless technology, such as MRI-guided high-intensity focused ultrasound, has again stirred interest in lesional approaches.In this article, we will discuss the historical development of surgical technique and targets, as well as the technological state-of-the-art of conventional and incisionless interventions for tremor due to Parkinson's disease, essential and dystonic tremor and tremor related to multiple sclerosis (MS) and midbrain lesions. We will also summarise technique-inherent advantages of each technology and compare their lesion characteristics. From this, we identify gaps in the current literature and derive future directions for functional lesional neurosurgery, in particularly potential trial designs, alternative targets and the unsolved problem of bilateral lesional treatment. The results of a systematic review and meta-analysis of the consistency, efficacy and side effect rate of lesional treatments for tremor are presented separately alongside this article

Focused ultrasound ablation as tremor treatment

BACKGROUND: The development of high-intensity magnetic resonance imaging (MRI)-guided focused ultrasound (MRIgFUS) ablation has widened the spectrum of interventional techniques for stereotactic functional neurosurgery of lesions. This has resulted in novel incisionless intervention approaches for the therapy of tremor disorders. The safety and efficacy is documented by recent study data. OBJECTIVES: This article encompasses a description of the technological basis and typical course of MRIgFUS interventions, a comparison to alternative open or incisionless surgical techniques as well as a review of the current evidence base for MRIgFUS ablation in the context of lesional interventions to treat tremor. MATERIAL AND METHODS: Narrative literature review and comparison. METHODS: RESULTS: Depending on the surgical target and tremor etiology published trials of MRIgFUS ablation report a reduction of tremor intensity of up to 80% after 6–12 months follow-up without the disadvantages of open brain surgery. CONCLUSION: The MRIgFUS functional neurosurgery is conducted only at a limited number of treatment sites. First data on lesions of the thalamic ventral intermediary nucleus (V.im.) as well as subthalamic fiber tracts have been published. These results indicate an effective and safe treatment of tremor disorders by MRIgFUS ablation. Incisionless lesional surgery using MRIgFUS is a significant addition to the interventional armamentarium for functional stereotactic neurosurgery and a potentially valuable alternative to established interventional therapy options for tremor disorders