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    Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial
    (2023) Yuluğ, Burak; Altay, Özlem; Li, Xiangyu; Hanoğlu, Lütfü; Çankaya, Şeyda; Lam, Simon; Velioğlu, Halil Aziz; Yang, Hong; Coşkun, Ebru; İdil, Ezgi; Nogaylar, Rahim; Özşimşek, Ahmet; Bayram, Cemil; Bolat, İsmail; Öner, Sena; Tozlu, Özlem Özdemir; Arslan, Mehmet Enes; Hacımüftüoğlu, Ahmet; Yıldırım, Serkan; Arif, Muhammad; Shoaie, Saeed; Zhang, Cheng; Nielsen, Jens; Turkez, Hasan; Boren, Jan; Uhlen, Mathias; Mardinoğlu, Adil
    Abstract Background Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the efect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the frst 28 days and twice daily between day 28 and day 84. The primary endpoint was the diference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efcacy of the CMA in AD patients. Results We showed a signifcant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P=0.00001, 29% improvement) in the CMA group. Moreover, there was a signifcant decline (P=0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of
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    Differentiation of claustrum resting-state functional connectivity in healthy aging, Alzheimer's disease, and Parkinson's disease
    (2023) Ayyıldız, Sevilay; Velioğlu, Halil Aziz; Ayyıldız, Behçet; Sütçübaşı, Bernis; Hanoğlu, Lütfü; Bayraktaroğlu, Zübeyir; Yıldırım, Süleyman; Atasever, Alper; Yuluğ, Burak
    The claustrum is a sheet-like of telencephalic gray matter structure whose function is poorly understood. The claustrum is considered a multimodal computing network due to its reciprocal connections with almost all cortical areas as well as subcortical structures. Although the claustrum has been involved in several neurodegenerative diseases, specific changes in connections of the claustrum remain unclear in Alzheimer's disease (AD), and Parkinson's disease (PD). Resting-state fMRI and T1-weighted structural 3D images from healthy elderly (n = 15), AD (n = 16), and PD (n = 12) subjects were analyzed. Seed-based FC analysis was performed using CONN FC toolbox and T1-weighted images were analyzed with the Computational Anatomy Toolbox for voxel-based morphometry analysis. While we observed a decreased FC between the left claustrum and sensorimotor cortex, auditory association cortex, and cortical regions associated with social cognition in PD compared with the healthy control group (HC), no significant difference was found in alterations in the FC of both claustrum comparing the HC and AD groups. In the AD group, high FC of claustrum with regions of sensorimotor cortex and cortical regions related to cognitive control, including cingulate gyrus, supramarginal gyrus, and insular cortex were demonstrated. In addition, the structural results show significantly decreased volume in bilateral claustrum in AD and PD compared with HC. There were no significant differences in the claustrum volumes between PD and AD groups so the FC may offer more precise findings in distinguishing changes for claustrum in AD and PD. © 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.
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    DLPF Targeted Repetitive Transcranial Magnetic Stimulation Improves Brain Glucose Metabolism Along with the Clinical and Electrophysiological Parameters in CBD Patients
    (2022) Toprak, Güven; Hanoğlu, Lütfü; Çakır, Tansel; Gümtekin, Bahar; Velioğlu, Halil Aziz; Yuluğ, Burak
    Background: Corticobasal Degeneration (CBD) is a rare neurological disease caused by the pathological accumulation of tau protein. The primary pathological features of CBD include progressive neurodegenerative processes resulting in remarkable frontoparietal and basal ganglia atrophy. Objective: Like in many other neurodegenerative disorders, there is still no effective disease-modifying drug therapy in CBD. Therefore, the development of new treatment methods is of great importance. In this study, we aimed to assess the stimulating effects of high-frequency DLPFC rTMS on the motor, cognitive and behavioral disturbances in four CBD patients. Methods: Four (three females, one male) CBD patients who had been diagnosed as CBD were enrolled in this study. Patients were evaluated before and after the rTMS procedure regarding the motor, neuropsychometric and behavioral tests. The results of statistical analysis of behavioral and neuropsychometric evaluation were assessed via SPSS 18.0 package program. Data are expressed as mean, standard deviation. Before and after values of the groups were compared with the Wilcoxon sign rank test, and p<0.05 was considered significant. Results: We have provided strong preliminary evidence that the improvement in clinical parameters was associated with the normalizations of the theta activity and glucose metabolism. Conclusion: Our current results are consistent with some previous trials showing a strong association between DLPFC targeted rTMS and electrophysiological normalizations in the left DLPFC.
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    The effect of Resveratrol on sphingosine-1 and Oxidative/ Nitrosative stress in an experimental heart ischemia reperfusion model
    (2022) Avnioğlu, Seda; Güngör, Meltem; Kurutaş, Ergül; Öztürk, Ünal; Demirhan, İlter; Bakaris, Sevgi; Velioğlu, Halil Aziz; Çankaya, Şeyda; Yuluğ, Burak
    Objectives: Resveratrol (RSV) is a natural polyphenolic compound showing significant antioxidant effects. In this study, we aimed to investigate the effects of resveratrol on the sphingosine-1-phosphate (S1P) and oxidative stress biomarkers in hearth ischemia-reperfusion (I/R). Materials and Methods: The biochemical and histopathological effects of RSV on cardiac ischemia-reperfusion injury were investigated through ELISA- and light microscope. Results: We observed statistically significant differences between the treatment group and the control group in terms of malondialdehyde (MDA) level, catalase (CAT) and superoxide dismutase (SOD) activities (p<0.05). Histopathologically, we also observed decreased Polymorphonuclear Leucocyte (PMNL) infiltration, myocardial edema, miyositolysis in the treatment group compared to the I/R and sham groups. Conclusion: Resveratrol may play an important role in cardiac I/R injury through its anti-inflammatory and antioxidant effects which were biochemically and histopathologically confirmed in the present study.
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    Therapeutic Role of Repetitive Transcranial Magnetic Stimulation in Alzheimer's and Parkinson's Disease: Electroencephalography Microstate Correlates
    (2022) Hanoğlu, Lütfü; Toplutaş, Eren; Sarıcaoğlu, Mevhibe; Velioğlu, Halil Aziz; Yıldız, Sultan; Yuluğ, Burak
    Introduction: The microstate analysis is a method to convert the electrical potentials on the multi-channel electrode array to topographical electroencephalography (EEG) data. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method that can modulate brain networks. This study explores the pathophysiological changes through microstate analysis in two different neurodegenerative diseases, Alzheimer's (AD) and Parkinson's disease (PD), characterized by motor and cognitive symptoms and analysis the effect of rTMS on the impaired cognitive and motor functions. Materials and methods: We included 18 AD, 8 PD patients, and 13 age-matched controls. For both groups, we applied 5 Hz rTMS on the left pre-SMA in PD patients while 20 Hz rTMS on the left lateral parietal region in AD patients. Each patient was re-evaluated 1 week after the end of the sessions, which included a detailed clinical evaluation and measurement of EEG microstates. Results: At the baseline, the common findings between our AD and PD patients were altered microstate (MS) B, MS D durations and transition frequencies between MS A-MS B, MS C-MS D while global explained variance (GEV) ratio and the extent and frequency of occurrence of MS A, MS B, and MS D were separately altered in AD patients. Although no specific microstate parameter adequately differentiated between AD and PD patients, we observed significant changes in MS B and MS D parameters in PD patients. Further, we observed that Mini-Mental State Examination (MMSE) performances were associated with the transition frequencies between MS A-MS B and MS C-MS D and GEV ratio. After left parietal rTMS application, we have observed significantly increased visual memory recognition and clock drawing scores after left parietal rTMS application associated with improved microstate conditions prominent, especially in the mean duration of MS C in AD patients. Also, pre-SMA rTMS resulted in significant improvement in motor scores and frequency of transitions from MS D to MS C in PD patients. Conclusion: This study shows that PD and AD can cause different and similar microstate changes that can be modulated through rTMS, suggesting the role of MS parameters and rTMS as a possible combination in monitoring the treatment effect in neurodegenerative diseases.
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    Therapeutic role of repetitive transcranial magnetic stimulation in alzheimer's and parkinson's disease: Electroencephalography microstate correlates
    (2022) Hanoğlu, Lütfü; Toplutaş, Eren; Sarıcaoğlu, Mevhibe; Velioğlu, Halil Aziz; Yıldız, Sultan; Yuluğ, Burak
    IntroductionThe microstate analysis is a method to convert the electrical potentials on the multi-channel electrode array to topographical electroencephalography (EEG) data. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method that can modulate brain networks. This study explores the pathophysiological changes through microstate analysis in two different neurodegenerative diseases, Alzheimer's (AD) and Parkinson's disease (PD), characterized by motor and cognitive symptoms and analysis the effect of rTMS on the impaired cognitive and motor functions. Materials and MethodsWe included 18 AD, 8 PD patients, and 13 age-matched controls. For both groups, we applied 5 Hz rTMS on the left pre-SMA in PD patients while 20 Hz rTMS on the left lateral parietal region in AD patients. Each patient was re-evaluated 1 week after the end of the sessions, which included a detailed clinical evaluation and measurement of EEG microstates. ResultsAt the baseline, the common findings between our AD and PD patients were altered microstate (MS) B, MS D durations and transition frequencies between MS A-MS B, MS C-MS D while global explained variance (GEV) ratio and the extent and frequency of occurrence of MS A, MS B, and MS D were separately altered in AD patients. Although no specific microstate parameter adequately differentiated between AD and PD patients, we observed significant changes in MS B and MS D parameters in PD patients. Further, we observed that Mini-Mental State Examination (MMSE) performances were associated with the transition frequencies between MS A-MS B and MS C-MS D and GEV ratio. After left parietal rTMS application, we have observed significantly increased visual memory recognition and clock drawing scores after left parietal rTMS application associated with improved microstate conditions prominent, especially in the mean duration of MS C in AD patients. Also, pre-SMA rTMS resulted in significant improvement in motor scores and frequency of transitions from MS D to MS C in PD patients. ConclusionThis study shows that PD and AD can cause different and similar microstate changes that can be modulated through rTMS, suggesting the role of MS parameters and rTMS as a possible combination in monitoring the treatment effect in neurodegenerative diseases.
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    Topological network mechanisms of clinical response to antidepressant treatment in drug-naive major depressive disorder
    (Churchill Livingstone, 2021) Uykur, Abdullah Burak; Yıldız, Sultan; Velioğlu, Halil Aziz; Özşimşek, Ahmet; Öktem, Ece Özdemir; Bayraktaroğlu, Zübeyir; Ergün, Tarkan; Lakadamyalı, Hatice; Hanoğlu, Lütfi; Hanoğlu, Lütfi; Çankaya, Şeyda; Saatçi, Özlem; Yuluğ, Burak
    Aim: There is rapidly increasing evidence that remission of MDD is associated with substantial changes in functional brain connectivity. These New data have provided a holistic view on the mechanism of antidepressants on multiple levels that goes beyond their conventional effects on neurotransmitters. Method: The study was approved by the Local Ethics Committee of Istanbul Medipol University (10840098-604.01.01-E.65129) and followed the Helsinki Declaration principles. In our study, we have evaluated the effect of six weeks of treatment with antidepressants (escitalopram and duloxetine), and tested the underlying brain functional connectivity through a Graph analysis approach in a well-defined first-episode, drug-naive, and non-comorbid population with MDD. Results: Beyond indicating that there was a significant correlation between the antidepressant response and topological characteristics of the brain, our results suggested that global rather than regional network alterations may be implicated in the antidepressant effect. Conclusion: Despite the small-sample size and non-controlled study design, our study provides important and relevant clinical data regarding the underlying mechanisms of the antidepressants on topological dynamics in the human brain. © 2020 Elsevier Ltd