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Öğe A structural and resting-state functional connectivity investigation of the pulvinar in elderly individuals and Alzheimer's disease patients(Wiley, 2023) Velioglu, Halil Aziz; Ayyildiz, Behcet; Ayyildiz, Sevilay; Sutcubasi, Bernis; Hanoglu, Lutfu; Bayraktaroglu, Zubeyir; Yulug, BurakIn Alzheimer's disease (AD), structural and functional changes in the brain may give rise to disruption of specific cognitive functions. The aim of this study is to investigate the functional connectivity alterations in the pulvinar's subdivisions and total pulvinar voxel-based morphometry (VBM) changes in individuals with AD and healthy controls. A seed-based functional connectivity analysis was applied to the anterior, inferior, lateral, and medial pulvinar in each hemisphere. Furthermore, VBM analysis was carried out to compare gray matter (GM) volume differences in the pulvinar and thalamus between the two groups. Connectivity analysis revealed that the pulvinar subdivisions had decreased connectivity in individuals with AD. In addition, the pulvinar and thalamus in each hemisphere were significantly smaller in the AD group. The pulvinar may have a role in AD-related cognitive impairments and the intrinsic connectivity network changes and GM loss in pulvinar subdivisions suggest the cognitive deterioration occurring in those with AD. HighlightsThe pulvinar may play a role in pathophysiology of cognitive impairments in those with Alzheimer's disease (AD).Decreased structural volume and functional connectivity were found in patients with AD.The inferior pulvinar is functionally the most affected subdivision by AD compared to the others.Öğe Brain temperature in healthy and diseased conditions: A review on the special implications of MRS for monitoring brain temperature(Elsevier France-Editions Scientifiques Medicales Elsevier, 2023) Yulug, Burak; Velioglu, Halil Aziz; Sayman, Dila; Cankaya, Seyda; Hanoglu, LutfuBrain temperature determines not only an individual's cognitive functionality but also the prognosis and mor-tality rates of many brain diseases. More specifically, brain temperature not only changes in response to different physiological events like yawning and stretching, but also plays a significant pathophysiological role in a number of neurological and neuropsychiatric illnesses. Here, we have outlined the function of brain hyperthermia in both diseased and healthy states, focusing particularly on the amyloid beta aggregation in Alzheimer's disease.Öğe Chemogenetic inhibition of MCH neurons does not alter memory performance in mice(Elsevier France-Editions Scientifiques Medicales Elsevier, 2022) Mutlu-Burnaz, Ozlem; Yulug, Burak; Oncul, Merve; Celik, Esref; Atasoy, Nilufer Sayar; Cankaya, Seyda; Hanoglu, LutfuMemory storage in the brain is one of the most extensively studied subjects in neuroscience. However, due to the highly complex structure of the memory-related systems in the brain, the mystery remains unsolved. Consoli-dation is one of the most important parts of the memory process, and one that can be affected by numerous neurodegenerative diseases. Hypothalamic melanin-concentrating hormone (MCH) neuronal activity has been of particular interest to researchers in terms of the association between sleep, neurodegenerative diseases, and memory consolidation. We used Pmch-Cre animals to investigate the role of MCH neuronal activity in memory consolidation. In order to observe the differences in memory consolidation, we chemogenetically inhibited MCH neurons using the DREADD method and measured hippocampus-dependent memory performance with a novel object recognition test applicable to early memory impairment in Alzheimer's disease. Our results revealed no significant improvement or worsening with MCH inhibition, suggesting that the role of MCH should now be evaluated in a wider setting.Öğe Depression is an independent risk factor for stroke reccurence and cognitive impairment in stroke patients(Springernature, 2025) Cankaya, Seyda; Safa, Shair Shah; Karakus, Ayse; Savcili, Mehmet; Hanoglu, Lutfu; Mardinoglu, Adil; Cetin, Fatma EcePost-stroke depression (PSD) is a significant sequela of cerebrovascular accidents, affecting a substantial proportion of stroke survivors. However, it is still unclear whether the existence of depression after stroke is an independent risk factor for stroke recurrence and if the increased risk of cognitive impairment in PSD is related to the location of stroke. We aimed to compare the role of cortical, subcortical and cortico-subcortical infarcts in the development of PSD and cognitive impairment, as well as the role of the existence of depression in stroke recurrence. In this study, a 52-week, randomised, double-blind study consisted of 1059 stroke patients (866 non-depressive and 193 untreated depressive persons) who were matched in terms of demographic and clinical parameters. The Mini Mental State Examination Test (MMSE), Executive function (Trail Making Test Part A), processing speed (colour naming condition of the Stroop test), episodic memory (Rey Auditory Verbal Learning Test [RAVLT], including delayed free recall), semantic memory (verbal fluency test [animal naming]), language processing (Boston Naming Test [(number correct]), visuospatial perception (the bells test) was assessed at the baseline. The lesion sites are subdivided as cortical, subcortical, and cortico-subcortical territory infarcts on MRI. The stroke recurrence ratio was also recorded after a year. In results, we observed a higher rate of depression associated with lesions affecting the cortico-subcortical structures in patients with PSD compared to non-depressive patients (p < 0.05). Our results further indicated impaired cognitive scores in patients with PSD compared to those with non-depressive individuals (p < 0.05). Regarding the risk of stroke recurrence, we also found an increased rate of stroke recurrence in PSD after 12 months (p < 0.05). In detail, binomial logistic regression analyses using the backward Wald method determined that patients with depression (p = 007; odds ratio (OR) = 1.64; CI 1.14-2.35), hypertension (p = 0.004; OR = 1.74; CI 1.19-2.55), atrial fibrillation (p = 0.007; OR = 1.61; CI 1.14-2.28) and older age (p = 0.019; OR = 1.02; CI 1.003-1.03) were significantly predictors for stroke recurrency. Our regression analysis further revealed that PSD was a predictive factor for disabling cognitive test scores (impaired executive function [p < 0.001; OR = 4.51; CI 3.24-6.27], reduced processing speed [p < 0.001; OR = 4.29; CI 3.12-5.91], episodic memory [p < 0.001; OR = 4.65; CI 3.37-6.42), semantic memory [p < 0.001; OR = 4.79; 3.47-6.61], visuospatial [p < 0.001; OR = 6.10; CI 4.36-8.55], and language function [p < 0.001; OR = 5.086; CI 3.67-7.05]) after adjusting for age and education. In conclusion, the present study provides strong evidence confirming the importance of depression in predicting cognitive impairment and recurrence in stroke patients. Despite these positive findings, our findings warrant the performance of further research to demonstrate the efficacy of treatment on stroke recurrence, together with other vascular risk factors and cognitive disorders.Öğe Left lateral parietal rTMS improves cognition and modulates resting brain connectivity in patients with Alzheimer?s disease: Possible role of BDNF and oxidative stress(Academic Press Inc Elsevier Science, 2021) Velioglu, Halil Aziz; Hanoglu, Lutfu; Bayraktaroglu, Zubeyir; Toprak, Guven; Guler, Eray Metin; Bektay, Muhammed Yunus; Mutlu-Burnaz, OzlemRepetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuromodulation technique which is increasingly used for cognitive impairment in Alzheimer?s Disease (AD). Although rTMS has been shown to modify Brain-Derived Neurotrophic Factor (BDNF) and oxidative stress levels in many neurological and psychiatric diseases, there is still no study evaluating the relationship between memory performance, BDNF, oxidative stress, and resting brain connectivity following rTMS in Alzheimer?s patients. Furthermore, there are increasing clinical data showing that the stimulation of strategic brain regions may lead to more robust improvements in memory functions compared to conventional rTMS. In this study, we aimed to evaluate the possible disease-modifying effects of rTMS on the lateral parietal cortex in AD patients who have the highest connectivity with the hippocampus. To fill the mentioned research gaps, we have evaluated the relationships between resting-state Functional Magnetic Resonance Imaging (fMRI), cognitive scores, blood BDNF levels, and total oxidative/antioxidant status to explain the therapeutic and potential disease-modifying effects of rTMS which has been applied at 20 Hz frequencies for two weeks. Our results showed significantly increased visual recognition memory functions and clock drawing test scores which were associated with elevated peripheral BDNF levels, and decreased oxidant status after two weeks of left lateral parietal TMS stimulation. Clinically our findings suggest that the left parietal region targeted rTMS application leads to significant improvement in familiarity-based cognition associated with the network connections between the left parietal region and the hippocampus.Öğe Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer's disease(Bmc, 2024) Meng, Lingqi; Jin, Han; Yulug, Burak; Altay, Ozlem; Li, Xiangyu; Hanoglu, Lutfu; Cankaya, SeydaAlzheimer's disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions. Second, we analyzed individual omics data and identified the key parameters involved in the severity of the dementia in AD patients. Next, we employed Artificial Intelligence (AI) based models to predict AD severity based on the significantly altered features identified in each omics analysis. Based on our integrative analysis, we found the clinical relevance of plasma proteins, including SKAP1 and NEFL, plasma metabolites including homovanillate and glutamate, and Paraprevotella clara in gut microbiome in predicting the AD severity. Finally, we validated the predictive power of our AI based models by generating additional multi-omics data from the same group of AD patients by following up for 3 months. Hence, we observed that these results may have important implications for the development of potential diagnostic and therapeutic approaches for AD patients.Öğe Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial(Oxford Univ Press, 2025) Yulug, Burak; Altay, Ozlem; Li, Xiangyu; Hanoglu, Lutfu; Cankaya, Seyda; Velioglu, Halil A.; Lam, SimonParkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).Öğe Neuroimaging-Guided Transcranial Magnetic and Direct Current Stimulation in MCI: Toward an Individual, Effective and Disease-Modifying Treatment(Sage Publications Inc, 2023) Hanoglu, Lutfu; Velioglu, Halil Aziz; Hanoglu, Taha; Yulug, BurakThe therapeutic approaches currently applied in Alzheimer's disease (AD) and similar neurodegenerative diseases are essentially based on pharmacological strategies. However, despite intensive research, the effectiveness of these treatments is limited to transient symptomatic effects, and they are still far from exhibiting a true therapeutic effect capable of altering prognosis. The lack of success of such pharmacotherapy-based protocols may be derived from the cases in the majority of trials being too advanced to benefit significantly in therapeutic terms at the clinical level. For neurodegenerative diseases, mild cognitive impairment (MCI) may be an early stage of the disease continuum, including Alzheimer's. Noninvasive brain stimulation (NIBS) techniques have been developed to modulate plasticity in the human cortex in the last few decades. NIBS techniques have made it possible to obtain unique findings concerning brain functions, and design novel approaches to treat various neurological and psychiatric conditions. In addition, its synaptic and cellular neurobiological effects, NIBS is an attractive treatment option in the early phases of neurodegenerative diseases, such as MCI, with its beneficial modifying effects on cellular neuroplasticity. However, there is still insufficient evidence about the potential positive clinical effects of NIBS on MCI. Furthermore, the huge variability of the clinical effects of NIBS limits its use. In this article, we reviewed the combinatory approach of NIBS with various neuroimaging and electrophysiological methods. Such methodologies may provide a new horizon to the path for personalized treatment, including a more individualized pathophysiology approach which might even define new specific targets for specific symptoms of neurodegenerations.Öğe Parietal memory network and memory encoding versus retrieval impairments in PD-MCI patients: A hippocampal volume and cortical thickness study(Wiley, 2024) Sahin, Serhat; Velioglu, Halil Aziz; Yulug, Burak; Bayraktaroglu, Zubeyir; Yildirim, Suleyman; Hanoglu, LutfuObjective: The pathophysiology behind memory impairment in Parkinson's Disease Mild Cognitive Impairment (PD-MCI) is unclear. This study aims to investigate the hippocampal and cortical atrophy patterns in PD-MCI patients with different types of memory impairments, categorized as Retrieval Failure (RF) and Encoding Failure (EF). Methods: The study included 16 healthy controls (HC) and 34 PD-MCI patients, divided into RF (N = 18) and EF (N = 16) groups based on their Verbal Memory Processes Test (VMPT) scores, including spontaneous recall, recognition, and Index of Sensitivity to Cueing (ISC). Hippocampal subfields and cortical thicknesses were measured using the FreeSurfer software for automatic segmentation. Results: Compared to the HC group, the EF group exhibited significant atrophy in the left lateral occipital region and the right caudal middle frontal, superior temporal, and inferior temporal regions (p < 0.05). The RF group displayed significant atrophy in the left lateral occipital, middle temporal, and precentral regions, as well as the right pars orbitalis and superior frontal regions (p < 0.05). Hippocampal subfield analysis revealed distinct volume differences between HC-EF and RF-EF groups, with significant reductions in the CA1, CA3, and CA4 subregions in the EF group, but no differences between HC and RF groups (p > 0.05). Conclusion: Gray matter atrophy patterns differ in PD-MCI patients with encoding and retrieval memory impairments. The significant hippocampal atrophy in the EF group, particularly in the CA subregions, highlights its potential role in disease progression and memory decline. Additionally, the convergence of atrophy in the lateral occipital cortex across both RF and EF groups suggests the involvement of the Parietal Memory Network (PMN) in PD-related memory impairment.Öğe Repetitive Transcranial Magnetic Stimulation Improves Hippocampal N-Acetlaspartate Levels and Visual Memory Scores in Alzheimer's Disease(Turkish Neuropsychiatry Assoc-Turk Noropsikiyatri Dernegi, 2024) Velioglu, Halil Aziz; Sayman, Dila; Hanoglu, Lutfu; Akan, Gulhan Ertan; Cankaya, Seyda; Yulug, BurakThe latest research into the pathophysiology of Alzheimer's Disease (AD) has included several cognitive deficits related to hippocampal functioning. However, current clinical research fails to consider the full extent of the heterogeneous cognitive spectrum of AD, resulting in a lack of the specific methods required to draw definitive diagnostic and therapeutic conclusions. This also includes in-vivo metabolic measurements for tailoring the diagnostic and therapeutic regimens in humans with AD. Magnetic resonance spectroscopy and repetitive transcranial magnetic stimulation (rTMS) are two novel diagnostic and therapeutic approaches that must be modified to treat AD. In the present study, we aimed to investigate the underlying therapeutic role of rTMS in humans with AD by evaluating the in -vivo hippocampal metabolites before and after rTMS treatment. Based on the data obtained using the fMRI data in our previous study and on the references reported in the literature, in the present study, we decided to use hippocampal NAA data after rTMS stimulation and found a significant increase in NAA levels. To the best of our knowledge, no other study has evaluated the effect of rTMS on hippocampal metabolites in humans with AD.Öğe rTMS reduces delta and increases theta oscillations in Alzheimer's disease: A visual-evoked and event-related potentials study(Wiley, 2024) Velioglu, Halil Aziz; Dudukcu, Esra Zeynep; Hanoglu, Lutfu; Guntekin, Bahar; Akturk, Tuba; Yulug, BurakBackground: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative therapy for Alzheimer's disease (AD) due to its ability to modulate neural networks and enhance cognitive function. This treatment offers the unique advantage of enabling real-time monitoring of immediate cognitive effects and dynamic brain changes through electroencephalography (EEG).Objective: This study focused on exploring the effects of left parietal rTMS stimulation on visual-evoked potentials (VEP) and visual event-related potentials (VERP) in AD patients.Methods: Sixteen AD patients were recruited for this longitudinal study. EEG data were collected within a Faraday cage both pre- and post-rTMS to evaluate its impact on potentials.Results: Significant alterations were found in both VEP and VERP oscillations. Specifically, delta power in VEP decreased, while theta power in VERP increased post-rTMS, indicating a modulation of brain activities.Discussion: These findings confirm the positive modulatory impact of rTMS on brain activities in AD, evidenced by improved cognitive scores. They align with previous studies highlighting the potential of rTMS in managing hyperexcitability and oscillatory disturbances in the AD cortex.Conclusion: Cognitive improvements post-rTMS endorse its potential as a promising neuromodulatory treatment for cognitive enhancement in AD, thereby providing critical insights into the neurophysiological anomalies in AD and possible therapeutic avenues.Öğe Smoking affects global and regional brain entropy in depression patients regardless of depression: Preliminary findings(Pergamon-Elsevier Science Ltd, 2024) Velioglu, Halil Aziz; Yildiz, Sultan; Ozdemir-Oktem, Ece; Cankaya, Seyda; Lundmark, Anton Kjell; Ozsimsek, Ahmet; Hanoglu, LutfuObjective: This study examines the effect of smoking on global and regional brain entropy in patients with Major Depressive Disorder (MDD), aiming to elucidate the relationship between smoking habits and brain network complexity in depression. Methods: The study enrolled 24 MDD patients, divided into smokers and non-smokers, from Alanya Alaaddin Keykubat University and Istanbul Medipol University. Resting-state fMRI data were acquired and processed. The complexity of neuronal activity was assessed using dispersion entropy, with statistical significance determined by a suite of tests including Kolmogorov -Smirnov, Student 's t-test, and Mann -Whitney U test. Results: The smoking cohort exhibited higher global brain entropy compared to the non-smoking group (p = 0.033), with significant differences in various brain networks, indicating that smoking may alter global brain activity and network dynamics in individuals with MDD. Conclusion: The study provides evidence that smoking is associated with increased brain entropy in MDD patients, suggesting that chronic smoking may influence cognitive and emotional networks. This underscores the importance of considering smoking history in the treatment and prognosis of MDD. The findings call for further research to understand the mechanistic links between smoking, brain entropy, and depression.Öğe Targeting the parietal memory network with tDCS in MCI: study protocol for a randomized controlled trial(Frontiers Media Sa, 2025) Cankaya, Seyda; Akturk, Aynur; Karakus, Ayse; Hanoglu, Lutfu; Mardinoglu, Adil; Yulug, BurakBackground: Mild cognitive impairment (MCI) is a critical transitional stage in dementia related disorders. In that context, dorsolateral prefrontal cortex (DLPFC), and lateral parietal cortex (LPC) are subjected to neuropathological changes in MCI. Furthermore, alterations in parietal memory network (PMN) integrity and default mode network (DMN) also occur in MCI. Transcranial direct current stimulation (tDCS) is a promising neuroprotective tool that might interfere with cognitive decline in Alzheimer's disease-MCI (aMCI) and Parkinson's disease-MCI (PD-MCI) when applied to DLPFC or LPC separately. Methods: This is a randomized and controlled study evaluating the effectiveness of tDCS in 120 patients (60 aMCI and 60 PD-MCI). Firstly, all patients will be randomly (1:1) divided into two groups: DLPFC (30 aMCI; 30 PD-MCI) and LPC (30 aMCI, 30 PD-MCI) for tDCS stimulation. Secondly, they will classify randomly (2:1) real and sham groups for tDCS applied to once a day for 10 days over 2 weeks. The stimulation will be delivered with a 2-mA current frequency and will last 20 min. The primary outcome assessment for this study will be the change in score from baseline to the end of (14-days and 90 days follow-up) the tDCS application for the neurocognitive tests. Potential outcome parameters will be discussed in the light of current literature to contribute to the new area of personalized non-invasive brain stimulation research in neurodegenerative diseases at early stages. The results of this study are expected to shed light on the neural underpinnings and pro-cognitive outcomes of tDCS. Potential outcome parameters will be discussed in the light of current literature to contribute to the new area of personalized non-invasive brain stimulation research in neurodegenerative diseases at early stages.Öğe The Savant Syndrome: a Gift or a Disability? A Deeper Look into Metabolic Correlates of Hidden Cognitive Capacity(Bentham Science Publ Ltd, 2023) Onin, Irem; Hanoglu, Lutfu; Yulug, BurakSavant syndrome is a rare and unusual condition that occurs in the presence of severe developmental disabilities, disorders, and injuries. The syndrome can be congenital from birth to childhood or acquired as a result of a brain injury or damage to the central nervous system. There are several findings that indicate that savant syndrome usually occurs with significant brain metabolism alterations resulting in critical brain network changes. These types of changes in the brain are usually explained by the tyranny of the left hemisphere theory, which indicates the inhibition of the left hemisphere to allow the right hemisphere to develop savant abilities. Another way to temporarily simulate these types of changes in the brain can be through different neuromodulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation. Such neuromodulation techniques might help us discover the hidden talent potential through modulating the brain network metabolism. We herein discussed the types of savant syndrome along with its relation to specific neurometabolic network alterations. Furthermore, we provide a perspective on how newly developed neuromodulation and cognitive rehabilitation techniques can help simulate savant syndrome in healthy individuals through modulating the brain network activity.
