Smoking affects global and regional brain entropy in depression patients regardless of depression: Preliminary findings.

OBJECTIVE: 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.

Repetitive Transcranial Magnetic Stimulation Improves Hippocampal N-Acetlaspartate Levels and Visual Memory Scores in Alzheimer's Disease.

The 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.

Altered blood parameters in "major depression" patients receiving repetitive transcranial magnetic stimulation (rTMS) therapy: a randomized case-control study.

Major depressive disorder (MDD) is a debilitating illness that includes depressive mood. Repetitive Transcranial Magnetic Stimulation (rTMS) is a therapy method used in the treatment of MDD. The purpose of this study was to assess neurotrophic factors, and oxidative stress levels in MDD patients and evaluate the changes in these parameters as a result of rTMS therapy. Twenty-five patients with MDD and twenty-six healthy volunteers with the same demographic characteristics were included in the study. Brain-derived neurotrophic factors were measured photometrically with commercial kits. Oxidative stress parameters were measured by the photometric method. Oxidative stress index (OSI) and disulfide (DIS) levels were calculated with mathematical formulas. In this study, total antioxidant status (TAS), total thiol (TT), and native thiol (NT) antioxidant parameters and brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and allopregnanolone (ALLO) levels were reduced in pre-rTMS with regard to the healthy control group; TOS, OSI, DIS, and S100 calcium-binding protein B (S100B) levels were increased statistically significantly (p < 0.01). Moreover, owing to TMS treatment; TAS, TT, NT, BDNF, GDNF, and ALLO levels were increased compared to pre-rTMS, while DIS, TOS, OSI, and S100B levels were decreased significantly (p < 0.01). The rTMS treatment reduces oxidative stress and restores thiol-disulfide balance in MDD patients. Additionally, rTMS modulates neurotrophic factors and neuroactive steroids, suggesting its potential as an antidepressant therapy. The changes in the biomarkers evaluated may help determine a more specific approach to treating MDD with rTMS therapy.

Diabetes-related clinical and microstructural white matter changes in patients with Alzheimer's disease.

AIM: Although there exists substantial epidemiological evidence indicating an elevated risk of dementia in individuals with diabetes, our understanding of the neuropathological underpinnings of the association between Type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) remains unclear. This study aims to unveil the microstructural brain changes associated with T2DM in AD and identify the clinical variables contributing to these changes. METHODS: In this retrospective study involving 64 patients with AD, 31 individuals had concurrent T2DM. The study involved a comparative analysis of diffusion tensor imaging (DTI) images and clinical features between patients with and without T2DM. The FSL FMRIB software library was used for comprehensive preprocessing and tractography analysis of DTI data. After eddy current correction, the "bedpost" model was utilized to model diffusion parameters. Linear regression analysis with a stepwise method was used to predict the clinical variables that could lead to microstructural white matter changes. RESULTS: We observed a significant impairment in the left superior longitudinal fasciculus (SLF) among patients with AD who also had T2DM. This impairment in patients with AD and T2DM was associated with an elevation in creatine levels. CONCLUSION: The white matter microstructure in the left SLF appears to be sensitive to the impairment of kidney function associated with T2DM in patients with AD. The emergence of AD in association with T2DM may be driven by mechanisms distinct from the typical AD pathology. Compromised renal function in AD could potentially contribute to impaired white matter integrity.

The functional role of the pulvinar in discriminating between objective and subjective cognitive impairment in major depressive disorder.

INTRODUCTION: Emotionally driven cognitive complaints represent a major diagnostic challenge for clinicians and indicate the importance of objective confirmation of the accuracy of depressive patients' descriptions of their cognitive symptoms. METHODS: We compared cognitive status and structural and functional brain connectivity changes in the pulvinar and hippocampus between patients with total depression and healthy controls. The depressive group was also classified as "amnestic" or "nonamnestic," based on the members' subjective reports concerning their forgetfulness. We then sought to determine whether these patients would differ in terms of objective neuroimaging and cognitive findings. RESULTS: The right pulvinar exhibited altered connectivity in individuals with depression with objective cognitive impairment, a finding which was not apparent in depressive patients with subjective cognitive impairment. DISCUSSION: The pulvinar may play a role in depression-related cognitive impairments. Connectivity network changes may differ between objective and subjective cognitive impairment in depression and may play a role in the increased risk of dementia in patients with depression.

rTMS reduces delta and increases theta oscillations in Alzheimer's disease: A visual-evoked and event-related potentials study.

BACKGROUND: 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.

Infection with COVID-19 is no longer a public emergency: But what about degenerative dementia?

Although no longer considered a public health threat, post-COVID cognitive syndrome continues to impact on a considerable proportion of individuals who were infected with COVID-19. Recent studies have also suggested that COVID may be represent a critical risk factor for the development of Alzheimer's disease (AD). We compared 17 COVID patients with 20 controls and evaluated the effects of COVID-19 on general cognitive performance, hippocampal volume, and connections using structural and seed-based connectivity analysis. We showed that COVID patients exhibited considerably worse cognitive functioning and increased hippocampal connectivity supported by the strong correlation between hippocampal connectivity and cognitive scores. Our findings of higher hippocampal connectivity with no observable hippocampal morphological changes even in mild COVID cases may be represent evidence of a prestructural compensatory mechanism for stimulating additional neuronal resources to combat cognitive dysfunction as recently shown for the prodromal stages of degenerative cognitive disorders. Our findings may be also important in light of recent data showing that other viral infections as well as COVID may constitute a critical risk factor for the development of AD. To our knowledge, this is the first study that investigated network differences in COVID patients, with a particular focus on compensatory hippocampal connectivity.

EGb 761 reduces Ca2+ influx and apoptosis after pentylenetetrazole treatment in a neuroblastoma cell line.

Background: Transient receptor potential (TRP) channels have been found to have significant implications in neuronal outgrowth, survival, inflammatory neurogenic pain, and various epileptogenic processes. Moreover, there is a growing body of evidence indicating that transient receptor potential (TRP) channels have a significant impact on epilepsy and its drug-resistant subtypes. Objective: We postulated that EGb 761 would modulate TRPA1 channels, thereby exhibiting anti-inflammatory and neuroprotective effects in a neuroblastoma cell line. Our rationale was to investigate the impact of EGb 761 in a controlled model of pentylenetetrazole-induced generalized epilepsy. Methodology: We evaluated the neuroprotective, antioxidant and anti-apoptotic effects of EGb 761 both before and after the pentylenetetrazole application in a neuroblastoma cell line. Specifically, we focused on the effects of EGB 761 on the activity of Transient receptor potential (TRP) channels. Results: EGb 761 applications both before and after the pentylenetetrazole incubation period reduced Ca release and restored apoptosis, ROS changes, mitochondrial depolarization and caspase levels, suggesting a prominent prophylactic and therapeutic effect of EGb 761 in the pentylenetetrazole-induced epileptogenesis process. Conclusion: Our basic mechanistic framework for elucidating the pathophysiological significance of fundamental ion mechanisms in a pentylenetetrazole treated neuroblastoma cell line provided compelling evidence for the favorable efficacy and safety profile of Egb 761 in human-relevant in vitro model of epilepsy. To the best of our knowledge, this is the first study to investigate the combined effects of EGb 761 and pentylenetetrazole on TRP channels and measure their activation level in a relevant model of human epileptic diseases.

Evaluating the Clinical Significance of Diazepam Binding Inhibitor in Alzheimer's Disease: A Comparison with Inflammatory, Oxidative, and Neurodegenerative Biomarkers.

INTRODUCTION: Alzheimer's disease (AD) is one of the pathologies that the scientific world is still desperate for. The aim of this study was the investigation of diazepam binding inhibitor (DBI) as a prognostic factor for AD prognosis. METHODS: A total of 120 participants were divided into 3 groups. Forty new diagnosed Alzheimer patients (NDG) who have been diagnosed but have not started AD treatment, 40 patients who diagnosed 5 years ago (D5YG), and 40 healthy control groups (CG) were included in the study. Levels of DBI, oxidative stress, inflammatory, and neurodegenerative biomarkers were compared between 3 groups. RESULTS: Plasma levels of DBI, oligomeric Aß, total tau, glial fibrillary acidic protein, α-synuclein, interleukin (IL) 1ß, IL6, tumor necrosis factor α, oxidative stress index, high-sensitive C-reactive protein, and DNA damage were found higher in D5YG and NDG as compared to CG (p < 0.001). On the contrary, plasma levels of total thiol, native thiol, vitamin D and vitamin B12 were lower in D5YG and NDG as compared to CG (p < 0.001). DISCUSSION: DBI may be a potential plasma biomarker and promising drug target for AD. It could help physicians make a comprehensive evaluation with cognitive and neurodegenerative tests.

Decreased frontal and orbital volumes and increased cerebellar volumes in patients with anosmia Of Unknown origin: A subtle connection?

PURPOSE: Neuroimaging studies have shown that anosmia is accompanied by a decreased olfactory bulb volume, yet little is known about alterations in cerebral and cerebellar lobule volumes. The purpose of this study was to investigate structural brain alterations in anosmic patients. METHODS: Sixteen anosmic patients (mean age 42.62 ± 16.57 years; 6 women and 10 men) and 16 healthy controls (mean age 43.37 ± 18.98 years; 9 women and 7 men) were included in this retrospective study. All subjects who underwent magnetic resonance imaging scans were analyzed using VolBrain and voxel-based morphometry after olfactory testing. RESULTS: Despite being statistically insignificant, analysis using VBM revealed greater gray matter (GM) and white matter in the anosmia group compared to the healthy subjects. However, decreased GM (p < 0.001) and increased cerebellar (p = 0.046) volumes were observed in the anosmic patients. CONCLUSIONS: The study revealed structural brain alterations in specific areas beyond the olfactory bulb. Our results indicate that the cerebellum may play an exceptional role in the olfactory process and that this will be worth evaluating with further dynamic neuroimaging studies.

Exosomes: A missing link between chronic systemic inflammation and Alzheimer's disease?

Exosomes are potent mediators of physiological and pathological processes. In Alzheimer's disease and inflammatory disorders, due to exosomes' distinctive ability to cross the blood-brain barrier, a bidirectional communication between the periphery and the central nervous system exists. Since exosomes can carry various biochemical molecules, this review investigates the role of exosomes as possible mediators between chronic systemic inflammatory diseases and Alzheimer's disease. Exosomes carry pro-inflammatory molecules generated in the periphery, travel to the central nervous system, and target glial and neuronal cells. Microglia and astrocytes then become activated, initiating chronic neuroinflammation. As the aging brain is more susceptible to such changes, this state of neuroinflammation can stimulate neuropathologies, impair amyloid-beta clearance capabilities, and generate dysregulated microRNAs that alter the expression of genes critical in Alzheimer's disease pathology. These processes, individually and collectively, become significant risk factors for the development of Alzheimer's disease.

Brain temperature in healthy and diseased conditions: A review on the special implications of MRS for monitoring brain temperature.

Brain temperature determines not only an individual's cognitive functionality but also the prognosis and mortality 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.

Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial.

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 effect 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 first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference 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 efficacy of the CMA in AD patients. RESULTS: We showed a significant 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 significant 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 proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. CONCLUSION: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131.

Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases.

BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. METHODS: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. FINDINGS: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. INTERPRETATION: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.

Differentiation of claustrum resting-state functional connectivity in healthy aging, Alzheimer's disease, and Parkinson's disease.

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.

A structural and resting-state functional connectivity investigation of the pulvinar in elderly individuals and Alzheimer's disease patients.

In 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. HIGHLIGHTS: The 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.

Neuroimaging-Guided Transcranial Magnetic and Direct Current Stimulation in MCI: Toward an Individual, Effective and Disease-Modifying Treatment.

The 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 combined 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.

Chemogenetic inhibition of MCH neurons does not alter memory performance in mice.

Memory 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. Consolidation 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.