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.

Differentiating MCI from depression through verbal memory scores.

INTRODUCTION: The present study aims to assess the differences between major depressive disorder (MDD) and mild cognitive impairment (MCI) in terms of verbal learning profile together with structural changes in the brain on magnetic resonance imaging (MRI) and to reveal predictive factors for MCI. METHODS: Fifty-six patients with MDD and 31 MCI subjects were assessed using the Turkish Verbal Memory Processes Test (VMPT). Brain MRI was used to evaluate sulcal atrophy (SA), ventricular atrophy, periventricular white matter hyperintensity (WMH), subcortical WMH, basal ganglia infarct, medial temporal lobe atrophy, and infratentorial infarct scores based on the Modified Visual MRI Rating Scale (MVMRS). The symptoms of depression were evaluated with the Beck Depression Inventory in both groups. Demographic factors, VMPT scores, and MVMRS scores between MDD and MCI groups were compared. Also, potential predictors of MCI were analyzed by binary logistic regression analyses. RESULTS: The total scores of VMPT and the scores of VMPT subgroups, including immediate memory, highest learning, total learning, and delayed recall, were significantly higher in the MDD groups compared to MCI patients (Mann-Whitney U, Student's t-test, p < 0.05), indicating that higher scores were associated with better memory. The total MVMRS score and a subgroup of MVMRS, the SA score, were significantly higher in MCI patients compared to the MDD group, suggesting more atrophic changes and a higher burden of infarction in MCI patients. In our statistical analyses, impaired immediate memory (p < 0.001; OR = 6.002; 95% CI: 1.996-18.042), increased SA (p = 0.008; OR = 1.522; 95% CI: 1.118-2.073), and education (p = 0.028; OR = 0.84; 95% CI: 0.719-0.981) were significant predictive values obtained through backward Wald elimination in the binary logistic regression model for detecting MCI. CONCLUSION: Our findings suggest that VMPT may potentially represent a novel neuropsychiatric test that might be combined with MRI-based morphometric evaluation methods, such as MVMRS.

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.

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.

Prognostic Factors For Functional Outcome in Patients with Mesencephalic Hemorrhage.

Introduction: Mesencephalic hemorrhage (MH) is a rare presentation of spontaneous intraparenchymal hemorrhage. This study aims to evaluate prognostic parameters of the MH outcome. Methods: We conducted an extensive search in the literature for cases with spontaneous, isolated mesencephalic hemorrhage. The study was conducted according to the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Sixty-two eligible cases have been reported in the literature as proven by CT or MRI, and to these, we added six cases confirmed by MRI. The modified Rankin Scale (mRS) was dichotomized into two groups as the favorable outcome (FO; score, 0-2) and unfavorable outcome (UO; score, 3-6). Results: Of the 68 patients studied, 26 (38%) presented with normal consciousness, 22 (32%) with lethargy , and 20 (29%) with stupor or coma. There was no cause of hemorrhage in 26 (65%) patients with FO and 12 (43%) with UO (p=0.059). In univariate analyses, neither arteriovenous malformations (p=0.33) nor cavernomas (p=0.19) were associated with outcome. Multiple logistic regression analysis revealed that hypertension (OR, 51.22; CI95%, 1.92-1370.24; P=0.019), consciousness (OR, 133.54; CI95%, 1.61-1113.3; P=0.03), NIHSS at admission (OR, 57.23; CI95%, 2.87-1141.2; p=0.008), and ventrodorsal hemorrhage size (≥1 cm) (OR, 61.83; CI95%, 2.15-1779.2; p=0.016) were significantly associated with UO. Three months after stroke, 40 patients (59%) had FO, 28 (41%) had UO, and 8 (12%) died. Conclusion: These results suggest that ventrodorsal size of hemorrhage and clinical severity at stroke onset are possible predictors of functional outcome after mesencephalic hemorrhage.

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.

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.

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.

Exploring Cognitive Impairment in Patients With Bilateral Capsular Genu Lesions.

OBJECTIVE: The authors investigated for presence of cognitive impairment after occurrence of bilateral lesions of the genu of the internal capsule (GIC). Clinical and neuropsychological features of unilateral GIC lesions have previously been studied, but the cognitive profile of bilateral lesions of the GIC has not been fully explored. METHODS: An investigation was conducted of neurocognitive deficits and computerized tomography MRI findings among 4,200 stroke patients with bilateral GIC involvement who were admitted to the hospital between January 2010 and October 2018. RESULTS: Eight patients with bilateral lesions of the capsular genu were identified and their data analyzed. Overall, behavioral and cognitive dysfunction were characterized by impairment of frontal, memory, and executive functions. Attention and abstraction were present among all eight patients (100%); apathy, abulia, and executive dysfunctions, among seven (87.5%); global mental dysfunction and planning deficits, among six (75.0%); short-term verbal memory deficits and language dysfunctions, among five (62.5%); long-term verbal memory deficits, among four (50.0%); and spatial memory deficits, reading, writing, counting dysfunctions, and anarthria, among two (25.0%). Four of the patients (50.0%) without a history of cognitive disorder showed severe mental deterioration compatible with the clinical picture of dementia. A clinical picture of dementia was still present in these patients 6 months after stroke. CONCLUSIONS: Bilateral lesions of the capsular genu appearing either simultaneously or at different times were significantly associated with executive dysfunctions.

Quantitative evaluation of brain volumes in drug-free major depressive disorder using MRI-Cloud method.

BACKGROUND: Quantitative analysis of the high-resolution T1-weighted images provides useful markers to measure anatomical changes during brain degeneration related to major depressive disorder (MDD). However, there are controversial findings regarding these volume alterations in MDD indicating even to increased volumes in some specific regions in MDD patients. METHODS: This study is a case-controlled study including 23 depression patients and 15 healthy subject person and 20-38 years of age, who have been treated at the Neurology and Psychiatry Department here. We compared specific anatomic regions between drug-free MDD patients and control group through MRI-Cloud, which is a novel brain imaging method that enables to analyze multiple brain regions simultaneously. RESULTS: We have found that frontal, temporal, and parietal hemispheric volumes and middle frontal gyrus, inferior frontal gyrus, superior parietal gyrus, cingulum-hippocampus, lateral fronto-orbital gyrus, superior temporal gyrus, superior temporal white matter, middle temporal gyrus subanatomic regions were significantly reduced bilaterally in MDD patients compared to the control group, while striatum, amygdala, putamen, and nucleus accumbens bilaterally increased in MDD group compared to the control group suggesting that besides the heterogeneity among studies, also comorbid factors such as anxiety and different personal traits could be responsible for these discrepant results. CONCLUSION: Our study gives a strong message that depression is associated with altered structural brain volumes, especially, in drug-free and first-episode MDD patients who present with similar duration and severity of depression while the role of demographic and comorbid risk factors should not be neglected.

Topological network mechanisms of clinical response to antidepressant treatment in drug-naive major depressive disorder.

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.

A rare entity of acquired idiopathic generalised anhidrosis which has been successfully treated with pulse steroid therapy: Does the histopathology predict the treatment response?

Acquired idiopathic generalised anhidrosis is an uncommon sweating disorder characterized by loss of sweating in the absence of any neurologic, metabolic or sweat gland abnormalities. Although some possible immunological and structural mechanisms have been proposed for this rare entity, the definitive pathophysiology is still un-clear. Despite some successfully treated cases with systemic corticosteroid application, the dose and route of steroid application are controversial. Here, we present a 41-year-old man with lack of genera-lised sweating who has been successfully treated with high dose pulse intravenous prednisolone. We have discussed his clinical and histopathological findings as well as the treatment options in view of the current literature.

Paracetamol alters empathy scores in healthy and headache subjects: Functional MRI correlates.

INTRODUCTION: Although previous evidence suggest that paracetamol decreases psychological reactivity in healthy subjects, there is still no confirmed correlation between the empathy scores and brain activity in healthy and headache patients after paracetamol treatment. MATERIAL AND METHODS: The study group included 16 patients with tension-type headache, and 12 healthy age-and sex-matched controls. After a detailed neurological examination Positive and Negative Affect Schedule (PANAS) and Empathy for Pain Scale (EPS) were applied to all subjects. Next, 1000 mg paracetamol tablet was administered orally, after administration of paracetamol, EPS were repeated, and fMRI was performed to all subjects. RESULTS: We have revealed increased empathy scores in the headache group after the paracetamol treatment which were associated with significant alterations in brain regions which play a critical role in the processing of empathy. DISCUSSION: The observed neuroimaging and clinical difference between healthy and headache subjects could be related to the fact that pain perception in healthy subjects might differ in some aspects from the mechanisms of empathy in headache-experienced patients. CONCLUSION: To the best of our knowledge, this is the first study that evaluated the paracetamol treatment and neural networks' correlation with pain empathy in healthy and headache individuals.

Melatonin affects the release of exosomes and tau-content in in vitro amyloid-beta toxicity model.

BACKGROUND: Recent studies have been revealed that oxidative damage is the main cause of aging and age-related neurodegenerative diseases like Alzheimer's disease (AD). Melatonin is secreted from the pineal gland and its secretion has been found to be altered in AD. In the last decade the role of exosomes in spreading toxic proteins and inducing the propagation of diseases like AD has been discussed. However, it is not known how melatonin affects the amount of exosomes released from the cells and the content of the exosomes. OBJECTIVE: Herein, we investigated the possible role of melatonin treatment in the releasing of exosomes and exosomal tau content in an in vitro Aß toxicity model. METHOD: SH-SY5Y cell line was used. The optimum concentration of Aß was determined by cell viability and cell proliferation tests. Melatonin (100 µM) was applied before and after Aß application. Total exosomes isolated from cell culture media were immunoprecipitated. The amount of released exosomes and their tau content were analyzed by Western blots. RESULTS: Our data demonstrated for the first time that melatonin treatment clearly affected the amount of released exosomes. It would decrease the amyloid beta load and toxicity by inhibiting exosome release. We also demonstated that melatonin also affected the level of tau carried by exosomes depending on whether melatonin was applied before or after Aß application. CONCLUSION: It is considered that the effect of melatonin in the release of exosomes and exosomal tau content would contribute the development of therapeutic strategies in AD and related disorders.

Minocycline Increases in-vitro Cortical Neuronal Cell Survival after Laser Induced Axotomy.

BACKGROUND: Antibiotic therapies targeting multiple regenerative mechanisms have the potential for neuroprotective effects, but the diversity of experimental strategies and analyses of non-standardised therapeutic trials are challenging. In this respect, there are no cases of successful clinical application of such candidate molecules when it comes to human patients. METHODS: After 24 hours of culturing, three different minocycline (Sigma-Aldrich, M9511, Germany) concentrations (1 µM, 10 µM and 100 µM) were added to the primary cortical neurons 15 minutes before laser axotomy procedure in order to observe protective effect of minocycline in these dosages. RESULTS: Here, we have shown that minocycline exerted a significant neuroprotective effect at 1 and 100µM doses. Beyond confirming the neuroprotective effect of minocycline in a more standardised and advanced in-vitro trauma model, our findings could have important implications for future studies that concentrate on the translational block between animal and human studies. CONCLUSION: Such sophisticated approaches might also help to conquer the influence of humanmade variabilities in critical experimental injury models. To the best of our knowledge, this is the first study showing that minocycline increases in-vitro neuronal cell survival after laser-axotomy.

The Association between HbA1c Levels, Olfactory Memory and Cognition in Normal, Pre-Diabetic and Diabetic Persons.

BACKGROUND AND AIM: Recent data have shown that olfactory dysfunction is strongly related to Alzheimer's Disease (AD) that is often preceded by olfactory deficits suggesting that olfactory dysfunction might represent an early indicator of future cognitive in prediabetes. METHODS: We have applied to a group of normal (n=15), prediabetic (n=16) and type 2 diabetic outpatients (n=15) olfactory testing, 1.5-T MRI scanner and detailed cognitive evaluation including the standard Mini-Mental State Examination (MMSE) form, Short Blessed Test (SBT), Letter Fluency Test (LFT) and the category fluency test with animal, Fruit and Vegetable Naming (CFT). RESULTS: We have shown that Odour Threshold (OT), Discrimination (OD), and Identification (OI) scores and most cognitive test results were significantly different in the prediabetes and diabetes group compared to those in the control group. OD and OT were significantly different between the prediabetes and diabetes group, although the cognitive test results were only significantly different in the prediabetes and diabetes group compared to those in the control group. In evaluating the association between OI, OT, OD scores and specific cognitive tests, we have found, that impaired olfactory identification was the only parameter that correlated significantly with the SBT both in the pre-diabetes and diabetes group. Although spot glucose values were only correlated with OT, HbA1c levels were correlated with OT, OD, and OI, as well as results of the letter fluency test suggesting that HbA1c levels rather than the spot glucose values play a critical role in specific cognitive dysfunction. CONCLUSION: To the best of our knowledge, this is the first prospective study to demonstrate a strong association between olfactory dysfunction and specific memory impairment in a population with prediabetes and diabetes suggesting that impaired olfactory identification might play an important role as a specific predictor of memory decline.