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Abstract: Savant 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.

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.

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 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.

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. PoLiMeR Innovative Training Network ; SNIC ; ScandiBio Therapeutics ; ScandiBio Therapeutics and Knut ; Knut och Alice Wallenbergs Stiftelse

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.

Background Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administrated Combined Metabolic Activators (CMA) to the AD rat model and observed that administration of CMA activated the mitochondrial functions and eventually improved the AD-associated histological parameters in the animals. CMA consists of NAD + and glutathione precursors and includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate. Methods Here, we designed a randomised, double-blinded, placebo-controlled phase-II trial and studied the effect of CMA administration on the global metabolism of AD patients. The primary endpoint was on the difference in cognitive 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. We also performed a comprehensive human plasma metabolome and proteome analysis. Results Based on our analysis, we showed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (p = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant enhancement (p = 0.0073) in ADAS-Cog scores between CMA and placebo groups in patients with higher ADAS-Cog scores. Improved cognitive functions were endorsed with relevant hippocampal volumes and cortical thickness alterations. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism are significantly improved after treatment. Conclusion In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions associated with the improved metabolome, proteome and structural neuroimaging parameters, suggesting a role for such a therapeutic regimen in treating patients, especially with severe AD. Trial registration: ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

The pulvinar is largest thalamic nucleus and has been subdivided into anterior pulvinar (PuA), inferior pulvinar (PuI), medial pulvinar (PuM) and, lateral pulvinar (PuL). Although the function of pulvinar is well known, its role in neurodegenerative diseases is still unclear. We aimed to examine the functional connectivity of PuA, PuI, PuM and, PuL in healthy controls (HC) and patients with Parkinson’s disease (PD). Resting-state fMRI and T1 weighted images of 15 healthy control (HC), and 12 PD patients were used in this study. SPM12 and CONN software were used to preprocessing the imaging data using published pipelines. Seed based resting-state fMRI analyses were carried out to compare the functional connectivity changes between groups. Besides, voxel-based morphometry (VBM) analysis was performed to compare gray matter volume differences between two groups. The bilateral PuI, PuL and PuM exhibited a decreased functional connectivity in the PD group compared to the HC group in the bilateral thalamus, posterior cingulate cortex, cerebellum, and brainstem. Moreover, pulvinar nuclei in each hemisphere had significantly smaller volume in the patients with PD compared to HC. This study highlights that the patients with PD have a smaller volume in pulvinar nuclei in each hemisphere compared to HC. The pulvinar showed less connectivity in the PD group compared to the HC, the diminished connectivity may be associated with hallucination, executive function, and working memory dysfunctions in PD.

Objective: The main objective of this research was to evaluate the correlation between the severity of hearing loss and the facial emotional recognition as a critical part of social cognition in elderly patients. Methods: The prospective study was comprised of 85 individuals. The participants were divided into 3 groups. The first group consisted of 30 subjects older than 65 years with a bilateral pure-tone average mean >30 dB HL. The second group consisted of 30 subjects older than 65 years with a PTA mean ≤30 dB HL. The third group consisted of 25 healthy subjects with ages ranging between 18 and 45 years and a PTA mean ≤25 dB HL. A Facial Emotion Identification Test and a Facial Emotion Discrimination Test were administered to all groups. Results: Elderly subjects with hearing loss performed significantly worse than the other 2 groups on the facial emotion identification and discrimination tests ( P Conclusions: Our results suggest that increased age might be associated with decreased facial emotion identification and discrimination scores, which could be deteriorated in the presence of significant hearing loss.

Background Brain death in Turkey was defined as death and was accepted by official and religious authorities in a relatively early period without sufficient discussion and social consensus. Thus, there is considerable distrust and hesitation about the concept of brain death and related organ donation in Turkish society. We created a sample story in which the concept will be clearly understood in detail. Herein, we targeted healthcare workers and evaluated their attitudes towars brain death. Moreover, we assessed the effects of race, religiousness, and political conservatism parameters on their attitude. Methods A total of 491 participants aged 18–70 hospital workers were included to this study in different fields. The participants were asked to answer the evaluation questions about their demographic characteristics and conservative and religious attitudes. Finally, they were evaluated with an example story about brain death that was clearly understood in detail, the participants were asked to answer the questions on a 5-point Likert scale. Results We observed that 49.6% of the answers showed a positive attitude before the explanatory story. Furthermore, we observed that a higher education level is the most determining factor for positive attitudes. When the concept of death is explained within the framework of a story, only 32.1% of respondents approved of donating their organs. However, if the person consents to donate their organs with their own decision, this rate increased to 75.2% with a high rate of agreement. If the person is a close relative with a positive request for donation, the approval rate of the donation was 63.4%. We also determined that a positive attitude towards organ donation was inversely correlated with a higher education level and religiosity. Conclusion There is considerable resistance in society to consider this as a biological death, although it is recognized both by medical and religious authorities as legal. Higher education and a liberal world perspective have a positive effect on attitude, while religious belief has a negative effect. Even when the brain death concept is clearly explained and the candidate donor has a positive view of brain death and organ donation, this obstacle can be overcome to a certain degree approaching rates reported in Western countries.

Background: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administrated Combined Metabolic Activators (CMA) to the AD rat model and observed that administration of CMA activated the mitochondrial functions and eventually improved the AD-associated histological parameters in the animals. CMA consists of NAD+ and glutathione precursors and includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate. Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II trial and studied the effect of CMA administration on the global metabolism of AD patients. The primary endpoint was on the difference in cognitive 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. We also performed a comprehensive human plasma metabolome and proteome analysis. Results: Based on our analysis, we showed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (p=0.00001, 29% improvement) in the CMA group. Moreover, there was a significant enhancement (p=0.0073) in ADAS-Cog scores between CMA and placebo groups in patients with higher ADAS-Cog scores. Improved cognitive functions were endorsed with relevant hippocampal volumes and cortical thickness alterations. Moreover, the plasma levels of proteins and metabolites associated with NAD+ and glutathione metabolism are significantly improved after treatment. Conclusion: In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions associated with the improved metabolome, proteome and structural neuroimaging parameters, suggesting a role for such a therapeutic regimen in treating patients, especially with severe AD.Trial registration: ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

BackgroundCharles Bonnet syndrome (CBS) is a prototype phenomenon for investigating complex visual hallucination. Our research focuses on resting state neural networks features of CBS patients with a comparison of patients with equally matched visual loss and healthy subjects in order to investigate the mechanism behind complex visual hallucinations.Material and MethodsFour CBS patients CBS(+), three patients with visual loss but no visual hallucinations CBS(-) and 15 healthy individuals (HS) undergo resting state fMRI recordings and their resting state data is analyzed for Default Mode Network (DMN) changes through dual regression analysis. Cognitive functions of the participants were also evaluated through Mini Mental State Examination and University of Miami - Parkinson’s Disease Hallucination Questionnaire (um-PDHQ)ResultsAlthough we found no difference in Default Mode Networks between CBS(-) and CBS(+), and between the CBS(-) and HC groups, we detected decreased connectivity in CBS(+) compared to the HC group especially in visual heteromodal association centers (bilateral lateral occipital gyrus, bilateral lingual gyrus, occipital pole, right medial temporal cortex, right temporo-occipital cortex) when left angular gyrus was selected as ROI.Similarly, we detected decreased connectivity in CBS(+) compared to HC in right medial frontal gyrus, right posterior cingulate gyrus, left inferior temporal gyrus, right supramarginal gyrus, and right angular gyrus when selected right superior frontal gyrus as ROI. In contrast, increased connectivity was detected in CBS +compared to HC, in bilateral occipital poles, bilateral occipital fusiform gyrus, bilateral intracalcarine cortex, right lingual gyrus and precuneus regions when left medial temporal gyrus was selected as ROI.ConclusionOur findings suggest a combined mechanism in CBS related to increased internal created images caused by decreased visual external input causing visual hallucinations as well as impaired frontotemporal resource tracking system that together impair cognitive processing.

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.

PubMed: 32061493 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 A? toxicity model. Method: SH-SY5Y cell line was used. The optimum concentration of A? was determined by cell viability and cell proliferation tests. Melatonin (100 µM) was applied before and after A? 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 A? 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. © 2019 Elsevier Ltd

PubMed: 33035413 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 unclear. Despite some successfully treated cases with systemic corticosteroid application, the dose and route of steroid application are controversial. Here, we present a 41-yearold man with lack of generalised 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. © 2020 Ifjusagi Lap-es Konyvkiado Vallalat. All rights reserved.

Demyelination is generally observed in different neurodegenerative disorders, including Multiple sclerosis (MS). It is known that high-dose biotin supplementation stabilizes MS progression. To reduce the effective dose of biotin, here we synthesized a new and superior form of biotin, which is a complex of magnesium ionically bound to biotin (MgB) and compared its dose-dependent effect with biotin alone after lysolecithin (LPC)-induced demyelination in rats. Myelination was studied with luxol fast blue staining and revealed that the most significant remyelination occurred in the MgB groups. We observed dose-dependent improved spatial memory in both biotin and MgB combined animals. Furthermore, we detected decreased inflammatory proteins in both treatment groups, which were more prominent in high-dose MgB treated animals, associated with improved NF-κB, OP, and MMP-9 proteins. We further analyzed biotin-related proteins and observed that both biotin and particularly MgB reverses the LPC-induced reduction of these proteins. Furthermore, we have observed that biotin but particularly MgB improves neuronal transmission proteins, Synapsin-1, PSD-93, and PSD 95. Moreover, increased BDNF, GAP-43, and ICAM were detected in both treatment groups, especially significant in high-dose MgB treated animals. Increased GFAP, which indicates reactive gliosis, was observed in LPC treated animals, which were reversed particularly by high-dose MgB treatment. The present data reveal the dose-dependent beneficial effect of biotin on demyelination processes. However, a combination of biotin with Mg resulted in a more potent effect than biotin alone. The robust impact of MgB encourages proof-of-concept studies with MgB in human MS 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. © 2022 the Alzheimer's Association. WOS:000904940000001 36576157 Q1

Aim: This study aimed to investigate the effects of favipravir used for treating Covid-19 infection and other infectious diseases, on migraine severity and frequency through VAS (Visual Analog Scale), MIDAS (Migraine Disability Assesment Scale). Methods: The study was planned retrospectively, from January 2020 to September 2021, to evaluate patient demographical features who have received migraine diagnosis before or after Covid-19 infection (3 months) admitted in the neurology outpatient clinics of Alanya Alaaddin Keykubat University Training and Research Hospital. Findings: From 70 patients in total 12 (17.1%) of the patients involved in the study were male, while 58 (82.9%) were female. 32 (45.7%) of patients used favipravir and 38 (54.3%) did not use Favipravir. The number of migraine attacks after Covid-19 were found significantly lower than the average of the VAS and Midas scores before covid infection. The average number of migraines before Covid-19 infection was 4.31 ± 2.80, which was found as 3.54 ± 3.07 after the Covid-19 infection. The effect of favipravir use on headache parameters before Covid-19 and after Covid-19 for patients were found similar (p> 0.05). Conclusion: Our study, provides valuable data on the effects of infection and/or isolation on migraine frequency and severity, possibly exerting a prophylactic effect for migraine type headaches.

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. 36515182

Introduction: The pre-supplementary motor area (Pre-SMA) plays a pivotal role in the control of voluntary motor control and freezing of gait (FOG) pathophysiological mechanism. Here, we aimed to modulate if the pre-SMA would have beneficial effects on motor and behavioural outcomes in freezing of gait. To test this hypothesis, we examined the left pre-SMA stimulating effect of repetitive Transcranial Magnetic Stimulation (rTMS) on motor, cognitive and behavioural parameters in Parkinson’s patients with FOG. Method: The study included 20 Parkinson’s patients with FOG (3 females, 17 males) who received the left Pre-SMA rTMS procedure. The clinical assessments were performed on all patients at the baseline and the patients were re-evaluated under the same clinical conditions one week after the end of the sessions. Results & Discussion: We found significant improvements in motor, cognitive and behavioural symptoms (p Conclusion: The high-frequency rTMS stimulation over the left preSMA has a restorative effect on the motor, cognitive and behavioural symptoms of Parkinson’s patients with FOG.

The neuropathologic hallmarks of Parkinson’s disease (PD) are associated with mitochondrial dysfunction and metabolic abnormalities. We have reported that the Combined Metabolic Activators (CMA), consisting of L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate can be used in treating metabolic abnormalities. These metabolic activators are the precursors of nicotinamide adenine dinucleotide (NAD+) and glutathione (GSH) and used in activation of mitochondrial and global metabolism. We have performed a placebo-controlled, phase-2 study in Alzheimer’s disease (AD) patients and reported that the cognitive functions in AD patients is significantly improved 29% in the CMA group whereas it is improved only 14% in the placebo group after 84 days of CMA administration. Here, we designed a randomized, double-blinded, placebo-controlled, phase-2 study in PD patients with CMA administration. We found that the cognitive functions in PD patients is significantly improved 21% in the CMA group, whereas it is improved only 11% in the placebo group after 84 days of CMA administration. We also found that the administration of CMA did not affect motor functions in PD patients. We performed a comprehensive multi-omics analysis of plasma proteins and metabolites, and revealed the molecular mechanism associated with the treatment of the patients. In conclusion, our results show that treating PD patients with CMAs leads to enhanced cognitive function, as recently reported in AD patients.

ZIRH, Ali/0000-0002-8811-2263 WOS: 000486093600010 PubMed: 31383472 Deep brain stimulation (DBS) is still a highly effective treatment option that significantly improves motor function in advanced PD. Moreover, previous findings have shown that Olfactory dysfunction (OD) has been found in a majority of patients with Parkinson's Disease (PD). Despite this, the effect of DBS on the olfactory function is not fully understood. Here we aimed to determine the effect of STN DBS on OD by evaluating the olfactory functions in the preoperative and postoperative early stages (1st and 3rd months) in forty-five PD patients and 40 healthy controls. The therapeutic effect of DBS on the improvement of motor functions was parallelly investigated. We have observed that there was a significant improvement in OI in the 1st month and in all olfactory parameters (OT, ODI, OI, and TDI) in the 3rd month. In evaluating the motor functional scores, we have revealed a statistically significant (p < 0.001) difference between preoperative UPDRS-motor score (23 +/- 7.3) and the postoperative 3rd month score (11.1 +/- 5.1). Although Beck Depression and Anxiety scores were improved to a certain level in the 3rd month, this improvement was not at a statistically significant level (p > 0.05). As a conclusion, we have shown that STN-DBS improves the smell functions in PD within three months suggesting that the therapeutic effects of DBS might have a wide range of therapeutic spectrum. Despite some limitations (i.e., short follow-up period) our study gives a critical message that future studies are needed to evaluate the functional correlates of STN-DBS treatment in PD patients. (C) 2019 Elsevier Ltd. All rights reserved.

Minocycline, a semisynthetic tetracycline-derived antibiotic, has been shown to exert anti-apoptotic, anti-inflammatory, and antioxidant effects. Furthermore, there is rapidly growing evidence suggesting that minocycline may have some neuroprotective activity in various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson’s disease (PD), Huntington’s disease, and multiple sclerosis. In this perspective review, we summarize the preclinical and clinical findings suggesting the neuroprotective role of minocycline in PD.

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. Alanya Alaaddin Keykubat University

WOS: 000596504400004 PubMed: 33127444 Objectives: Charles Bonnet Syndrome (CBS) is a rare clinical condition which has been defined as complex visual hallucinations (CVH) due to visual loss. This study investigated differences in the EEG power spectral density (PSD) and magnitude-squared coherences between patients with eye disease and hallucinations (VH+), and the control subjects with eye disease without hallucinations (VH-). Methods: 19 scalp channels EEG was recorded in four VH+ (CBS) and four VH- subjects during an eyes-closed resting condition. Artefact-free epochs were analyzed to obtain PSD values in the delta, theta, alpha1, alpha2, beta1, beta2 and gamma frequency bands. Coherence values were calculated through inter-hemispheric and intra-hemispheric electrodes pairs of interest. All subjects were performed with neuropsychological and behavioral assessments to evaluate cognitive functions. Results: The VH + group had increase PSD in theta, beta2 and gamma bands in central, parietal and occipital (O2) areas. The synchronicity was altered particularly in parietal and frontal-parietal regions especially at theta and alpha1 respectively. Conclusions: The aberrant activity in occipital and parietal regions suggest the mechanism of CBS. This is a major electrophysiological study of understanding CBS and visual hallucinations.

Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analysed the brain transcriptomics data of more than 600 AD patients using genome-scale metabolic models and provided supporting evidence of mitochondrial dysfunction related to the pathophysiologic mechanisms of AD progression. Subsequently, we investigated, in a rat model of AD, the oral administration of Combined Metabolic Activators (CMA), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMA includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate, salt form of L-carnitine. The study revealed that supplementation of the CMA improved the AD-associated histological parameters in the animals. Finally, we designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMA improves cognitive functions in AD patients. As decreased AD Assessment Scale-cognitive subscale (ADAS-Cog) score is the indicator of the improved cognitive function in AD patients, we observed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (Log2FC= -0.37, (29% improvement), p-value=0.00001) in the CMA group. We also observed a significant decrease in the placebo group on Day 84 vs Day 0 (Log2FC= -0.19, (14% improvement), p-value=0.001) possibly due to the recommendations of exercise and Mediterranean diet to all AD patients and/or a placebo effect apparent in the early stages of AD clinical trials. A comprehensive analysis of the human plasma metabolome and proteome revealed that plasma levels of proteins and metabolites associated with redox metabolism are significantly improved after treatment. In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases. Funding: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation. The authors would like to thank the Metabolon Inc. (Durham, USA) for generation of metabolomics data, and ChromaDex Inc. (Irvine, CA, USA) for providing NR. AM and HY acknowledge support from the PoLiMeR Innovative Training Network (Marie Sklodowska-Curie Grant Agreement No. 812616) which has received funding from the European Union’s Horizon 2020 research and innovation programme. Declaration of Interest: AM, JB and MU are the founder and shareholders of ScandiBio Therapeutics. The other authors declare no competing interests. Ethical Approval: All experiments for the treatment of the animals were approved by the Ethics Committee of Ataturk University, and were conducted following the National Institutes of Health Guide for Care and Use of Laboratory Animals.

Repetitive 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. Istanbul Medipol University Research Fund ; Research Institute for Health and Technologies (SABITA), Regenerative and Restorative Medicine Research Center (REMER), functional Imaging and Cognitive-Affective Neuroscience Lab (fINCAN)

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.

Cankaya, Seyda/0000-0001-5309-0351 WOS: 000556833000037 PubMed: 32376158 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. (C) 2020 Elsevier Ltd. All rights reserved.

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.

Toprak, Guven/0000-0003-4856-9987; Saricaoglu, Mevhibe/0000-0002-1289-4641 WOS: 000525932300006 PubMed: 32057924 It has been already shown that the motor symptoms of the Parkinson's Disease (PD) have been improved with high frequency rTMS although there is no consensus on the most suitable target brain localization for a maximal therapeutic efficacy. Here, we aimed to compare the therapeutic effect of high frequency (5Hz) rTMS stimulation on primary motor cortex (M1) and pre-supplementary (pre SMA) regions in patients with PD who were still on pharmacological treatment. The study included right-hand dominant16 patients with PD (5 females, 11 males) with demographically and clinically similar characteristics which were randomly assigned to group 1 (n=8) and group 2 (n=8) and received left M1 and the left pre-SMA rTMS procedure, respectively. Total and sequential motor scores of the Unified Parkinson's Disease Rating Scale (UPDRSmotor) were applied to all patients at the baseline and the patients were re-evaluated under the same clinical conditions one week after the end of the sessions. Comparisons of the UPDRS-motor scores between two groups yielded significant improvements after the rTMS on pre-SMA compared to M1 (M1 p=0.14; pre-SMA p=0.01). which were especially significant for the bradykinesia (p=0.04) and axial score related items (p=0.01). This is the first study that shows the effect of rTMS on pre-SMA and it appears to be a promising option in the treatment of PD.

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.