Dendritic spines and their role in the pathogenesis of neurodevelopmental and neurological disorders.

Since Cajal introduced dendritic spines in the 19th century, they have attained considerable attention, especially in neuropsychiatric and neurologic disorders. Multiple roles of dendritic spine malfunction and pathology in the progression of various diseases have been reported. Thus, it is inevitable to consider these structures as new therapeutic targets for treating neuropsychiatric and neurologic disorders such as autism spectrum disorders, schizophrenia, dementia, Down syndrome, etc. Therefore, we attempted to prepare a narrative review of the literature regarding the role of dendritic spines in the pathogenesis of aforementioned diseases and to shed new light on their pathophysiology.

Initial Experience of 18 F-FET PET-MR Image Fusion for Evaluation of Recurrent Primary Brain Tumors.

Background An accurate monitoring technique is crucial in brain tumors to choose the best treatment approach after surgery and/or chemoradiation. Radiological assessment of brain tumors is widely based on the magnetic resonance imaging (MRI) modality in this regard; however, MRI criteria are unable to precisely differentiate tumoral tissue from treatment-related changes. This study was conducted to evaluate whether fused MRI and O-(2- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) positron emission tomography (PET) can improve the diagnostic accuracy of the practitioners to discriminate treatment-related changes from true recurrence of brain tumor. Methods We retrospectively analyzed 18 F-FET PET/computed tomography (CT) of 11 patients with histopathologically proven brain tumors that were suspicious for recurrence changes after 3 to 4 months of surgery. All the patients underwent MRI and 18 F-FET PET/CT. As a third assessment, fused 18 F-FET PET/MRI was also acquired. Finally, the diagnostic accuracy of the applied modalities was compared. Results Eleven patients aged 27 to 73 years with a mean age of 47 ± 13 years were enrolled. According to the results, 9/11 cases (82%) showed positive MRI and 6 cases (55%) showed positive PET/CT and PET/MRI. Tumoral recurrence was observed in six patients (55%) in the follow-up period. Based on the follow-up results, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 64, 85, 25, 67, and 50%, respectively, for MRI alone and 91, 85, 100, 100, and 80%, respectively, for both PET/CT and PET/MRI. Conclusion This study found that 18 F-FET PET-MR image fusion in the management of brain tumors might improve recurrence detection; however, further well-designed studies are needed to verify these preliminary data.

Diversifying autism neuroimaging research: An arterial spin labeling review.

LAY ABSTRACT: Brain function and health depend on cerebral blood flow to secure the necessary delivery of oxygen and nutrients to the brain tissue. However, cerebral blood flow appears to be altered in autistic compared to non-autistic individuals, potentially suggesting this difference to be a cause and potential identification point of autism. Recent technological development enables precise and non-invasive measurement of cerebral blood flow via the magnetic resonance imaging method referred to as arterial spin labeling. However, most neuroimaging studies still prefer using the physiologically indirect measure derived from functional magnetic resonance imaging. Therefore, this review examines the use of arterial spin labeling to further investigate the neurobiology of autism. Furthermore, the review includes a comparison of results from molecular imaging and arterial spin labeling followed by a discussion concerning the future direction and potential of arterial spin labeling. We found that arterial spin labeling study results are consistent with those of molecular imaging, especially after considering the effect of age and sex. In addition, arterial spin labeling has numerous application possibilities besides the quantification of cerebral blood flow. Therefore, we encourage researchers to explore and consider the application of arterial spin labeling for future scientific studies in the quest to better understand the neurobiology of autism.

The neural effects of oxytocin administration in autism spectrum disorders studied by fMRI: A systematic review.

PURPOSE: Oxytocin (OXT) is a hypothalamic neuropeptide that is released from the posterior pituitary gland and at specific targets in the central nervous system (CNS). The prosocial effects of OXT acting in the CNS present it as a potential therapeutic agent for the treatment of aspects of autism spectrum disorder (ASD). In this article, we systematically review the functional MRI (fMRI) literature that reports task-state and resting-state fMRI (rsfMRI) studies of the neural effects of single or multiple dose intranasal OXT (IN-OXT) administration in individuals with ASD. METHOD: We searched four databases for relevant documents (PubMed, Web of Science, Scopus, and Google Scholar) using the keywords "autism spectrum disorder", "Asperger Syndrome", "oxytocin", and "fMRI". Moreover, we made a manual search to assess the quality of our automatic search. The search was confined to English language articles published in the interval February 2013 until March 2021. RESULTS: The search yielded 12 fMRI studies with OXT intervention, including 288 individuals with ASD (age 8-55 years) enrolled in randomized, double-blind, placebo-controlled, parallel designs, within-subject-crossover experimental OXT trials. Studies reporting activation task and rsfMRI were summarized with region of interest (ROI) or whole-brain voxel wise analysis. The systematic review of the 12 studies supported the proposition that IN-OXT administration alters brain activation in individuals with ASD. The effects of IN-OXT interacted with the type of the task and the overall results did not indicate restoration of normal brain activation in ASD signature regions albeit the lack of statistical evidence. CONCLUSION: A large body of evidence consistently indicates that OXT alters activation to fMRI in brain networks of individuals with ASD, but with uncertain implications for alleviation of their social deficits.

Pretreatment with nicotinamide mononucleotide increases the effect of ischaemic postconditioning on cardioprotection and mitochondrial function following ex vivo myocardial reperfusion injury in aged rats.

The present study aims to evaluate the combined effect of ischaemic postconditioning (IPostC) and nicotinamide mononucleotide (NMN) on cardioprotection and mitochondrial function in aged rats subjected to myocardial ischaemia-reperfusion (IR) injury. Sixty aged Wistar rats were randomly divided into five groups (n = 12), including sham, control, NMN, IPostC, and NMN + IPostC. Regional ischaemia was induced by 30-min occlusion of the left anterior descending coronary artery (LAD) followed by 60-min reperfusion. IPostC was applied at the onset of reperfusion, by six cycles of 10-s reperfusion/ischaemia. NMN (100 mg/kg) was intraperitoneally injected every other day for 28 days before IR. Myocardial haemodynamics and infarct size (IS) were measured, and the left ventricles samples were harvested to assess cardiac mitochondrial function. The results showed that all treatments reduced lactate dehydrogenase release compared to those of the control group. IPostC alone failed to reduce IS and myocardial function. However, NMN and combined therapy could significantly improve myocardial function and decrease the IS compared to the control animals. Moreover, the effects of combined therapy on the decrease of IS, mitochondrial reactive oxygen species (ROS), and improvement of mitochondrial membrane potential (MMP) were greater than those of stand-alone treatments. These results demonstrated that cardioprotection by combined therapy with NMN + IPostC was superior to individual treatments, and pretreatment of aged rats with NMN was able to correct the failure of IPostC in protecting the hearts of aged rats against IR injury.

On the learning of addictive behavior: Sensation-seeking propensity predicts dopamine turnover in dorsal striatum.

We asked if sensation-seeking is linked to premorbid personality characteristics in patients with addictive disorders, or the characteristics follow the sensation-seeking activity. We interpreted the former as a state associated with normal rates of dopamine synthesis, and the latter as a trait of individuals with abnormally high rates of synthesis. We previously determined dopaminergic receptor density in striatum, and we now tested the hypothesis that an elevated dopaminergic condition with increased extracellular dopamine and receptor density follows increased dopamine synthesis capacity in highly sensation-seeking individuals, as measured by positron emission tomography of 18 men with tracer fluorodopa (FDOPA). We detected a site in left caudate nucleus where the volume of distribution of FDOPA-derived metabolites correlated negatively with FDOPA metabolite turnover, consistent with decreased metabolite breakdown in highly sensation-seeking subjects. High rates of sensation-seeking attenuated the dopamine turnover in association with a low rate of dopamine recycling, low dopamine oxidation, and elevated extracellular dopamine and receptors in caudate nucleus. In contrast, low rates of sensation-seeking were associated with rapid dopamine recycling, rapid dopamine oxidation, low extracellular dopamine, and low receptor density. We conclude that the modulation of dopaminergic neurotransmission associated with sensation-seeking is a state of sensation-seeking, rather than a trait of personality following abnormal regulation of dopaminergic neurotransmission.

Relative Strengths of Three Linearizations of Receptor Availability: Saturation, Inhibition, and Occupancy Plots.

We derived three widely used linearizations from the definition of receptor availability in molecular imaging with positron emission tomography (PET). The purpose of the present research was to determine the convergence of the results of the 3 methods in terms of 3 parameters-occupancy (s), distribution volume of the nondisplaceable reference binding compartment (VND), and nondisplaceable reference binding potential (BPND) of the radioligand-in the absence of a gold standard. We tested 104 cases culled from the literature and calculated the goodness of fit of the least-squares and Deming II methods of linear regression when applied to the determination of s, VND, and BPND using the goodness-of-fit parameters R2, coefficient of variation (root-mean-square error [RMSE]), and the infinity norm (‖X‖∞) with both regression methods. We observed superior convergence among the values of s, VND, and BPND for the inhibition and occupancy plots. The inhibition plot emerged as the plot with a slightly higher degree of convergence (based on R2, RMSE, and ‖X‖∞ value). With two regression methods (the least-squares method [LSM] and the Deming II [DM] method), the estimated values of s, VND, and BPND generally converged. The inhibition and occupancy plots yielded the best fits to the data, according to the goodness-of-fit parameters, due primarily to absence of commingling of the dependent and independent variables tested with the saturation (original Lassen) plot. In the presence of noise, the inhibition and occupancy plots yielded higher convergences.

The role of multimodal MRI in mild cognitive impairment and Alzheimer's disease.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD), where neurodegeneration is not as considerable, thereby potentially increasing the effect of treatments. Therefore, highly sensitive and specific classification of subjects with MCI is necessary, where various MRI modalities have displayed promise. METHODS: Structural, diffusion, and resting-state (RS) functional MRI analyses were performed on the AD (n = 26), MCI (n = 5), and healthy control (HC) (n = 14) group. Structural analysis was performed via voxel-based morphometry (VBM) and volumetric subcortical segmentation analysis. Fractional anisotropy and mean diffusivity were estimated during the diffusion analysis. RS analysis investigated seed-based functional connectivity. Classification via support vector machine was performed to evaluate which MRI modality most accurately differentiated the groups. Multiple linear regression was conducted to evaluate the MRI modalities correlation with clinical assessment scores. RESULTS: Classification of MCI and HC displayed highest accuracy based on diffusion MRI, which besides demonstrated high correlation with clinical scores. Classification was equally accurate in AD, when using VBM or diffusion tensor imaging measures. Yet, more variance was explained by VBM measures in the clinical assessment scores of the AD group. CONCLUSIONS: This study highlights the potential of diffusion MRI in differentiating MCI from HC and AD. However, the results need to be interpreted with caution as sample size and artifacts in the MRI data probably influenced the results.

Nicotinamide mononucleotide and melatonin counteract myocardial ischemia-reperfusion injury by activating SIRT3/FOXO1 and reducing apoptosis in aged male rats.

It has been documented that aging increases the risk of cardiovascular disease including myocardial ischemia/reperfusion (IR) injury and acute myocardial infarction. In this study, we aimed to investigate the individual or combined effects of nicotinamide mononucleotide (NMN) and melatonin (Mel) treatment on apoptotic markers, expression of SIRT3, and FOXO1, and infarct size of the aged myocardium subjected to IR injury. Sixty aged Wistar rats (22-24 months) were assigned to five groups including sham, IR, NMN+IR, Mel+IR, and NMN+Mel+IR (combination therapy). Isolated hearts were exposed to 30-min regional ischemia followed by 60-min reperfusion. NMN (100 mg/kg/day/i.p.) was injected every second day starting on day 28 before IR injury. Melatonin was added to the perfusion solution five minutes prior to and until 15 min after the start of reperfusion. The infarct size was assessed by computerized planimetry. The mRNA levels of SIRT3, FOXO1, and apoptotic genes Bax, Bcl-2, and Caspase-3 were estimated by real-time PCR. All treatments reduced infarct size as compared with the IR group. Melatonin and NMN upregulated the gene expression of Bcl-2, SIRT3, and FOXO1 and downregulated the gene expression of Bax, and Caspase-3, in comparison to the IR group. Also, the protein levels of SIRT3, quantified by Western blotting, were upregulated by the interventions. The effects of combination therapy were significantly greater than those of melatonin or NMN alone. These findings indicate that the combined administration of NMN and melatonin can protect the aged heart against IR injury by decreasing apoptosis and activating the SIRT3/FOXO1 pathway.

Hippocampal neurodegeneration and rhythms mirror each other during acute spinal cord injury in male rats.

Spinal Cord Injury (SCI), triggers neurodegenerative changes in the spinal cord, and simultaneously alters oscillatory manifestations of motor cortex. However, these disturbances may not be limited to motor areas and other parts such as hippocampus, which is vital in the neurogenesis and cognitive function, may be affected in the neurogenic and oscillatory manners. Addressing this remarkable complication of SCI, we evaluated the hippocampal neurogenesis and rhythms through acute phase of SCI. In the present study, we used 40 male rats (Sham.W1 = 10, SCI.W1 = 10, Sham.W2 = 10, SCI.W2 = 10), and findings revealed that contusive SCI declines hippocampal rhythms (Delta, Theta, Beta, Gamma) power and max-frequency. Also, there was a significant decrease in the DCX + and BrdU + cells of the dentate gyrus; correlated significantly with rhythms power decline. Considering the TUNEL assay analysis, there were significantly greater apoptotic cells, in the CA1, CA3, and DG regions of injured animals. Furthermore, according to the western blotting analysis, the expression of receptors (NMDA, GABAA, Muscarinic1), which are essential in the neurogenesis and generation of rhythms significantly attenuated following SCI. Our study demonstrated that acute SCI, alters the power and max-frequency of hippocampal rhythms parallel with changes in the hippocampal neurogenesis, apoptosis, and receptors expression.

Dual-phase 68Ga-PSMA-11 PET/CT may increase the rate of detected lesions in prostate cancer patients.

BACKGROUND: This study was conducted to compare the early static (3-6 min post-injection (p.i.)) and standard whole body (1 h, p.i.) 68Ga-PSMA-11 PET/CT imaging for detection of lesions in prostate cancer (PC) patients. MATERIALS AND METHODS: In this study, PC patients suspected of recurrence underwent 68Ga-PSMA-11 PET/CT. Early static images were acquired from the pelvis and the lower abdomen 3-5 minutes after radiotracer injection and, a routine whole body scan was performed from the skull to the mid-thigh 1 h after injection. Quantitative analysis (SUVmax) was evaluated in suspicious lesions. RESULTS: Of 19 evaluated PC patients with a median age of 72 ± 1.66 years (range: 55-85 years) and prostate-specific antigen (PSA) of 1.72 ± 6.11 ng/ml (range: 0.1-100 ng/ml) (median ± SE), 16 showed positive in the whole body PET/CT. All of the patients with positive whole body scans due to pelvic involvement had positive early scan results. Totally, 22 lesions were detected in both early and delay scans in the pelvic which 16 were related to prostate involvement, 4 were related to lymph node involvement, and 2 were related to bone involvement. Moreover, in addition to the mentioned 22 lesions, early PET imaging successfully detected local recurrence in a patient who was negative on WB PET/ CT; this lesion was masked in the delay scan due to bladder activity. The median SUVmax values of the early and delay scans were 3.69 ± 1.07 (median ± SE) (range: 1.2-14.5) and 5.85 ± 1.69 (range: 3.1-23.4), respectively. (p = 0.005). CONCLUSION: Early static 68Ga-PSMA-11 PET/CT imaging might discriminate metastases from urinary bladder activity. Therefore, early static imaging in combination with whole body 60-min p.i. imaging can improve the detection of local involvement pelvic disease.

Comparison of cognitive flexibility, appropriate risk-taking and reaction time in individuals with and without adult ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) is a developmental and psychiatric disorder that affects different aspects of an individual life, such as cognitive functions. ADHD comprise a complex symptomatology such as cognitive flexibility and inappropriate risk-taking. We aimed to compare cognitive flexibility and appropriate risk-taking of adults with and without ADHD. For this purpose, the Conners' Adult ADHD Rating Scale (CAARS) was used to screen 580 students of Tehran University in Iran. Forty participants who scored highest in CAARS were invited to have a clinical interview with a trained psychiatrist. The diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), using the Wender Utah Rating Scale (WURS). Finally, thirty individuals were diagnosed with ADHD. Meanwhile, the 30 students with the lowest scores on the CAARS and General Health Questionnaire (GHQ) were included as the control group. The two groups then were compared using the Cognitive Flexibility Inventory (CFI) and the Iowa Gambling Task (IGT). The results of the one-way ANOVA indicated that scores of case group in the components of cognitive flexibility were significantly lower in the patients compared to the control group. Also, the ADHD group had lower scores concerning appropriate risk-taking and had a shorter reaction time. Findings of the current study might help to open further avenues in the rehabilitation of cognitive flexibility and controlling reward-seeking and risk-seeking impulses.

Application of [68Ga]PSMA PET/CT in Diagnosis and Management of Prostate Cancer Patients.

PURPOSE: The early and accurate diagnosis of locoregional recurrence or metastasis in prostate cancer (PC) has a significant impact on treatment options. Prostatic-specific membrane antigen (PSMA) positron emission tomography (PET)/x-ray computed tomograph (CT) imaging has recently been introduced as a novel procedure in managing PC. The aim of this study was to evaluate the efficacy of [68Ga]PSMA PET/CT in managing PC patients and to compare the detection rate of PET/CT and bone scans (BSs) in detecting bone metastasis. PROCEDURES: We evaluated 415 patients with PC who underwent [68Ga]PSMA PET/CT between March 2015 and September 2018. The patients were classified into three groups: staging, biomedical recurrence (BCR), and follow-up or monitoring, based on the intent to perform PET/CT. RESULTS: We evaluated 415 patients aged 41-99 (68.25 ± 9.59). Of these patients, 344 (82.9 %) had at least one localized lesion. The detection rates were 48.3 %, 52.6 %, 74.4 %, 79.6 %, and 93.9 % for a PSA value of < 0.2 ng/ml, ≥ 0.2-< 0.5 ng/ml, ≥ 0.5-< 1 ng/ml, ≥ 1-< 2 ng/ml, and ≥ 2 ng/ml, respectively (p < 0.05). The detection rates increased significantly with higher GSs; the rates were 68.3 % (28/41), 74.5 % (73/98), 93.9 % (46/49), and 91 % (61/67) for a GS of < 7, 7, 8, and > 8, respectively (p < 0.05). An ideal cut-off value of > 1.16 ng/ml was obtained for PSA value, which equates to specificity of 75 % and sensitivity of 77 %. In comparing BSs and PET/CT, a region-based analysis showed the superiority of PET/CT over BSs for all regions expect the skull (p < 0.05). PET/CT detected 258 suspicious regions, 255 of which were metastatic and three of which were equivocal. BSs detected only 223 suspicious regions, 203 of which were metastatic and 20 of which were equivocal. CONCLUSIONS: [68Ga]PSMA PET/CT showed a high detection rate for lesions in PC patients. PSA level, GS, and a PSA doubling time of less than 6 months were shown to be the affective variables. In addition, 68Ga-PSMA PET/CT showed better performance in detecting bone lesions than BSs.

Melatonin and Nicotinamide Mononucleotide Attenuate Myocardial Ischemia/Reperfusion Injury via Modulation of Mitochondrial Function and Hemodynamic Parameters in Aged Rats.

Ischemic heart diseases are the major reasons for disability and mortality in elderly individuals. In this study, we tried to examine the combined effects of nicotinamide mononucleotide (NMN) preconditioning and melatonin postconditioning on cardioprotection and mitochondrial function in ischemia/reperfusion (I/R) injury of aged male rats. Sixty aged Wistar rats were randomly allocated to 5 groups, including sham, control, NMN-receiving, melatonin-receiving, and combined therapy (NMN+melatonin). Isolated hearts were mounted on Langendorff apparatus and then underwent 30-minue ligation of left anterior descending coronary artery to induce regional ischemic insult, followed by 60 minutes of reperfusion. Nicotinamide mononucleotide (100 mg/kg/d intraperitoneally) was administered for every other day for 28 days before I/R. Melatonin added to perfusion solution, 5 minutes prior to the reperfusion up to 15 minutes early reperfusion. Myocardial hemodynamic and infarct size (IS) were measured, and the left ventricles samples were obtained to evaluate cardiac mitochondrial function and oxidative stress markers. Melatonin postconditioning and NMN had significant cardioprotective effects in aged rats; they could improve hemodynamic parameters and reduce IS and lactate dehydrogenase release compared to those of control group. Moreover, pretreatment with NMN increased the cardioprotection by melatonin. All treatments reduced oxidative stress and mitochondrial reactive oxygen species (ROS) levels and improved mitochondrial membrane potential and restored NAD+/NADH ratio. The effects of combined therapy on reduction of mitochondrial ROS and oxidative status and improvement of mitochondrial membrane potential were greater than those of alone treatments. Combination of melatonin and NMN can be a promising strategy to attenuate myocardial I/R damages in aged hearts. Restoration of mitochondrial function may substantially contribute to this cardioprotection.

Avicenna (980-1037 CE) and his Early Description and Classification of Dementia.

According to the World Health Organization (WHO), dementia is a disorder that occurs as result of a neurodegenerative process in brain, and usually is chronic or progressive by nature. Most descriptions of senile dementia date back to Alois Alzheimer. In 1906, Alzheimer described the first patient, Auguste Deter, who suffered from the disorder that later became known as Alzheimer's disease. Although, the history of the disease before 1906 is quite rich, little has been said about the contributions of ancient and medieval physicians to the understanding of dementia. Over the centuries, the concept of senile dementia changed from an inevitable mental decline with aging, to different sets of clinical features with narrow limits of diagnosis of a disease in its own right. Documentation of the historical origins of prevention, diagnosis, and therapies of dementia would make an important contribution to a more complete understanding of this pathological degeneration of dementia. The present review focuses on the contributions of Avicenna (AD 980-1037) to the development of diagnosis and the discovery of etiology of different forms of dementia, with the goal of revealing the extent to which dementia was understood in the golden age of Islam in Persia.

Cerebrolysin attenuates ethanol-induced spatial memory impairments through inhibition of hippocampal oxidative stress and apoptotic cell death in rats.

The present study investigates the potential neuroprotective effect of cerebrolysin (CBL), a combination of neurotrophic factors, on the cognitive and biochemical alterations induced by chronic ethanol administration in rats. The animals were divided into five groups as follows: control; ethanol (4 g/kg, for 30 days) plus normal saline (Ethanol + NS); ethanol plus CBL 1 mL/kg (Ethanol + CBL 1), ethanol plus CBL 2.5 mL/kg (Ethanol + CBL 2.5); and ethanol plus CBL 5 mL/kg (Ethanol + CBL 5). The Morris water maze (MWM) test was performed to assess cognitive impairment. The status of the lipid peroxidation marker MDA, antioxidant capacity, as well as alterations of the apoptotic factors such as Bcl-2, BAX, and cleaved caspase-9 and -3, were evaluated in the hippocampus. The results showed that CBL treatment not only normalized the increased MDA levels in the alcoholic rats and enhanced antioxidant defense, but also reduced the Bax/Bcl-2 ratio and cleaved caspase-9 and -3 in the hippocampus. These results were parallel with improvement in spatial memory performance in the MWM test. The findings of the present study provide evidence for the promising therapeutic effect of CBL in chronic ethanol consumption through counteracting oxidative stress and apoptosis markers.

Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions.

Nicotinamide adenine dinucleotide (NAD+) has been described as central coenzyme of redox reactions and is a key regulator of stress resistance and longevity. Aging is a multifactorial and irreversible process that is characterized by a gradual diminution in physiological functions in an organism over time, leading to development of age-associated pathologies and eventually increasing the probability of death. Ischemia is the lack of nutritive blood flow that causes damage and mortality that mostly occurs in various organs during aging. During the process of aging and related ischemic conditions, NAD+ levels decline and lead to nuclear and mitochondrial dysfunctions, resulting in age-related pathologies. The majority of studies have shown that restoring of NAD+ using supplementation with intermediates such as nicotinamide mononucleotide and nicotinamide riboside can be a valuable strategy for recovery of ischemic injury and age-associated defects. This review summarizes the molecular mechanisms responsible for the reduction in NAD+ levels during ischemic disorders and aging, as well as a particular focus is given to the recent progress in the understanding of NAD+ precursor's effects on aging and ischemia.

Mitochondrial DNA G15927A and G15928A variations in patients with multiple sclerosis.

BACKGROUND: Modern genetics has offered a fresh perspective on the pathology of Multiple Sclerosis (MS). As mitochondrial DNA (mtDNA) variations are held to be potential contributors to the complex pathobiology of MS, the present study tests the claim that mtDNA G15927A or G15928A variations, or both, are associated with MS in an Iranian population. MATERIALS AND METHODS: Following DNA extraction from blood samples of 100 subjects with relapsing-remitting MS, and 100 healthy unrelated control subjects, PCR-RFLP analyses was carried out by HpaII restriction enzyme reaction. Electrophoresis was then performed with 3% Agarose gel. As the restriction enzyme did not differentiate between two neighboring nucleotide positions (G15927A and G15928A), all PCR products with a variant allele were sequenced to determine the exact position of the variation. RESULTS: The MtDNA G15927A or G15928A variations were observed in 11 of all 100 cases of MS (11%) and in 7 of 100 healthy control subjects (7%) (P = 0.3, OR = 1.6, 95% CI = 0.5-5.2). Having sequenced all the PCR products with the variant allele (11 cases and 7 controls), the mtDNA G15927A variation was found in one of the 100 cases (1%) and 3 of 100 controls (3%) (P = 0.3, OR = 0.3, 95% CI = 0.0-4.1). Therefore, the mtDNA G15928A variation was present in 10 of the 100 cases (10%) and in 4 of 100 controls (4%) (P = 0.09, OR = 2.6, 95% CI = 0.7-12.0). CONCLUSION: Neither mtDNA variation, G15927A or G15928A, was associated with MS in the studied Iranian population. There was a non-significant association of the G15927A and the G15928A variations separately with MS.

Correction: D-galactose-induced brain ageing model: A systematic review and meta-analysis on cognitive outcomes and oxidative stress indices.

[This corrects the article DOI: 10.1371/journal.pone.0184122.].