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.

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.

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.

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.

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.

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.

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.

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.

No evidence of association between optic neuritis and secondary LHON mtDNA mutations in patients with multiple sclerosis.

Leber's Hereditary Optic Neuropathy (LHON) shares features with Multiple Sclerosis (MS). Both diseases develop optic lesions. Frequent secondary LHON mutations in MS patients may explain the optic damage. Here, we tested the hypothesis that secondary LHON mutations are associated with optic neuritis (ON) in MS patients. We recruited 56 MS subjects with ON and 47 MS subjects without ON. DNA was extracted by salting out, after sampling of peripheral blood from each participant. We completed Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis with appropriate primers and restriction endonucleases for seven secondary LHON mutations. Products were visualized using 3% agarose gel electrophoresis with the aid of DNA safe stain in a UV transilluminator. Accuracy of the genotyping procedure was confirmed by sequencing. Data was analyzed using chi square and Fisher exact tests and logistic regression analysis. There was no significant difference between the numbers of MS subjects with ON and without ON that carried secondary LHON mutations (T4216C [P=0.1], A4917G [P=0.2], G13708A [P=0.6], G15257A [P=1], G15812A [P=0.8], G15927A [P=1], G15928A [P=0.4]). The evidence from the present study are not consistent with the hypothesis that secondary LHON mutations are associated with ON in MS subjects.

Revisiting nicotine's role in the ageing brain and cognitive impairment.

Brain ageing is a complex process which in its pathologic form is associated with learning and memory dysfunction or cognitive impairment. During ageing, changes in cholinergic innervations and reduced acetylcholinergic tonus may trigger a series of molecular pathways participating in oxidative stress, excitotoxicity, amyloid-ß toxicity, apoptosis, neuroinflammation, and perturb neurotrophic factors in the brain. Nicotine is an exogenous agonist of nicotinic acetylcholine receptors (nAChRs) and acts as a pharmacological chaperone in the regulation of nAChR expression, potentially intervening in age-related changes in diverse molecular pathways leading to pathology. Although nicotine has therapeutic potential, paradoxical effects have been reported, possibly due to its inverted U-shape dose-response effects or pharmacokinetic factors. Additionally, nicotine administration should result in optimum therapeutic effects without imparting abuse potential or toxicity. Overall, this review aims to compile the previous and most recent data on nicotine and its effects on cognition-related mechanisms and age-related cognitive impairment.

MtDNA T4216C variation in multiple sclerosis: a systematic review and meta-analysis.

MtDNA T4216C variation has frequently been investigated in Multiple Sclerosis (MS) patients; nonetheless, controversy has existed about the evidence of association of this variation with susceptibility to MS. The present systematic review and meta-analysis converge the results of the preceding publications, pertaining to association of mtDNA T4216C variation with susceptibility to MS, into a common conclusion. A computerized literature search in English was carried out to retrieve relevant publications from which required data were extracted. Using a fixed effect model, pooled odds ratio (OR), 95 % confidence interval (95 % CI), and P value were calculated for association of mtDNA T4216C variation with susceptibility to MS. The pooled results showed that there was a significant association between mtDNA T4216C variation and MS (OR = 1.38, 95 % CI = 1.13-1.67, P = 0.001). The present systematic review and meta-analysis suggest that mtDNA T4216C variation is a contributory factor in susceptibility to MS.

Parkinson's disease and mitochondrial gene variations: a review.

Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The pathogenesis of PD is a complex process, with genetics as an important contributing factor. This factor may stem from mitochondrial gene variations and mutations as well as from nuclear gene variations and mutations. More recently, a particular role of mitochondrial dysfunction has been suggested, arising from mitochondrial DNA variations or acquired mutations in PD pathogenesis. The present review summarizes and weighs the evidence in support of mitochondrial DNA (mtDNA) variations as important contributors to the development and course of PD.

Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy.

BACKGROUND & AIMS: It is unclear whether patients with hepatic encephalopathy (HE) have disturbed brain oxygen metabolism and blood flow. METHODS: We measured cerebral oxygen metabolism rate (CMRO(2)) by using (15)O-oxygen positron emission tomography (PET); and cerebral blood flow (CBF) by using (15)O-water PET in 6 patients with liver cirrhosis and an acute episode of overt HE, 6 cirrhotic patients without HE, and 7 healthy subjects. RESULTS: Neither whole-brain CMRO(2) nor CBF differed significantly between cirrhotic patients without HE and healthy subjects, but were both significantly reduced in cirrhotic patients with HE (P < .01). CMRO(2) was 0.96 +/- 0.07 mumol oxygen/mL brain tissue/min (mean +/- SEM) in cirrhotic patients with HE, 1.34 +/- 0.08 in cirrhotic patients without HE, and 1.35 +/- 0.05 in healthy subjects; and CBF was 0.29 +/- 0.01 mL blood/mL brain tissue/min in patients with HE, 0.47 +/- 0.02 in patients without HE, and 0.49 +/- 0.03 in healthy subjects. CMRO(2) and CBF were correlated, and both variables correlated negatively with arterial ammonia concentration. Analysis of regional values, using individual magnetic resonance co-registrations, showed that the reductions in CMRO(2) and CBF in patients with HE were essentially generalized throughout the brain. CONCLUSIONS: The observations imply that reduced cerebral oxygen consumption and blood flow in cirrhotic patients with an acute episode of overt HE are associated with HE and not cirrhosis as such, and that the primary event in the pathogenesis of HE could be inhibition of cerebral energy metabolism by increased blood ammonia.