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This study was funded by The Scientific and Technological Research Council of Turkey (TUBITAK) 1001 Grant #115S219 and Istanbul University Scientific Research Projects Unit project #1567/42362. Objective: To investigate metabolic changes of mild cognitive impairment in Parkinson’s disease (PD-MCI) using proton magnetic resonance spectroscopic imaging (1H-MRSI). Methods: Sixteen healthy controls (HC), 26 cognitively normal Parkinson’s disease (PD-CN) patients, and 34 PD-MCI patients were scanned in this prospective study. Neuropsychological tests were performed, and three-dimensional 1H-MRSI was obtained at 3 T. Metabolic parameters and neuropsychological test scores were compared between PD-MCI, PD-CN, and HC. The correlations between neuropsychological test scores and metabolic intensities were also assessed. Supervised machine learning algorithms were applied to classify HC, PD-CN, and PD-MCI groups based on metabolite levels. Results: PD-MCI had a lower corrected total N-acetylaspartate over total creatine ratio (tNAA/tCr) in the right precentral gyrus, corresponding to the sensorimotor network (p = 0.01), and a lower tNAA over myoinositol ratio (tNAA/mI) at a part of the default mode network, corresponding to the retrosplenial cortex (p = 0.04) than PD-CN. The HC and PD-MCI patients were classified with an accuracy of 86.4% (sensitivity = 72.7% and specificity = 81.8%) using bagged trees. Conclusion: 1H-MRSI revealed metabolic changes in the default mode, ventral attention/salience, and sensorimotor networks of PD-MCI patients, which could be summarized mainly as ‘posterior cortical metabolic changes’ related with cognitive dysfunction. Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) Istanbul University Publisher's Version Q3 WOS:000828927500002 PubMed ID: 35867235

The pathophysiology of switch-of lateralization and bilateral temporal asynchrony, which are scalp EEG ictal propagation patterns (iPP) in temporal lobe epilepsy (TLE), is poorly understood. We aimed to analyse functional connectivity (FC) of the temporal lobe and related areas in patients with TLE with iPP (iPP-TLE) and without iPP (non-iPP TLE). Twelve patients with iPP-TLE, 13 patients with non-iPP TLE, and 13 healthy controls (HC) underwent resting-state functional MRI (fMRI). Seed-based FC was analysed between the homologous insulae, hippocampi, amygdalae, parahippocampal, superior temporal, and middle temporal gyri. FC was reduced between homologous temporal lobe areas in patients with TLE compared with HCs. Patients with non-iPP TLE displayed decreased FC between the homologous parahippocampal and superior temporal gyri, and patients with iPP-TLE had lower FC between the homologous insulae, parahippocampal and superior temporal gyri compared with HC. Furthermore, patients with iPP-TLE tended to have lower FC between the bilateral insulae when compared with patients with non-iPP TLE. Reduced FC of interhemispheric connections between temporal lobes and related areas might be an adaptive change to protect contralateral areas in seizure propagation. The insula showed decreased FC between two hemispheres in patients with iPP-TLE, assuming a role in ictal scalp propagation pattern changes in TLE.

PubMed: ID34619619 Mild cognitive impairment of Parkinson's disease (PD) may be an early manifestation that may progressively worsen to dementia. Cognitive decline has been associated with changes in the brain perfusion pattern. This study aimed to evaluate cerebral blood flow (CBF) deficits specific to different stages of cognitive decline. Seventeen patients with cognitively normal PD (PD-CN), 18 patients with PD with mild cognitive impairment (PD-MCI), and 16 patients with PD with dementia (PDD) were included in this study. The participants were scanned using a 3 T Philips MRI scanner. Arterial spin labelling magnetic resonance (ASL-MR) images were acquired, followed by calculation of the CBF maps, and registration onto the MNI152 brain atlas. A whole-brain voxel-based CBF comparison was performed among the patient groups using age as a covariate. The mean age of patients with PDD was significantly higher than that of patients with PD-MCI (P = 0.015) and PD-CN (P = 0.001). The CBF values of the three groups were significantly different in the left cuneus of the visual network (VN), left inferior frontal gyrus of the frontoparietal network (FPN), and left dorsomedial nucleus of the thalamus. PDD had lower perfusion values than PD-MCI group in the same regions detected in the main group analysis. Additionally, comparison of PDD with PD-CN and non-demented groups revealed that the perfusion reduction extended into the bilateral cuneus of the VN, bilateral thalami, and left inferior frontal gyrus of the FPN. PDD could be separated from PD-MCI and PD-CN stages with CBF deficits in non-dopaminergically mediated posterior and dopaminergically mediated frontal networks. Publisher's Version

Background: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson’s disease (PD). Objective: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA) mutations, which pose a significant risk for developing PD. Methods: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBAmc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach. Results: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBAmc and HC groups, respectively (p = 0.012). Significant increased connectivity Conclusion: Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD.

The most prominent functional magnetic resonance imaging findings about social anxiety disorder are increased activity in emotional regulation areas (amygdala, insula, hippocampus, dorsal anterior cingulate cortex) and fear circuit, and altered activity in prefrontal cortex. This study aims to investigate network abnormalities during resting state.Resting state functional magnetic resonance images of 21 drug-free patients with social anxiety disorder and 21 healthy controls (matched on age, gender, and years of education) were recorded. Resting state functional connectivity networks were obtained with independent component analysis, and were compared by using the voxel based t-test between the two groups.Patients with social anxiety disorder displayed decreased intrinsic functional connectivity in the anterior component of the salience network (left orbitofrontal cortex) and increased intrinsic functional connectivity in the posterior component of the salience network (left supramarginal gyrus).Most of the studies about social anxiety disorder mainly focused on fear circuit and emotional regulation areas by using anxiety provoking tasks or by using seed based analysis of functional connectivity. By applying a whole-brain independent component analysis, we found altered functional connectivity in the salience network, but no significant difference was found in the fear circuit areas. Our results suggest that abnormal connectivity in the salience network might play a crucial role in the neurobiology of social anxiety disorder.

Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) is currently diagnosed based on an arbitrarily predefined standard deviation of neuropsychological test scores, and more objective biomarkers for PD-MCI diagnosis are needed. The purpose of this study was to define possible brain perfusion-based biomarkers of not only mild cognitive impairment, but also risky gene carriers in PD using arterial spin labeling magnetic resonance imaging (ASL-MRI). Fifteen healthy controls (HC), 26 cognitively normal PD (PD-CN), and 27 PD-MCI subjects participated in this study. ASL-MRI data were acquired by signal targeting with alternating radio-frequency labeling with Look-Locker sequence at 3 T. Single nucleotide polymorphism genotyping for rs9468 [microtubule-associated protein tau (MAPT) H1/H1 versus H1/H2 haplotype] was performed using a Stratagene Mx3005p real-time polymerase chain-reaction system (Agilent Technologies, USA). There were 15 subjects with MAPT H1/H1 and 11 subjects with MAPT H1/H2 within PD-MCI, and 33 subjects with MAPT H1/H1 and 19 subjects with MAPT H1/H2 within all PD. Voxel-wise differences of cerebral blood flow (CBF) values between HC, PD-CN and PD-MCI were assessed by one-way analysis of variance followed by pairwise post hoc comparisons. Further, the subgroup of PD patients carrying the risky MAPT H1/H1 haplotype was compared with noncarriers (MAPT H1/H2 haplotype) in terms of CBF by a two-sample t test. A pattern that could be summarized as "posterior hypoperfusion" (PH) differentiated the PD-MCI group from the HC group with an accuracy of 92.6% (sensitivity = 93%, specificity = 93%). Additionally, the PD patients with MAPT H1/H1 haplotype had decreased perfusion than the ones with H1/H2 haplotype at the posterior areas of the visual network (VN), default mode network (DMN), and dorsal attention network (DAN). The PH-type pattern in ASL-MRI could be employed as a biomarker of both current cognitive impairment and future cognitive decline in PD.

Introduction Cognitive impairment is common in Parkinson's disease (PD) and PD patients with mild cognitive impairment (PD-MCI) are at increased risk of developing Parkinson's disease dementia (PDD). Reliable biomarkers are required for objective identification of cognitive decline in PD. In this pilot study, serum levels of well-known mediators of neuroinflammation were measured in PD patients with or without MCI to find out the involvement of neuroinflammation and microglial activation in PD-MCI. Methods 36 PD-MCI, 25 PD patients with normal cognition (PD-NC) and 19 healthy controls were recruited. Serum levels of NLR family pyrin domain containing 1 (NLRP1), NLRP3, caspase-1, NF-kB, IL-1b and IL-18 were measured by ELISA and a panel of neuropsychological tests was administered. Results PD-MCI patients showed significantly reduced levels of NF-kB, IL-1b and IL-18, whereas NLRP1, NLRP3 and caspase-1 levels were comparable among PD-NC and PD-MCI patients. IL-18 levels were positively correlated with Addenbrooke's Cognitive Examination-Revised and Symbol Digit Modalities Test scores. Conclusion Levels of several microglial activation mediators are reduced in PD-MCI patients inferring a protective role to certain inflammation factors against cognitive decline in PD.

PubMed ID: 32632889 Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) is currently diagnosed based on an arbitrarily predefined standard deviation of neuropsychological test scores, and more objective biomarkers for PD-MCI diagnosis are needed. The purpose of this study was to define possible brain perfusion-based biomarkers of not only mild cognitive impairment, but also risky gene carriers in PD using arterial spin labeling magnetic resonance imaging (ASL-MRI). Fifteen healthy controls (HC), 26 cognitively normal PD (PD-CN), and 27 PD-MCI subjects participated in this study. ASL-MRI data were acquired by signal targeting with alternating radio-frequency labeling with Look-Locker sequence at 3 T. Single nucleotide polymorphism genotyping for rs9468 [microtubule-associated protein tau (MAPT) H1/H1 versus H1/H2 haplotype] was performed using a Stratagene Mx3005p real-time polymerase chain-reaction system (Agilent Technologies, USA). There were 15 subjects withMAPTH1/H1 and 11 subjects withMAPTH1/H2 within PD-MCI, and 33 subjects withMAPTH1/H1 and 19 subjects withMAPTH1/H2 within all PD. Voxel-wise differences of cerebral blood flow (CBF) values between HC, PD-CN and PD-MCI were assessed by one-way analysis of variance followed by pairwise post hoc comparisons. Further, the subgroup of PD patients carrying the riskyMAPTH1/H1 haplotype was compared with noncarriers (MAPTH1/H2 haplotype) in terms of CBF by a two-samplettest. A pattern that could be summarized as "posterior hypoperfusion" (PH) differentiated the PD-MCI group from the HC group with an accuracy of 92.6% (sensitivity = 93%, specificity = 93%). Additionally, the PD patients withMAPTH1/H1 haplotype had decreased perfusion than the ones with H1/H2 haplotype at the posterior areas of the visual network (VN), default mode network (DMN), and dorsal attention network (DAN). The PH-type pattern in ASL-MRI could be employed as a biomarker of both current cognitive impairment and future cognitive decline in PD. This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) 1001 Grant #115S219 and Istanbul University Scientific Research Projects Unit Project #1567/42362 Publisher's Version

Neuroimaging research about social anxiety disorder (SAD) points to hyperactivity in the fear circuit and altered connectivity between the fear circuit and the intrinsic connectivity networks that modulate it. We investigated intrinsic functional connectivity changes in SAD patients by taking into consideration the commonly overlooked comorbidity of attention deficit hyperactivity disorder (ADHD). We compared intrinsic functional connectivity alterations in 16 patients with pure SAD, 18 patients with SAD and comorbid ADHD and 21 healthy controls using seed-to-voxel functional connectivity analyses. Hypoconnectivity of the right fusiform gyrus with the left lingual gyrus was the unique difference between whole SAD group and healthy controls, while in the pure SAD group the fusiform gyrus displayed hypoconnectivity with the posterior default mode network (DMN) regions. In contrast, ADHD comorbidity was associated with hyperconnectivities of the salience network (SN) with the fusiform cortex and the posterior DMN regions, and hyperconnectivities of the posterior DMN with visual, somatosensory and motor cortices. The dichotomic dissociation of the SAD related functional connectivity changes into hypoconnectivities in the pure SAD group vs hyperconnectivities in the SAD-ADHD group leads also to the question, whether ADHD treatment can be considered an alternative for selected SAD cases.

This study aims to specify biomarkers of Parkinson's disease mild cognitive impairment (PD-MCI) based on fractional anisotropy (FA) and mean diffusivity (MD) maps obtained from diffusion weighted magnetic resonance imaging (DWMRI). T1 and diffusion weighted MR images collected from 27 cognitively normal Parkinson's disease (PD-CN), 32 mild cognitively impaired Parkinson's disease (PD-MCI), and 18 healthy control (HC) volunteers, at a clinical 3T MR scanner, were processed using FMRIB Software Library (FSL)'s toolboxes. Average regional values of FA and MD maps and tract based spatial statistics (TBSS) were utilized to define statistically significant differences between the participant subject groups.

Objective To analyze the functional connectivity (FC) of temporal lobe and related areas in patients with temporal lobe epilepsy (TLE) showing unilateral lateralized ictal discharges (uniTLE) and unusual ictal propagation patterns (UiP) defined as ‘switch-of lateralization’ and ‘bilateral asynchrony’ in scalp EEG. Methods Twelve TLE patients with UiP (6 with left and 6 with right seizure-onset) and 13 patients with uniTLE (7 with left and 6 with right seizure-onset) and 13 healthy controls (HC) underwent resting state functional MRI. ROI-to-ROI FC analyses were carried out between homologous insula, hippocampi, parahippocampal gyri, amygdala, superior temporal and middle temporal gyri. Results All TLE patients showed reduced overall FC compared to HC, where univariate comparisons revealed that the connectivities were significantly reduced between right and left insula, parahippocampal and superior temporal gyri. MANOVA among the 3 groups revealed that the uniTLE patients displayed a lower FC between the homologous parahippocampal gyri, while patients with UiP had lower FC between the homologous insula, parahippocampal and superior temporal gyri when compared with the HC. Furthermore, TLE patients with UiP showed significantly lower FC between the bilateral insula when compared with uniTLE patients. Discussion While the reduction level of the resting-state FC between the homologous temporal lobe structures may depend on neural loss, a network change to protect contralateral temporal areas might also play role in further reduced FC in TLE with UiP. This might support the presence of independent epileptogenic zones bilaterally rather than a propagation from the contralateral hemisphere.

Hsp70 chaperones play important roles in cells including protein folding, trafficking, degradation and enabling survival under stress conditions. DnaK is an E. coli Hsp70 homolog comprising an ATPase domain and a substrate-binding domain. DnaK has two substrate-affinity states: ATP binding lowers the affinity of the substrate, whereas its hydrolysis leads to a higher affinity of substrate for binding. ATP-dependent communication between the two domains is essential for chaperone function and mediated via a conserved hydrophobic linker (384GDVKDVLLL392). Previous studies showed that when the linker interacts with the ATPase domain, which was studied by the construct containing the entire linker, DnaK(1-392), an enhanced ATPase rate is observed compared to the construct lacking the conserved 389VLLL392 linker region, DnaK(1-388). This observation suggests that structural rearrangements caused by linker docking adopt the ATPase domain in a closed conformation, leading to an enhanced, pH-dependent ATPase activity. Here, our aim is to delineate the residues that are responsible for the linker induced conformational rearrangements. In that line, using molecular dynamic simulations we identified a putative network of interactions through Arg71-Glu81-Asp85-Thr225-His226 at the lobe interface of the ATPase domain that might be critical in stabilization of the domain in the so called “open” and “closed” conformational equilibrium. We made point mutations for these sites on the two ATPase domain constructs, and studied the structural and functional effects of these residues on the ATPase domain as a function of pH using various biophysical and biochemical methods. Mutations' effects studied by equilibrium thermodynamic measurements showed variations for the constructs, but dramatic changes were observed in the dynamics of the constructs. Our results suggest the linker as a controller for ATPase domain dynamics changes partly through the identified network.

Hsp70 chaperones play mportant roles in cells including protein folding, trafficking, degradation and enabling survival under stress conditions. DnaK is an Echerichia coli Hsp70 homolog comprising a 44 kDa ATPase domain (NBD) and a 25 kDa substrate-binding domain (SBD). DnaK has two nucleotide substrate-affinity states: In the ATP-bound low substrate-affinity state, substrate binding and release occur rapidly, whereas in the ADP-bound high substrate-affinity state, slower substrate binding and release kinetics are observed. Communication between the two domains is essential for chaperone function and is mediated via a conserved hydrophobic linker region (384GDVKDVLLL392). Previous studies showed that when this flexible linker interacts with the ATPase domain, which was studied by the construct containing the entire linker, DnaK(1-392), an enhanced ATPase rate is observed compared to the construct lacking the conserved 389VLLL392 linker region, DnaK(1-388). This observation suggests that structural rearrangements caused by linker docking adopt the ATPase domain in a closed conformation, leading to an enhanced, pH-dependent ATPase activity. Here, our aim is to delineate the residues that are responsible for the linker induced conformational rearrangements. In that line, using molecular dynamic simulations we identified two sets of amino acids at the lobe interface of the ATPase domain that might be critical in the stabilization of the domain in the so called “open” and “closed” conformations. We made point mutations for these sites on both DnaK(1-392) and DnaK(1-388) constructs, and studied the structural and functional effects of these residues on the ATPase domain using pH varied stability measurements by circular dichroism and activity measurements as a function of pH, respectively. Our experimental results also point to the significance of these residues in the domain rearrangements when triggered by linker binding.