Altered Cortico–Striatal Functional Connectivity During Resting State in Obsessive–Compulsive Disorder

Background: Neuroimaging studies show that obsessive–compulsive disorder (OCD) is characterized by an alteration of the cortico–striato–thalamo–cortical (CSTC) system in terms of an imbalance of activity between the direct and the indirect loop of the CSTC. As resting-state functional connectivity (FC) studies investigated only specific parts of the CSTC in patients with OCD up to now, the present study aimed at exploring FC in the CSTC as a whole. Methods: We investigated potential alterations in resting-state FC within the CSTC system in 44 OCD patients and 40 healthy controls by taking into consideration all relevant nodes of the direct and indirect CSTC loop. Results: Compared to healthy controls, OCD patients showed an increased FC between the left subthalamic nucleus (STN) and the left external globus pallidus (GPe), as well as an increased FC between the left GPe and the left internal globus pallidus (GPi). Conclusion: These findings may contribute to a better understanding of the OCD pathophysiology by providing further information on the connectivity alterations within specific regions of the CSTC system. In particular, increased FC between the STN and the left GPe may play a major role in OCD pathology. This assumption is consistent with the fact that these regions are also the main target sites of therapeutic deep brain stimulation in OCD

The resting-brain of obsessive-compulsive disorder

Obsessive–compulsive disorder (OCD) is one of the most debilitating psychiatric conditions, having a dramatic impact on patients’ daily living. In this work, we aimed to explore resting-state functional connectivity in OCD patients, using an independent component analysis. Eighty individuals (40 patients and 40 healthy controls) performed a resting state fMRI protocol. OCD patients displayed reduced functional connectivity (FC) in visual and sensorimotor networks. In addition, patients displayed decreased FC between sensory networks and increased FC between default-mode and cerebellar networks.Pedro Silva Moreira was supported by the FCT fellowship grant with the number PDE/BDE/113601/2015 from the PhD-iHES program; Paulo Marques was funded by the Fundação Calouste Gulbenkian (Contract grant number: P-139977; project “Better mental health during ageing based on temporal prediction of individual brain ageing trajectories (TEMPO)”); Ricardo Magalhães was supported by the FCT fellowship grant with the number PDE/BDE/113604/2015 from the PhD-iHES program; Madalena Esteves was supported by the FCT fellowship grant with the number SFRH/BD/52291/2013 from the PhDOC program. The present work was supported by SwitchBox-FP7-HEALTH2010-grant 259772-2 and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER)

Microglial activation and connectivity in Alzheimer disease and aging

OBJECTIVE Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. METHODS We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity. RESULTS We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner. INTERPRETATION Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies.

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases

Associations between sex, body mass index and the individual microglial response in Alzheimer’s disease

Background and objectives 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer’s disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between β-amyloid-accumulation and microglial activation in AD. Methods 49 patients with AD (29 females, all Aβ-positive) and 15 Aβ-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and β-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aβ-PET on TSPO-PET was used to determine the Aβ-plaque-dependent microglial response (slope) and the Aβ-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI). Results In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aβ-PET z-scores were similar. The Aβ-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD − 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aβ-plaque-dependent microglial response was not different between sexes. The Aβ-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aβ-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005). Conclusion While microglia response to fibrillar Aβ is similar between sexes, women with AD show a stronger Aβ-plaque-independent microglia response. This sex difference in Aβ-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aβ-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD

Factors Related to Microalbuminuria in Patients with Chronic Obstructive Pulmonary Disease

WOS: 000346149200011PubMed: 25491689Background. Chronic obstructive pulmonary disease (COPD) is characterized by inhaled particles and gases inducing chronic inflammation of the airways accompanied by a not fully reversible airflow limitation. Systemic inflammation has an important role in the pathogenesis of COPD. In parallel, several comorbidites can be observed. Microalbuminuria is related to endothelial dysfunction. Microalbuminuria was increased in exacerbation periods of COPD. Objectives. The aim of the study was evaluate to the presence of microalbuminuria (MA) in patients with chronic obstructive pulmonary disease (COPD) and its relationship to inflammation, arterial blood gas parameters and 24-hour ambulatory blood pressure alterations. Material and Methods. Seventy COPD patients and 40 healthy volunteers were enrolled in the study. 24-h ambulatory blood pressure monitoring (ABPM) results, including pressure and pulse rates of the subjects were recorded and the cases were classified as "dipper" if a normal fall of more than 10% in blood pressure was observed at night and "non-dipper" if not. Routine renal function tests were performed, C-reactive protein (CRP) values were examined and urine samples were obtained to scrutinize the presence of MA. Patients were allocated into two groups, those with and without MA. The spirometry and arterial blood gas results of the patients were recorded. Results. The urinary albumin creatinin ratio (64.8 +/- 91.8), CRP (21 +/- 14.8), nocturnal systolic and diastolic blood pressure (118 +/- 14 and 72 +/- 10), nocturnal and diurnal pulse (87 +/- 17 and 90 +/- 14), nocturnal pulse pressure (49 +/- 11), mean pulse (89 +/- 15), mean pulse pressure (48 +/- 10) and the number of non-dipper subjects (65) were found significantly higher in the COPD group than in the control group (10.6 +/- 6, 5.4 +/- 2.4, 105 +/- 6 and 68 +/- 7, 70 +/- 10 and 78 +/- 11, 42 +/- 1, 75 +/- 11, 42 +/- 7 and 5, respectively); (p < 0.001, < 0.001, < 0.001 and 0.041, < 0.001 and < 0.001, < 0.001, < 0.001, < 0.001 and < 0.001, respectively). Nocturnal pulse (89 +/- 17) and CRP (23.5 +/- 14.8) were found to be significantly higher in COPD patients with MA than in COPD patients without MA (78 +/- 8 and 8.8 +/- 6.3, respectively); (p = 0.021 and < 0.001, respectively). Conclusions. The facts that CRP, a systemic inflammation marker, and mean nocturnal pulse pressure values were significantly higher in the group with MA among COPD patients, and that ambulatory blood pressure values did not differ between COPD patients with and without MA, suggest both a possible role of inflammation in MA development in COPD patients and a relationship between MA and increased heart rate

The usage of third molars to determine legally relevant age thresholds in Turkey

From a forensic perspective, attaining the ages of 12, 15 and 18 is particularly important with respect to the Turkish Penal Code (TPC). The aim of this study is to obtain data regarding third molar development in the Turkish population for age estimation and to investigate the contribution of third molar development to age estimation in relation to the TPC. The study was applied with panoramic radiography on 379 male and 405 female subjects. The mineralization status of the third molars were evaluated on the basis of Demirjian's classification system. It was determined that 0' and A' stages for under-12 years of age, B' and C' stages for under-15, D' stage for under-18, E' and F' stages for over-12, G' stage for over-15 and H' stage for over-18 were specific stages for both genders. Specific stages that are detected according to the developmental stages of the third molars were not found to be adequately precise for distinguishing legal age thresholds. However, this study shows that matured third molars (reaching H stage) are indicative of an individual's being over 18years of age for both genders in Turkey