Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily... Show moreNeurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery.Evidence level: 1Technical Efficacy: Stage 3 Show less
Hack, R.J.; Cerfontaine, M.N.; Gravesteijn, G.; Tap, S.; Hafkemeijer, A.; Grond, J. van der; ... ; Oberstein, S.A.J.L. 2022
BACKGROUND: A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical... Show moreBACKGROUND: A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of NOTCH3 EGFr group. In this study, we determined the relative disease-modifying effects of NOTCH3 EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers. METHODS: Patients with CADASIL participated in a single-center, prospective cohort study (DiViNAS [Disease Variability in NOTCH3 Associated Small Vessel Disease]) between 2017 and 2020. The study protocol included a clinical assessment, neuropsychological test battery and brain magnetic resonance imaging on a single research day. Multivariable linear, logistic and Cox regression models were used to cross-sectionally assess the effect of CADASIL modifiers on clinical severity (stroke, disability, processing speed) and neuroimaging markers (WMH volume, peak width of skeletonized mean diffusivity, lacune volume, brain volume, cerebral microbleed count). RESULTS: Two hundred patients with CADASIL participated, of which 103 harbored a NOTCH3 EGFr 1-6 variant and 97 an EGFr 7-34 variant. NOTCH3 EGFr 1-6 group was the most important modifier of age at first stroke (hazard ratio, 2.45 [95% CI, 1.39-4.31]; P=0.002), lacune volume (odds ratio, 4.31 [95% CI, 2.31-8.04]; P=4.0x 10(-6)), WMH volume (B=0.81 [95% CI, 0.60-1.02]; P=1.1x 10(-12)), and peak width of skeletonized mean diffusivity (B=0.65 [95% CI, 0.44-0.87]; P=1.6x 10(-8)). EGFr 1-6 patients had a significantly higher WMH volume in the anterior temporal lobes and superior frontal gyri and a higher burden of enlarged perivascular spaces. After NOTCH3 EGFr group, male sex and hypertension were the next most important modifiers of clinical outcomes and neuroimaging markers. CONCLUSIONS: NOTCH3 EGFr group is the most important CADASIL disease modifier not only for age at first stroke and WMH volume but also strikingly so for a whole battery of clinically relevant disease measures such as lacune volume and peak width of skeletonized mean diffusivity. NOTCH3 EGFr group is followed in importance by sex, hypertension, diabetes, and smoking. Show less
Dekkers, A.J.; Amaya, J.M.; Meulen, M. van der; Biermasz, N.R.; Meijer, O.C.; Pereira, A.M. 2022
The metabolic and cardiovascular clinical manifestations in patients with Cushing's syndrome (CS) are generally well known. However, recent studies have broadened the perspective of the effects of... Show moreThe metabolic and cardiovascular clinical manifestations in patients with Cushing's syndrome (CS) are generally well known. However, recent studies have broadened the perspective of the effects of hypercortisolism, showing that both endogenous and exogenous glucocorticoid excess alter brain functioning on several time scales. Consequently, cognitive deficits and neuropsychological symptoms are highly prevalent during both active CS and CS in remission, as well as during glucocorticoid treatment. In this review, we discuss the effects of endogenous hypercortisolism and exogenously induced glucocorticoid excess on the brain, as well as the prevalence of cognitive and neuropsychological deficits and their course after biochemical remission. Furthermore, we propose possible mechanisms that may underly neuronal changes, based on experimental models and in vitro studies. Finally, we offer recommendations for future studies. Show less
Nawijn, L.; Dinga, R.; Aghajani, M.; Tol, M.J. van; Wee, N.J.A. van der; Wunder, A.; ... ; Penninx, B.W.H.J. 2022
Background: Comorbid anxiety disorders and anxious distress are highly prevalent in major depressive disorder (MDD). The presence of the DSM-5 anxious distress specifier (ADS) has been associated... Show moreBackground: Comorbid anxiety disorders and anxious distress are highly prevalent in major depressive disorder (MDD). The presence of the DSM-5 anxious distress specifier (ADS) has been associated with worse treatment outcomes and chronic disease course. However, little is known about the neurobiological correlates of anxious distress in MDD. Methods: We probed the relation between the DSM-5 ADS and task-related reactivity to emotional faces, as well as resting-state functional connectivity patterns of intrinsic salience and basal ganglia networks in unmedicated MDD patients with (MDD/ADS+, N = 24) and without ADS (MDD/ADS-, N = 48) and healthy controls (HC, N = 59). Both categorical and dimensional measures of ADS were investigated. Results: MDD/ADS+ patients had higher left amygdala responses to emotional faces compared to MDD/ADS- patients (p = .015)-part of a larger striato-limbic cluster. MDD/ADS+ did not differ from MDD/ADS- or controls in resting-state functional connectivity of the salience or basal ganglia networks. Conclusions: Current findings suggest that amygdala and striato-limbic hyperactivity to emotional faces may be a neurobiological hallmark specific to MDD with anxious distress, relative to MDD without anxious distress. This may provide preliminary indications of the underlying mechanisms of anxious distress in depression, and underline the importance to account for heterogeneity in depression research. Show less
Inglese, F.; Kim, M.; Steup-Beekman, G.M.; Huizinga, T.W.J.; Buchem, M.A. van; Bresser, J. de; ... ; Ronen, I. 2022
Introduction/PurposeSystemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes.... Show moreIntroduction/PurposeSystemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes. Structural brain abnormalities are commonly found in SLE and NPSLE, but their role in diagnosis is limited, and their usefulness in distinguishing between NPSLE patients and patients in which the NP symptoms are not primarily attributed to SLE (non-NPSLE) is non-existent. Self-supervised contrastive learning algorithms proved to be useful in classification tasks in rare diseases with limited number of datasets. Our aim was to apply self-supervised contrastive learning on T-1-weighted images acquired from a well-defined cohort of SLE patients, aiming to distinguish between NPSLE and non-NPSLE patients. Subjects and MethodsWe used 3T MRI T-1-weighted images of 163 patients. The training set comprised 68 non-NPSLE and 34 NPSLE patients. We applied random geometric transformations between iterations to augment our data sets. The ML pipeline consisted of convolutional base encoder and linear projector. To test the classification task, the projector was removed and one linear layer was measured. Validation of the method consisted of 6 repeated random sub-samplings, each using a random selection of a small group of patients of both subtypes. ResultsIn the 6 trials, between 79% and 83% of the patients were correctly classified as NPSLE or non-NPSLE. For a qualitative evaluation of spatial distribution of the common features found in both groups, Gradient-weighted Class Activation Maps (Grad-CAM) were examined. Thresholded Grad-CAM maps show areas of common features identified for the NPSLE cohort, while no such communality was found for the non-NPSLE group. Discussion/ConclusionThe self-supervised contrastive learning model was effective in capturing common brain MRI features from a limited but well-defined cohort of SLE patients with NP symptoms. The interpretation of the Grad-CAM results is not straightforward, but indicates involvement of the lateral and third ventricles, periventricular white matter and basal cisterns. We believe that the common features found in the NPSLE population in this study indicate a combination of tissue loss, local atrophy and to some extent that of periventricular white matter lesions, which are commonly found in NPSLE patients and appear hypointense on T-1-weighted images. Show less
The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the... Show moreThe hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl-trinitrate (GTN)-induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level-dependent (BOLD) response to oral glucose ingestion with 3T-functional magnetic resonance imaging (MRI) in 27 women, 16 with migraine without aura and 11 controls group matched for age and body mass index (BMI), on 1 day without prior GTN administration and on a second day after GTN administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN-triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between- and within-group effects. Without prior GTN infusion, the BOLD response to glucose was similar in migraine participants and controls (P = .41). After prior GTN infusion, recovery occurred steeper and faster in migraineurs (versus Day 1; P < .0001) and in those who developed an attack versus those who did not (P < .0001). Prior GTN infusion did not alter the glucose-induced response in controls (versus baseline; P = .71). Just before spontaneous attacks, the BOLD-response recovery was also faster (P < .0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN-provoked and spontaneous migraine attacks. Show less
Hack, R.J.; Rutten, J.W.; Person, T.N.; Li, J.; Khan, A.; Griessenauer, C.J.; ... ; Zand, R. 2020
Background and Purpose:Cysteine altering NOTCH3 variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy... Show moreBackground and Purpose:Cysteine altering NOTCH3 variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, have a population frequency of 1:300 worldwide. Using a large population database, and taking genotype as a starting point, we aimed to determine whether individuals harboring a NOTCH3 cysteine altering variant have a higher load of small vessel disease markers on brain magnetic resonance imaging than controls, as well as a higher risk of stroke and cognitive impairment.Methods:A cross-sectional study using integrated clinical, neuroimaging, and whole-exome sequencing data of 92 456 participants from the Geisinger DiscovEHR initiative cohort. The case group consisted of individuals harboring a NOTCH3 cysteine altering variant (n=118). The control group consisted of randomly selected age- and sex-matched individuals who did not have any nonsynonymous variants in NOTCH3 (n=184). Medical records including brain magnetic resonance imagings were evaluated for clinical and neuroimaging findings associated with small vessel disease. Group comparisons were done using Fisher exact test and ordinal logistic regression models. Risk of stroke was assessed using Cox regression.Results:Of the 118 cases, 39.0% were men, mean age 58.1 +/- 16.9 years; 12.6% had a history of stroke, compared with 4.9% of controls. The risk of stroke was significantly increased after age 65 years (hazard ratio, 6.0 [95% CI, 1.4-26.3]). Dementia, mild cognitive impairment, migraine with aura and depression were equally prevalent in cases and controls. Twenty-nine cases (25%) and 45 controls (24%) had an available brain magnetic resonance imaging. After age 65 years, cases had a higher white matter lesion burden and more lacunes. A severe small vessel disease phenotype compatible with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy was rarely seen.Conclusions:Cysteine altering NOTCH3 variants are an important contributor to the risk of stroke, lacunes, and white matter hyperintensities in the elderly population. Show less
Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of... Show moreAnxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders. Show less
Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first... Show moreBackground and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A).In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes:CALCRL(2q32.1),KLHL24(3q27.1),VCAN(5q27.1), andPOLR2F(22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only. Show less
The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide.... Show moreThe ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses. Show less
Piasecka, M.; Papakokkinou, E.; Valassi, E.; Santos, A.; Webb, S.M.; Vries, F. de; ... ; Ragnarsson, O. 2020
Psychiatric and neurocognitive symptoms due to hypercortisolism were already described by Harvey Cushing in his original paper on patients with Cushing's syndrome (CS). Nowadays, it is well known... Show morePsychiatric and neurocognitive symptoms due to hypercortisolism were already described by Harvey Cushing in his original paper on patients with Cushing's syndrome (CS). Nowadays, it is well known that psychiatric and cognitive complaints are two of the most common, and most distressing, symptoms in patients with CS. Psychiatric symptoms are indeed a major clinical manifestation of CS. The most commonly observed psychiatric conditions are depression and anxiety, whilst mania and psychosis are less common. Several domains of cognitive function are impaired at diagnosis, including episodic and working memory, executive function and attention. Following treatment, one-fourth of the patients still experience depressed mood, and the cognitive impairments are only partially restored. Consequently, quality of life in patients with CS is severely and persistently affected. Neuroimaging studies have also illustrated the deleterious effects of hypercortisolism on the brain by demonstrating reduced grey matter volumes and cortical thickness, altered resting-state functional responses and during cognitive tasks, as well as widespread reduced white matter integrity, especially in structures important for cognitive function and emotional processing, both before and after successful abrogation of hypercortisolism. In this paper, we summarize the current knowledge on the psychiatric and neurocognitive consequences of hypercortisolism in patients with CS, both before, and after successful treatment. In addition, we review the structural and functional brain abnormalities associated with hypercortisolism and discuss the influence of these factors on quality of life. Show less
Tolner, E.A.; Chen, S.P.; Eikermann-Haerter, K. 2019
Objective To review and discuss the literature on the role of cortical structure and function in migraine. Discussion Structural and functional findings suggest that changes in cortical morphology... Show moreObjective To review and discuss the literature on the role of cortical structure and function in migraine. Discussion Structural and functional findings suggest that changes in cortical morphology and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks. Conclusion Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications. Show less
Panman, J.L.; Y.Y. to; Ende, E.L. van der; Poos, J.M.; Jiskoot, L.C.; Meeter, L.H.H.; ... ; Hafkemeijer, A. 2019
