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- Jester-Broms, Jonas
(författare)
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Characterization of habenular neurocircuitry. A potential novel target for treating depression.
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the last decade, there has been an explosion of interest within the psychiatric research community in a small diencephalic brain region called the habenula. It has been uncovered as a key regulator of monoaminergic transmission, playing a fundamental role in decision making, behavioral flexibility, inhibitory control, sleep, pain and analgesia. Perturbation of the habenular neurocircutry in animals produce effects that mimic rewards and punishments, animals actively seek habenula inactivation while avoiding activation. From a psychiatric viewpoint, the habenula is a promising target for diseases like depression, drug dependence and ADHD. Given that the morphology and connectivity of the habenula is highly conserved throughout the vertebrate subphylum, animal research is both valid and necessary to map the circuitry and neuronal populations that constitute the habenular complex. Due to the small size and position of the habenula, techniques for modulating this brain area in humans are both invasive, difficult and risky. To overcome this issue, we have characterized an orphan G protein-coupled receptor (Gpr151) that may serve as a future non-invasive target for habenula modulation. We demonstrate that it is highly enriched in the habenular circuitry, with a pattern that is evolutionary conserved. Using monosynaptic pseudorabies and adenoassociated viral tracing techniques we have dissected the connectivity of the habenular neurons expressing the orphan G-protein coupled receptor Gpr151. We have also performed initial screening experiments with the aim of identifying ligands to the receptor. Our results indicate that Gpr151 can possibly modulate a brain network providing a link between the basal forebrain and neuromodulatory brain stem targets, a circuitry with a involved in a multitude of functions with importance for psychiatric disease. Moreover, we continued the characterization of the inhibitory interneurons in the habenula, a neuronal population which has received very little attention previously. The existence of various types of intrinsic neurons within the habenular nucleus adds to the already very complex picture of this intriguing structure. Psychiatry is in dire need of new effective treatments, and the habenula and Gpr151 might provide possible novel targets for psychopharmacological research and future drug development.
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| 2. |
- Ossenkoppele, Rik, et al.
(författare)
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Assessment of Demographic, Genetic, and Imaging Variables Associated with Brain Resilience and Cognitive Resilience to Pathological Tau in Patients with Alzheimer Disease
- 2020
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 77:5, s. 632-642
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ϵ4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, Setting, an Participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main Outcomes and Measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ϵ4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β =-0.15, P =.02) and young patients (standardized β =-0.20, P =.006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P <.001) and global cortical thickness (standardized β = 0.23, P <.001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] =-0.235 [0.111], P =.03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and Relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.
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