| 1. |
- De Geer, Lina
(författare)
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Cardiac dysfunction in septic shock : Observational studies on characteristics and outcome
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Cardiac dysfunction is a well-known complication of sepsis, but its characteristics and consequences, especially on a longer term, remain unclear. The aim of this thesis was to study the characteristics and the implications of cardiac dysfunction for outcome in intensive care unit (ICU) patients with septic shock.Purpose: First, to assess the ability of a cardiac biomarker to predict outcome in ICU patients. Second, to characterise cardiac dysfunction in septic shock using speckle tracking echocardiography. Third, to investigate the reliability of echocardiographic methods used to describe cardiac dysfunction in septic shock. Fourth, to study long-term cardiac outcome in severe sepsis and septic shock patients.Materials and methods: The cardiac biomarker amino-terminal pro-brain natriuretic peptide (NTproBNP) was collected in 481 patients on ICU admission and its ability to predict death was assessed. In 50 patients with septic shock, echocardiography was performed on ICU admission and was repeated during and after ICU stay. Measurements of cardiac strain using speckle tracking echocardiography were assessed in relation to other echocardiographic function parameters, NT-proBNP and severity of illness scores, and their change over time was analysed. Echocardiograms from patients with septic shock were independently evaluated by two physicians and the results analysed regarding measurement variability. A nationwide-registry-based open cohort of 9,520 severe sepsis and septic shock ICU patients discharged alive from the ICU was analysed together with a non-septic control group matched for age, sex and severity of illness. In patients who died after ICU discharge, information on causes of death was collected.Results: A discriminatory level of significance of NT-proBNP on ICU admission was identified at ≥1,380 ng/L, above which NT-proBNP was an independent predictor of death. With increasing levels of NT-proBNP, patients were more severely ill, had a longer ICU stay and were more often admitted with septic shock. Cardiac strain was frequently impaired in septic shock patients but was not superior to other echocardiographic measurements in detecting cardiac dysfunction. Cardiac strain correlated with other echocardiographic function parameters and with NT-proBNP, and was the least user-dependent echocardiographic parameter in septic shock patients. Cardiac strain remained unchanged over time, did not differ between survivors and non-survivors and could not predict an increased risk of death. During a follow-up of up to nearly 6 years after ICU discharge, 3,954 (42%) of sepsis patients died, 654 (17%) with cardiac failure as the cause of death. With increasing severity of illness on admission, the risk of death with cardiac failure as the cause of death after ICU discharge increased. In comparison to other ICU patients with similar severity of illness, however, the risk of death due to cardiac was not increased in patients with severe sepsis or septic shock.Conclusions: Laboratory or echocardiographic signs of cardiac dysfunction are commonly seen in ICU patients in general and in septic shock patients in particular. The assessment of cardiac dysfunction in patients with septic shock is, however, complicated by pre-existing comorbidities, by treatment given in the ICU and by critical illness in itself. Signs of cardiac dysfunction, and the increasing risk of death related to cardiac failure seen after remission of sepsis, may therefore be reflections of critical illness per se, rather than of sepsis.
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| 2. |
- Oppedal, Kristian, et al.
(författare)
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Hazardous drinkers in Norwegian hospitals - a cross-sectional study of prevalence and drinking patterns among somatic patients
- 2011
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Ingår i: Norsk Epidemiologi. - : Norwegian University of Science and Technology (NTNU) Library. - 0803-2491. ; 21:1, s. 93-98
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Tidskriftsartikel (refereegranskat)abstract
- Background: High alcohol intake has been associated with increased risk of hospital admission, increased complication rates, and prolonged hospital stay. Thus, hospital admission may present a relevant opportunity for alcohol intervention. To understand the potential of alcohol interventions we need knowledge about patients’ drinking patterns. The aim of this study was therefore to determine the drinking patterns in a Norwegian hospital population.Methods: A multicentre cross-sectional survey was carried out at three university hospitals. Patients were asked about alcohol intake one month prior to admission/outpatient treatment. The questionnaire included weekly alcohol intake calculated by frequency X quantity as well as episodes of binge drinking (drinking more than 5 AU during a single day). AUDIT-C was used to determine the frequency of patients having a hazardous drinking pattern during the 12 months prior to hospital treatment.Results: In total we assessed 2,932 patients for eligibility. A total of 2,350 patients fulfilled the inclusion criteria. We included 1,522 patients (65%) in the analyses. Six percent of the women and 11% of the men reported drinking more than the weekly limits of nine alcohol units (AU) for women and 14 AU for men. Fourteen percent of the women and 29% of the men reported binge drinking during the last month. The frequency of women scoring more or equal to 4 points on AUDIT-C was 20%. The frequency of men scoring more or equal to 5 points was 25%.Conclusion: Hazardous drinking among Norwegian hospital patients may be more prevalent than what has been reported for the Norwegian population in general. Binge drinking is the dominant drinking pattern.
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| 3. |
- Parish, CL, et al.
(författare)
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Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice
- 2008
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 118:1, s. 149-160
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Tidskriftsartikel (refereegranskat)abstract
- Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did conventional FGF2-treated VMNs. VMN-Wnt5a cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain DA cells. Transplantation of these cells into parkinsonian mice resulted in significant cellular and functional recovery. Importantly, no tumors were detected and only a few transplanted grafts contained sporadic nestin-expressing progenitors. Our findings show that Wnt5a improves the differentiation and functional integration of stem cell-derived DA neurons in vivo and define Wnt5a-treated neural stem cells as an efficient and safe source of DA neurons for cell replacement therapy in PD.
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| 4. |
- Seiz, Emma G., et al.
(författare)
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Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-X-L
- 2012
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 318:19, s. 2446-2459
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the molecular programs of the generation of human dopaminergic neurons (DAn) from their ventral mesencephalic (VM) precursors is of key importance for basic studies, progress in cell therapy, drug screening and pharmacology in the context of Parkinson's disease. The nature of human DAn precursors in vitro is poorly understood, their properties unstable, and their availability highly limited. Here we present positive evidence that human VM precursors retaining their genuine properties and long-term capacity to generate A9 type Substantia nigra human DAn (hVM1 model cell line) can be propagated in culture. During a one month differentiation, these cells activate all key genes needed to progress from pro-neural and pro-dopaminergic precursors to mature and functional DAn. For the first time, we demonstrate that gene cascades are correctly activated during differentiation, resulting in the generation of mature DAn. These DAn have morphological and functional properties undistinguishable from those generated by VM primary neuronal cultures. In addition, we have found that the forced expression of Bcl-X-L induces an increase in the expression of key developmental genes (MSX1, NGN2), maintenance of PITX3 expression temporal profile, and also enhances genes involved in DAn long-term function, maintenance and survival (EN1, LMX1B, NURR1 and PITX3). As a result, Bcl-X-L anticipates and enhances DAn generation. (C) 2012 Elsevier Inc. All rights reserved.
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| 5. |
- Tönnesen, Jan, et al.
(författare)
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Epilepsy and optogenetics : Can seizures be controlled by light?
- 2017
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Ingår i: Clinical Science. - 0143-5221. ; 131:14, s. 1605-1616
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Forskningsöversikt (refereegranskat)abstract
- Over the past decade, 'optogenetics' has been consolidated as a game-changing tool in the neuroscience field, by allowing optical control of neuronal activity with high cell-type specificity. The ability to activate or inhibit targeted neurons at millisecond resolution not only offers an investigative tool, but potentially also provides a therapeutic intervention strategy for acute correction of aberrant neuronal activity. As efficient therapeutic tools are in short supply for neurological disorders, optogenetic technology has therefore spurred considerable enthusiasm and fostered a new wave of translational studies in neuroscience. Epilepsy is among the disorders that have been widely explored. Partial epilepsies are characterized by seizures arising from excessive excitatory neuronal activity that emerges from a focal area. Based on the constricted seizure focus, it appears feasible to intercept partial seizures by acutely shutting down excitatory neurons by means of optogenetics. The availability of both inhibitory and excitatory optogenetic probes, along with the available targeting strategies for respective excitatory or inhibitory neurons, allows multiple conceivable scenarios for controlling abnormal circuit activity. Several such scenarios have been explored in the settings of experimental epilepsy and have provided encouraging translational findings and revealed interesting and unexpected new aspects of epileptogenesis. However, it has also emerged that considerable challenges persist before clinical translation becomes feasible. This review provides a general introduction to optogenetics, and an overview of findings that are relevant for understanding how optogenetics may be utilized therapeutically as a highly innovative treatment for epilepsy.
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| 6. |
- Tønnesen, Jan, et al.
(författare)
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Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D(2) autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.
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| 7. |
- Tønnesen, Jan, et al.
(författare)
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Functional properties of the human ventral mesencephalic neural stem cell line hVM1.
- 2010
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 223, s. 653-656
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Tidskriftsartikel (refereegranskat)abstract
- The human fetal ventral mesencephalon-derived stem cell line, hVM1, yields high number of tyrosine hydroxylase-expressing presumed dopaminergic neurons upon in vitro differentiation. Here we report that cells generated from this line differentiate into a neuronal phenotype, express electrophysiological properties of functional neurons and respond to neurotransmitters in vitro. However, the electrophysiological properties are immature and the cells require longer maturation time than possible under in vitro conditions.
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| 8. |
- Tönnesen, Jan
(författare)
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Gene Therapy for Neurological Disorders
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gene therapy is an attractive strategy for neurological disorders, such as Parkinson’s disease and epilepsy, for several reasons. Introduction of genes with a therapeutic potential can be achieved locally, by accurate injections in the compromised tissue, and release of a transgene therapeutic substance can be regulated by the surrounding host neural circuitry. The gene therapy approach circumvents any issues pertaining to drug transport across the blood-brain barrier, or biometabolism of drugs before reaching their target, as can happen with conventional chemical drugs when administered orally or systemically. Two strategies are available for providing gene therapy. One is direct injection of the gene vector into the targeted tissue, referred to as in vivo gene therapy; the other is introduction of cells that are previously transduced to express the gene of interest, referred to as ex vivo gene therapy. A prerequisite for successfully applying neural ex vivo gene therapy is stem cell sources of neurons, which can be transfected with the therapeutic gene, and upon injection, integrate functionally in a diseased tissue and express the gene. This thesis explores and develops experimental gene therapeutic approaches to enhance therapies in neurological disorders. Through the first three papers the focus is on stem cell therapy for Parkinson’s disease. Progressively more advanced genetic tools are applied to develop and describe stem cell-derived dopaminergic neurons for use in experimental Parkinson’s disease. In Paper I, human neural stem cells are genetically immortalized, to enable unlimited expansion of the cells. However, these cells fail to reach maturity under the presented circumstances. Paper II and III introduces a protocol for successfully generating mature dopaminergic neurons from mouse neural stem cells, by genetically introducing the dopaminergic factor Wnt5a in the cells. The resulting dopaminergic neurons are characterized with electrophysiological tools, to gain information on their functional properties. Genetically introduced, optically controlled membrane proteins are used to investigate the integration of the dopaminergic neurons in a host tissue after transplantation. Such optogenetic probes can independently target host or transplanted cells, and with millisecond resolution activate or inhibit these, in response to optical activation with defined light-sources. Through this novel optogenetic approach, it is demonstrated that the host tissue neurons and the transplanted dopaminergic neurons can communicate, and influence the activity of each other. Paper IV applies optogenetic cell control, but utilizes it as an in vivo gene therapeutic tool, instead of as an investigative tool as above. We establish an experimental epilepsy model based on electrical stimulations, which elicit excessive, synchronized neural activity in an experimental tissue preparation. An optogenetic probe is genetically introduced to the neurons of the tissue preparation, and through optical activation of the probe, the neurons can be instantly inhibited. When optically inhibiting neurons at the onset of epileptiform activity, the duration of this activity was reduced to 20-50 % of the duration in control neurons. Considering that more than 30 % of epilepsy patients do not respond well to available anti-epileptic drugs, and that these drugs commonly has adverse cognitive side effects, the suggested role of optogenetic cell control in epilepsy holds great promises, though this research is still at an early stage. This thesis provides new knowledge on experimental research and therapy approaches, which will contribute to understand and develop stem cell and gene therapies for neurological disorders.
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| 9. |
- Tönnesen, Jan
(författare)
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Optogenetic cell control in experimental models of neurological disorders
- 2013
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 255, s. 35-43
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Forskningsöversikt (refereegranskat)abstract
- The complexity of the brain, in which different neuronal cell types are interspersed and complexly interconnected, has posed a major obstacle in identifying pathophysiological mechanisms underlying prevalent neurological disorders. This is largely based in the inability of classical experimental approaches to target defined neural populations at sufficient temporal and spatial resolution. As a consequence, effective clinical therapies for prevalent neurological disorders are largely lacking. Recently developed optogenetic probes are genetically expressed photosensitive ion channels and pumps that in principal overcome these limitations. Optogenetic probes allow millisecond resolution functional control over selected optogenetically transduced neuronal populations targeted based on promoter activity. This optical cell control scheme has already been applied to answer fundamental questions pertaining to neurological disorders by allowing researchers to experimentally intercept, or induce, pathophysiological neuronal signaling activity in a highly controlled manner. Offering high temporal resolution control over neural activity at high cellular specificity, optogenetic tools constitute a game changer in research aiming at understanding pathophysiological signaling mechanisms in neurological disorders and in developing therapeutic strategies to correct these. In this regard, recent experimental work has provided new insights in underlying mechanisms, as well as preliminary proof-of-principle for optogenetic therapies, of several neurological disorders, including Parkinson's disease, epilepsy and progressive blindness. This review synthesizes experimental work where optogenetic tools have been applied to explore pathologic neural network activity in models of neurological disorders. (C) 2013 Elsevier B.V. All rights reserved.
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| 10. |
- Tønnesen, Jan, et al.
(författare)
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Optogenetic control of epileptiform activity.
- 2009
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:29, s. 12162-12167
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Tidskriftsartikel (refereegranskat)abstract
- The optogenetic approach to gain control over neuronal excitability both in vitro and in vivo has emerged as a fascinating scientific tool to explore neuronal networks, but it also opens possibilities for developing novel treatment strategies for neurologic conditions. We have explored whether such an optogenetic approach using the light-driven halorhodopsin chloride pump from Natronomonas pharaonis (NpHR), modified for mammalian CNS expression to hyperpolarize central neurons, may inhibit excessive hyperexcitability and epileptiform activity. We show that a lentiviral vector containing the NpHR gene under the calcium/calmodulin-dependent protein kinase IIalpha promoter transduces principal cells of the hippocampus and cortex and hyperpolarizes these cells, preventing generation of action potentials and epileptiform activity during optical stimulation. This study proves a principle, that selective hyperpolarization of principal cortical neurons by NpHR is sufficient to curtail paroxysmal activity in transduced neurons and can inhibit stimulation train-induced bursting in hippocampal organotypic slice cultures, which represents a model tissue of pharmacoresistant epilepsy. This study demonstrates that the optogenetic approach may prove useful for controlling epileptiform activity and opens a future perspective to develop it into a strategy to treat epilepsy.
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| 11. |
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| 12. |
- Tönnesen, Jan, et al.
(författare)
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Toward an Optogenetic Therapy for Epilepsy
- 2017
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Ingår i: Optogenetics : From Neuronal Function to Mapping and Disease Biology - From Neuronal Function to Mapping and Disease Biology. - 9781107053014 ; , s. 292-307
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Bokkapitel (refereegranskat)
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| 13. |
- Tønnesen, Siren, et al.
(författare)
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Brain Age Prediction Reveals Aberrant Brain White Matter in Schizophrenia and Bipolar Disorder : A Multisample Diffusion Tensor Imaging Study
- 2020
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 2451-9022 .- 2451-9030. ; 5:12, s. 1095-1103
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts.METHODS: We trained 6 cross-validated models using different combinations of DTI data from 927 HC subjects (18-94 years of age) and applied the models to the test sets including 648 patients with SZ (18-66 years of age), 185 patients with BD (18-64 years of age), and 990 HC subjects (17-68 years of age), estimating the brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.RESULTS: Tenfold cross-validation revealed high accuracy for all models. Compared with HC subjects, the model including all feature sets significantly overestimated the age of patients with SZ (Cohen's d = -0.29) and patients with BD (Cohen's d = 0.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy-based models showed larger group differences than the models based on other DTI-derived metrics.CONCLUSIONS: Brain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.
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