Doctoral Theses / Doktorsavhandlingar Institutionen för neurovetenskap och fysiologi

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Fluid biomarkers for frontotemporal lobar degeneration and related diseases — discovery and clinical validation
(2025-09-26) Joel, Simrén
Frontotemporal dementia (FTD) spectrum disease encompasses a wide range of progressive clinical syndromes, including behavioral changes, progressive language deterioration, sometimes in combination with motor neuron disease or parkinsonian syndromes. These syndromes are often associated with frontotemporal lobar degeneration (FTLD), a neurodegenerative condition defined by the loss of neurons in the frontal and temporal lobes of the brain and the presence of insoluble protein deposits. Although less common than Alzheimer’s disease (AD), it is a leading cause of early onset dementia. A significant proportion of individuals affected by FTD have a history of dementia among relatives, and up to a third have mutations in genes that are determinately causing the disease. There are currently no effective treatments for the disease, which may in part be due to large clinical and pathophysiological heterogeneity, which hampers development of effective drugs that target the underlying biology of the disease. Biomarkers – quantifiable measures reflecting biological processes – are likely to be important for clinical management, understanding disease evolution, and therapeutic development. The work in this thesis sought to expand the understanding of biomarkers for the FTD disease spectrum and move the field one step closer to biomarker-based management of these conditions. In paper I, we sought to develop reference limits for a blood-based biomarker of neuronal damage, neurofilament light (NfL), which has been shown to be of use in differential diagnostics where FTLD is suspected, in disease monitoring, and therapeutic trials. We developed age-stratified reference limits across the lifespan for plasma NfL based on its concentration in healthy individuals, facilitating its interpretation in clinical settings. In paper II, we sought to explore novel preanalytical techniques to simplify the handling of blood samples in remote settings. We found that delayed processing of blood samples, in which NfL was then measured, did not meaningfully change its stability. Further, “filter papers” (so called dried blood or plasma spots) were shown to be a complementary option. Both simplifications suggest the feasibility of remote testing in epidemiological studies and possibly to remotely monitor disease or treatments in the future. To expand the armamentarium of biomarkers reflecting FTLD pathophysiology, papers III and IV utilized untargeted mass spectrometry to explore all quantifiable proteins (“the proteome”) in the cerebrospinal fluid (CSF). In paper III, we found a range of proteins quantifiable in CSF discriminating different causes of genetic FTLD from non-mutation carriers, as well as distinct proteomic signatures in each genetic form. Some markers were also changed already in presymptomatic mutation carriers. In paper IV, we observed that many proteins previously identified in paper III – linked to synaptic dysfunction, neuronal loss, immune responses, and metabolic processes – were also altered in individuals with different FTLD subtypes. In paper IV, we additionally found that there were both overlapping, and distinct changes when comparing FTLD with other causes of progressive cognitive impairment, such as AD and Lewy body disease. Notably, FTLD subtypes were surprisingly similar in paper IV. In paper V, we investigated a novel method to measure ~120 proteins of potential relevance to neurodegenerative disease in plasma of individuals with genetic FTD. We found clear changes in established biomarkers, such as NfL, but also in less explored candidates, that should be subject to follow-up studies. Altogether, the work in this thesis expanded the utility of NfL in the context of FTLD and provided novel candidates for further research in biomarkers of FTLD pathophysiology, which may ultimately lead to a panel of clinically useful biomarkers able distinguish between FTLD forms and enable their treatment.
Cerebrospinal Fluid - Composition and Dynamics Across Contexts
(2025-09-18) Lyckenvik, Tim
Cerebrospinal fluid (CSF) offers a rare vantage point into the hidden chemistry of the brain. Its composition arises from a finely tuned balance of production, circulation, and interstitial exchange, regulated by ion homeostasis, transporter activity, and physiological states such as sleep. This thesis explores CSF not only as a source of biomarkers but as a dynamic reporter of brain physiology. Paper I establishes reference values for CSF ion concentrations in healthy adults and shows that they differ markedly from serum, reflecting a CNS-specific ionic environment that stabilises neuronal excitability. These levels appear tightly regulated, largely unaffected by age, sex, or blood–brain barrier integrity, but modestly influenced by hydration. Paper II tests how deviations from this physiological profile affect human neuronal networks in vitro. BrainPhys™, despite its intent to mimic CSF, induces epileptiform activity likely due to elevated K+; raising K+ alone reproduces much of this effect, suggesting that serum-like media may drive hyperexcitation. Paper III examines sleep-dependent changes in CSF composition. Molecules associated with synaptic activity decline after sleep, whereas structural cell components remain unchanged. This pattern supports the idea of selective rather than bulk clearance during sleep and adds nuance to the glymphatic hypothesis. Paper IV investigates CSF in patients with opioid use disorder, showing elevated inflammatory markers and signs of ion dilution. By normalising to Aβ40 as a reference for dilution, group differences became clearer, highlighting the importance of accounting for fluid dynamics in CSF studies. Together, these studies illustrate how CSF composition varies across physiological and pathological contexts. Rather than providing definitive answers, these findings open new perspectives on how ion homeostasis, excitability, sleep, and inflammation intersect, and highlight the need for careful interpretation when linking CSF chemistry to brain function.
White adipose tissue functionality - Biological sex- and PCOS-related differences
(2025-09-16) Perian, Charlène
Adipose tissue is a dynamic energy storage and endocrine organ that plays a central role in metabolic regulation. Its function and distribution differ between the sexes, influencing the susceptibility to metabolic and endocrine disorders. One example is polycystic ovary syndrome (PCOS), a common endocrine disorder affecting women. This thesis explores how sex differences and androgen excess in PCOS shape the structure and function of adipose tissue and how these differences contribute to metabolic and hormonal imbalances. In Paper I, we demonstrated that macrophage-mediated intracellular collagen degradation is a critical process in healthy adipose tissue expansion. Our findings highlight that this process is disrupted in obese insulin resistant mice, associated with accumulation of collagen fragments within the tissue. These fragments may contribute to fibroinflammatory processes in obesity. In Paper II, we explored sex differences in adipose tissue extracellular matrix. Females showed a more adaptive subcutaneous adipose tissue remodelling, with lower tissue stiffness and higher adipocyte precursor cell proliferation than males. These findings were supported by human data, suggesting that sex-specific differences in collagen composition influence adipose tissue function and metabolic health. In Paper III, proteomic and phosphoproteomic analyses revealed that women with PCOS have altered muscle and adipose tissue protein expression, including changes in lipid metabolism, muscle fibre composition, and possibly mitochondrial functions. Electrical stimulation significantly impacted protein and phosphorylation profiles related to tissue remodelling. In Paper IV, we investigated adipose tissue dysfunction in two mouse models of PCOS. Chronic androgen exposure led to weight gain, adipocyte hypertrophy, reduced adipocyte precursor cells proliferation, and altered immune cell profiles, particularly in visceral adipose tissue. In contrast, prenatal androgen exposure led to a slightly increased fat mass without weight gain, enhanced adipocyte precursor cell proliferation and reduced adipogenesis. In vitro findings suggest that insulin resistance and macrophage-produced factors influence the functionality of adipocyte precursor cells in PCOS. In conclusion, differences in collagen remodelling, adipocyte precursor cell activity, and insulin signalling contribute to sex- and PCOS-related differences in adipose tissue functionality.
The framing of Swedish forensic mental health services - Practical implications of ethical valuation, legally defined goals, and patients' needs
(2025-09-10) Pedersen, Sven Henrik
Forensic mental health services (FMHS) face challenges due to a limited evidence base for common interventions and an unclear framing of their fundamental task in relation to the patients they serve. This creates difficulties for organizing care and developing services in a consistent and meaningful way. The overarching aim of this thesis is to contribute to a clearer framing of FMHS by examining how ethically relevant values are enacted and experienced in practice (studies I and II), by operationalizing the goals established in forensic mental health law (study III), and by exploring how patient needs relate to service organization (study IV). Study I is based on interviews with thirteen individuals under FMHS care. It shows that experiences of distress and disempowerment can be consistent with what is understood as beneficent professional conduct. This suggests that outcomes of professional actions depend not only on intent but arguably also on context. Study II explores value practices as described in interviews with patients and professionals participating in administrative court hearings. The study shows that abstract values may offer insufficient guidance in practice and that values beyond risk reduction and mental health are prioritized. Study III uses qualitative comparative analysis of Camberwell Assessment of Need – Forensic version assessments to identify rehabilitative need profiles associated with outpatient status. The analysis indicates that no single need domain is decisive; rather, satisfied and unsatisfied needs combine in diverse ways, pointing to a flexible operationalization of legal goals and an expanded view of relevant needs. Study IV uses latent class analysis to identify subgroups within the FMHS patient population based on rehabilitation needs. The analysis supports the identification of three meaningful subtypes of patients, each implying different tasks for FMHS and different possible endpoints for care. Taken together, the findings suggest that the task of FMHS involves a broader and more complex set of objectives than is commonly assumed. Some of these may extend beyond what FMHS can provide alone, and the goals of care may vary between different groups of patients. FMHS must therefore accommodate complexity without becoming arbitrary and delineate its responsibilities in relation to adjacent services.
Taking older persons seriously: Exploring personcentred and participatory approaches for fair responsibility in health and social care
(2025-09-04) Hermansen Østby, Roar
Introduction and aim: As the older population grows, the need for care that respects their preferences becomes increasingly important. Frail and pre-frail persons, especially those in or approaching residential aged care facilities, often face barriers to participation and influence. The aim was to explore person-centred and participatory approaches to healthcare and social services with and for frail and pre-frail older persons, while ensuring opportunities for fair responsibility in knowledge creation. Methods: Study I examined the applicability of photo-elicitation interviews as a method for engaging older persons residing in residential aged care facilities in conversations about everyday life. Building on study I, study II identified key concerns raised by residents themselves. Study III explored organisational capability for person-centred care through focus groups with residential aged care staff and managers. Study IV evaluated two health promotion interventions in a randomised controlled trial with prefrail older persons living in ordinary housing. Results: Photo-elicitation interviews enabled frail older persons to participate meaningfully in research. Institutional and organisational barriers limit older persons’ influence in residential aged care, but person-centred approaches, supported by committed staff and inclusive communication may foster capability and participation. Health promotion interventions showed that tailored support can sustain participation in leisure activities among pre-frail older persons. Conclusion: To ensure credible person-centred care, older persons need to be actively involved in research, not only as care recipients but as co-creators of knowledge. A person-centred research approach is essential for both research and practice to align care with lived experiences and promoting meaningful participation and occupational justice. Without it, care risks becoming standardised and disconnected from those it aims to serve.
Pathophysiological mechanisms and clinical value of novel blood-based tau biomarkers
(2025-08-27) Gonzalez Ortiz, Fernando
The use of fluid biomarkers, which serve as biological signatures of physiological processes or disease states, has a great impact on the field of neurology when it comes to providing tools to better understand, diagnose, and monitor various neurological disorders. Blood-based biomarkers are particularly valuable in conditions where clinical symptoms overlap or when diagnosis relies on invasive procedures such as cerebrospinal fluid analysis or neuroimaging. In Alzheimer’s disease (AD), blood-based tau biomarkers enable the early detection of pathology, even before significant clinical symptoms arise, potentially facilitating timely interventions. Moreover, tau biomarkers have demonstrated utility in acute neurological conditions such as traumatic brain injury and acute ischemic stroke, where blood levels of different tau variants are associated with the severity of central nervous system injury and clinical outcomes. This thesis focuses on two newly developed immunoassays, Brain-derived tau (BD-tau) and the University of Gothenburg p-tau217, explores their clinical utility across a spectrum of neuro-logical disorders, with particular emphasis on AD. We present plasma BD-tau as a biomarker for AD-type neurodegeneration showing strong associations with amyloid pathology and neuro-degenerative changes across the AD continuum. In acute ischemic stroke, plasma BD-tau levels strongly correlate with cerebral infarct volume and clinical outcomes, supporting its use as a marker to monitor brain injury following stroke. Plasma p-tau217, on the other hand, demonstrates excellent performance in identifying individuals at the earliest stages of AD, namely, preclinical and prodromal AD. It performs on par with commercially available p-tau217 assays and outperforms markers such as plasma p-tau181 and p-tau231 in the early diagnosis and prognosis of future cognitive decline, further establishing it as a robust diagnostic and prognostic tool in AD. Finally, we evaluated the versatility of BD-tau and p-tau217 in other neurological conditions. Plasma p-tau217 was found to be elevated in Niemann-Pick disease type C (NPC), pointing to shared mechanisms of tau pathology and tangle formation between AD and NPC. Similarly, plasma BD-tau and p-tau217 show both diagnostic and prognostic value in Creutzfeldt–Jakob disease (CJD), distinguishing it from other rapidly progressive dementias. Altogether, the findings presented in this thesis underscore the clinical value and versatility of blood-based tau biomarkers, while also offering insights into the mechanisms underlying tau pathology in various conditions. In AD, they can complement clinical evaluation and serve as accessible tools for early diagnosis and monitoring. In other neurological conditions, they provide important mechanistic insights and show potential for assessing disease severity, particularly in acute conditions, and as prognostic and progression biomarkers in disorders such as NPC and CJD.
Female Offenders of Lethal and Severe Violence - Mental Health, Risk Factors for Criminality and Offence Behaviour
(2025-08-20) Trägårdh, Karin
In about 10 % of homicides, offenders are females, forming an understudied group. The main aim of this thesis is to identify the qualities that distinguish female offenders of lethal and severe violence in terms of mental health, risk factors for violent criminality, and offence behaviour. Paper I examines incidence rates of female- and male-perpetrated homicide from 1990-2010 and explores similarities and differences between female and male homicide offenders for both those with child versus adult victims. The results indicate that homicide rates by both female and male offenders declined, with gender differences more prominent among offenders with adult victims. Paper II characterises female offenders of lethal and severe violence, with versus without a severe mental disorder (SMD), regarding demographics, mental health, substance use, and crime characteristics. Findings reveal that most female offenders faced challenges such as unemployment, adverse experiences, and mental health issues, and committed their crime within close relations. However, those with an SMD more often exhibited psychotic disorders and a more diverse range of victim-offender relationships, while they less often had substance use issues and prior criminality. Paper III investigates female offenders of lethal and severe violence, with versus without an SMD, assessing levels of psychopathy and type of violence. The females displayed relatively low levels of psychopathy (PCL-R) and primarily reactive rather than instrumental motives (Violent Incident Coding Sheet). The SMD group showed lower levels of psychopathy, and provocation, and higher levels of arousal and short-term planning. Paper IV examines, using established instruments, the relation between measures of risk for violence and of aggression in a life history perspective among female offenders of lethal and severe violence, identifying the strongest factors associated with lethal violence. The findings suggest that individuals charged with lethal offences exhibited fewer risk and aggression factors than those involved in non-lethal violence. In conclusion, female offenders of lethal and severe violence are characterised by adverse experiences and complex features, highlighting the need for targeted interventions across health care, social services, and law enforcement.
Addressing knowledge gaps in the brain ghrelin signalling system - its neural circuitry and role in foodlinked behaviours
(2025-08-18) Poelman, Renée
The drive to seek out and consume food is a fundamental survival mechanism, orchestrated by the brain through a range of behaviours in response to both intrinsic signals of energy status and external food-related cues. Disruption or faulty processing of these signals can lead to disordered eating behaviour across the body weight spectrum. For example, the availability of high-calorie, palatable foods and abundance of environmental cues are thought to stimulate overconsumption and contribute to the global obesity epidemic or, in contrast to this, loss of appetite in conditions such as anorexia nervosa, cancer cachexia or frailty can be detrimental. A better understanding of the brain mechanisms controlling food-linked behaviours is essential for developing effective, non-invasive therapies. Among the many signalling molecules that modulate networks controlling feeding behaviour, the hormone ghrelin stands alone as the only orexigenic (pro-feeding) hormone and represents a powerful tool to access and modulate brain networks involved in feeding control. This thesis addresses important gaps in our understanding of the brain ghrelin signalling system, focussing on its neural circuitry and its role in food-linked behaviours, using advanced neural circuit mapping techniques to explore both mechanistic and translational aspects. First, we demonstrate that the ghrelin mimetic GHRP-6 can stimulate the brain ghrelin signalling system through non-invasive intranasal application, reproducing many of the known effects of peripheral ghrelin administration in mice, including increased food intake, growth hormone release and activation of cells in the arcuate nucleus (Arc) including AgRP and GHRH neurones. In the second and third studies of this thesis, we used chemogenetic re-activation to functionally characterize hunger-responsive neuronal ensembles in the dor-somedial hypothalamus and Arc, demonstrating that re-activation of these ensembles stimulated food intake, and was able to drive food motivated behaviour. In the fourth and final study, we show that ghrelin’s role in hunger extends to increase attention-linked behaviours and food intake in the presence of a food cue in a novel behavioural task adapted for mice. Together, the studies in this thesis expand our understanding of the brain ghrelin signalling system. They identify novel functional circuits involved in hunger and food-motivated behaviour and obtained new insights into how ghrelin modulates behaviour towards environmental cues. Finally, a new, non-invasive strategy to stimulate the brain ghrelin signalling system has been proposed, which holds translational value
The Neurobiological Pathway Towards Suicidal Ideation - Cerebrospinal Fluid Markers, Cognitive Impairment and Brain Imaging
(2025-07-03) Rymo, Irma
In recent years, there has been increasing recognition of neurobiological factors as critical contributors to the vulnerability underlying suicidal behavior. This thesis examines the associations between synaptic dysfunction, mild cognitive impairment, structural brain changes, and suicidal ideation within population-based samples of older adults. Paper I included 86 women from the year 1992 cohort of the Prospective Population Study of Women (PPSW), all of whom participated in psychiatric assessments and underwent lumbar puncture (LP). Paper II involved 916 participants drawn from both the PPSW and the year 2000 cohort of the Gothenburg H70 Birth cohort study. Cognitive status was evaluated using the Winblad et al. criteria. Paper III investigated 322 participants from the 2014 cohort of the Gothenburg H70 Birth Cohort Study who also underwent LP. Paper IV included 774 individuals from the same cohort who underwent brain magnetic resonance imaging (MRI). Paper I identified elevated cerebrospinal fluid (CSF) levels of YKL-40 and GAP-43 in women reporting past month suicidal ideation. Higher CSF GAP- 43 levels were also related to feelings of worthlessness. Paper II found that mild cognitive impairment (MCI) was associated with life-weariness and death wishes reported within the past year, as demonstrated in adjusted regression models. MCI was also related to lifetime experiences of life-weariness. Paper III identified a connection between high CSF Ng level and lifetime reports of life-weariness, death wishes, and thoughts of taking one’s own life, that remained after taking CSF levels of Aβ42, T-Tau, and P-Tau into account. Paper IV found that individuals with a lifetime history of serious suicidal ideation exhibited larger white matter lesions (WML) volumes compared to those without such ideation. However, this association did not persist after adjusting for relevant covariates in the logistic regression model. To conclude, these findings suggest that neurobiological factors—including synaptic dysfunction, cognitive impairment, and distinct structural brain changes—may contribute to suicidal ideation among older adults.
Blood-based biomarkers in epilepsy
(2025-05-20) Akel, Sarah
Blood-based biomarkers hold promise as minimally invasive and scalable tools to complement current diagnostic methods and potentially support clinical decision-making in epilepsy. This thesis explores blood biomarkers in four original research papers to identify candidate markers through proteomics and to further characterize existing markers of brain injury and neurodegeneration in epilepsy. In Paper I, levels of neurofilament-light (NfL), glial fibrillary acidic protein (GFAP), and total-tau were analyzed in plasma. The findings revealed elevated NfL and GFAP in individuals with recent seizures compared to those with seizure freedom. Paper III expands on this by comparing the same markers, along with serum S100 calcium-binding protein B and neuron-specific enolase, between drug-resistant epilepsy (DRE) and monotherapy-controlled epilepsy. As in the previous study, higher levels of NfL and GFAP were observed in the DRE group. NfL levels remained elevated even after excluding participants with prior strokes or brain lesions. Papers II and IV investigated seizure-related changes of proteins using plasma proteomics. Paper II identified four differentially expressed proteins (CDH15, PHOSPHO1, LTBP3, and PAEP) in individuals with recent seizures. Paper IV applied a machine-learning (ML) approach to analyze four larger protein panels, revealing 51 consensus proteins between the two ML models, of which 23 were considered top differentially expressed. Enrichment analysis highlighted several inflammatory and immune processes and pathways. This research further emphasizes the potential of integrating blood biomarkers into epilepsy care and research. Longitudinal studies are necessary to track biomarker fluctuations over time in relation to seizures and treatment responses. Such studies will also help to identify optimal time frames for sampling.
Surface electromyography for improving upper limb function after stroke - Development of new rehabilitation tools
(2025-05-15) Muñoz Novoa, María José
Background: Upper limb impairment is a major consequence after stroke, significantly affecting independence and quality of life. Various rehabilitation technologies have been developed to improve upper limb function, including surface electromyography (sEMG). Aim: This thesis explores the potential of sEMG-driven interventions to enhance upper limb function after stroke, employing qualitative and quantitative approaches. Methods: Study I summarized the current evidence on sEMG-driven interventions for upper limb rehabilitation after stroke through a systematic review and meta-analysis, investigating the effects of different types of sEMG-based therapies. Study II introduced a novel intervention that combined myoelectric pattern recognition (MPR) , virtual reality (VR), and serious gaming. This intervention was evaluated using a single-case experimental design to assess its feasibility and preliminary effectiveness in improving upper limb function in individuals with chronic stroke. Study III employed a qualitative approach to explore the experiences and perceptions of participants involved in Study II. Lastly, Study IV used a co-design approach involving individuals with stroke, clinicians and rehabilitation experts to refine and assess the usability of a training tool that uses a smart textile sleeve sEMG biofeedback system designed for self-administered upper limb rehabilitation. Results: In Study I, 24 studies (n = 808) were included. Twenty of these studies reported significant improvements in upper limb function following sEMG interventions; however, the meta-analysis revealed no significant differences in overall effect between sEMG and non-sEMG interventions (14 studies), nor among different types of sEMG interventions (7 studies). In Study II (n = 6), all participants showed improvement on motor function, with five exceeding the minimal clinically important difference. Additionally, four participants demonstrated improvements in activity capacity and grip strength, with three out of four kinematic assessments conducted showing clinically meaningful results. Study III revealed that participants valued the intervention, found it unique and meaningful, and reported increased awareness and use of their paretic arm in daily life activities. They noted that “many factors come into play to make it work,” including their own role, the training system, and support from therapists. Study IV (n = 19) found that individuals with stroke and clinicians considered the smart textile sEMG biofeedback tool easy to use and a promising solution for self-administered upper limb rehabilitation at home, while also providing valuable feedback for future improvements. Conclusion: sEMG-driven interventions show promising results as complementary tools for improving upper limb function after stroke. While the overall effect compared to conventional therapies remains inconclusive, significant improvements were observed, particularly among individuals with severe impairments in the chronic phase. Participants across studies reported positive experiences with novel sEMG technologies that offer real-time visual feedback and recognized the potential of these tools to support focused arm training and self-administered rehabilitation at home. Furthermore, user-centered design and interdisciplinary collaboration added value to the development of these technologies and strengthened the findings. Further research is needed to assess the efficacy of sEMG-driven interventions in improving upper limb function after stroke and to explore their long-term outcomes. Efforts should focus on enhancing usability for home-based applications to support broader access to evidence-based rehabilitation for individuals living with the long-term consequences after stroke.
Adolescent-onset anorexia nervosa in the acute stage and after 30 years
(2025-04-29) Rydberg Dobrescu, Sandra
Anorexia nervosa (AN) is a severe eating disorder (ED) that predominantly affects females in early adolescence. The overarching aim of this thesis has been to examine individuals with adolescent-onset AN in the acute stage, with regard to the neuropsychological profile, and 30 years after the onset of AN regarding overall outcome. Study I-III were based on a group of 51 individuals with adolescent-onset AN recruited by community screening and followed prospectively since the mid 1980’s (AN group) together with a healthy age-, gender-, and school-matched comparison group (COMP group). In Study I, 30-years after the onset of AN, at mean age 44, ED symptoms, psychiatric morbidity, global functioning and quality of life were examined. In Study II, the perinatal status, mental and physical health of the offspring born to the females in the AN group were explored and compared with health outcomes of the children in the COMP group. In Study III, health care utilisation, social assistance, sick leave and disability pension were examined. Data were collected from Swedish national registers. Study IV was based on 20 adolescent females with acute AN, their parents and 28 healthy comparison cases. The cognitive profile was explored, using neuropsychological tests, and its associations with autism spectrum disorder (ASD) and ADHD were investigated. Results showed that at 30-year follow-up no individuals were deceased, 64% showed full ED symptom recovery, 19% had an ED and 38% had other psychiatric disorders in the AN group. Later age at onset of AN and premorbid perfectionism predicted a good outcome. Birth weight, length, head circumference and ponderal index were significantly reduced in the children of mothers in the AN group. Few differences in childhood psychiatric health were found across the two groups of offspring. However, parental interviews showed an overrepresentation of current psychiatric diagnoses in the children of mothers in the AN group. Endocrinological, immune and metabolic disorders were more common in the offspring in the AN group. The healthcare utilisation was increased in the AN group and 22% had received disability pension. In Study IV, neuropsychological tasks revealed a more detail-oriented processing style in weight-restored adolescents with AN. A possible link between neuropsychological deficits and traits of ASD and ADHD could not be confirmed. In summary, three decades after adolescent-onset AN, the outcome was favorable for the majority of the AN cases. However, one in five had an ED, a minority depended on society for their income and the offspring exhibited some unfavorable health outcomes. More efforts need to be directed towards preventing AN from developing into a protracted course with consequences on both an individual and health economic level. With the goal of potentially reducing negative perinatal outcomes in the offspring of women with current or previous EDs, we suggest that screening procedures for EDs are implemented in maternal care. Previous theories of an endophenotype in AN, characterized by a tendency to focus on details rather than perceiving the whole, were supported in this thesis and have implications for treatment strategies that address this cognitive style.
P-tau212: a novel biomarker for tau pathology in specific neurodegenerative diseases
(2025-04-25) Kac, Przemyslaw
Tau protein is involved in multiple physiological processes in the central nervous system, one of which is microtubule stabilization. Post-translational modifications of tau, such as phosphorylation strictly regulate this process. Dysregulation leads to pathological tau lesions, including mislocalization, propagation, and aggregation. In consequence, tau aggregation is a hallmark of the neurodegenerative diseases group called tauopathies. The most prevalent tauopathy is Alzheimer’s Disease (AD) – a leading cause of dementia. AD develops much earlier in people with Down Syndrome (DS), reaching a lifetime risk of over 90% in the seventh decade of life. Other pathologically and clinically defined tauopathies belong to the frontotemporal lobar degeneration (FTLD) tau type. Definitive diagnosis of tauopathies can be achieved only post-mortem, and commonly, there is an overlap between clinical manifestations. Therefore, reliable, robust, and accessible ante-mortem biomarkers to differentiate tauopathies are urgently needed. Currently, nothing like that exists for FTLD, however, we experience rapid development of blood-based biomarkers for AD, i.e. phosphorylated tau (p-tau) species. Yet, they differ in their diagnostic performance, which may be linked to various biological mechanisms underlying their formation. The principal objective of this thesis was to assess the utility of some understudied p-tau epitopes as biomarkers for neurodegenerative diseases, one such example being p-tau212, which is located in the rich region of tau that makes it susceptible to multiple kinases. One of those is dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). The gene for this kinase is located at chromosome 21 in the DS critical region. Additionally, p-tau212 was linked to neurodegeneration, aggregation, and microtubule assembly impairment. Following the optimization and validation of plasma and CSF p-tau212 immunoassays, their diagnostic performance was evaluated in AD biomarker-positive and negative cohorts, sporadic AD cohorts, AD Down Syndrome cohorts, post-mortem AD cohorts, and preclinical AD cohorts. Additionally, the utility of CSF p-tau212 was assessed in the post-mortem validated FTLD cohort. Results were compared with other existing biomarkers. We show that plasma p-tau212 has high diagnostic accuracy to differentiate AD from control groups, and in few cases, the performance is significantly better than currently existing biomarkers. Plasma p-tau212 is increased in preclinical, sporadic, prodromal, and DSAD. Plasma p-tau212 increased approximately 15 years before the onset of AD in DS and before established positron emission tomography cutoff points. In addition, we have found elevated levels and high diagnostic accuracy of CSF p-tau212 to differentiate clinical FTLD cases with different proteinopathies underlying the manifestations. In conclusion, the result of this thesis is developed and validated a new fluid biomarker for AD and FTLD. Its diagnostic performance challenges currently available methods, and the robustness of the assays makes it cost-effective and easy to implement biomarkers for diagnosis of ongoing AD and FTLD-tau pathophysiological processes, clinical trial recruitment purposes, therapy monitoring, target engagement for anti-amyloid drugs and DYRK1A modulators, and theragnostic.
Guillian-Barré syndrome: Epidemiology and biomarkers in blood and cerebrospinal fluid
(2025-04-15) Hafsteinsdóttir, Brynhildur
Guillain-Barré syndrome (GBS) is a rare, potentially life-threatening disease. The incidence of GBS varies, and clusters can occur related to the increased prevalence of triggering events. Most patients recover well, but some are left with permanent disability or die. This thesis aimed to investigate the epidemiological aspects of Guillain-Barré syndrome in Iceland and the Västra Götaland region (VGR) and explore potential fluid biomarkers for diagnosis and outcome. Papers I and II are retrospective population-based epidemiological studies. Paper I studies the incidence and long-term outcomes of GBS in Iceland from 1995 to 2014. The average annual incidence was 1.1 per 100.000 person-years. At the last follow-up, an average of 6.5 years, 14% had severe disability. Mortality was increased up to three years after diagnosis. Paper II investigated the impact of the COVID-19 pandemic on the incidence of GBS in the VGR. The incidence significantly decreased during the pandemic compared to the years immediately prior. Papers III and IV are retrospective cohort studies on fluid biomarkers in GBS. In paper III, neurofilament light chain (NfL) parameters were explored as diagnostic and prognostic markers in GBS. The results show that serum NfL Z-score at diagnosis predicts short- and long-term outcomes. Patients with GBS had lower NfL CSF/serum ratio and NfL index (NfL ratio/albumin quotient) than healthy controls, patients with multiple sclerosis and amyotrophic lateral sclerosis. In paper IV, brain-derived tau (BD tau) was investigated as a prognostic biomarker in GBS, and high levels at diagnosis were associated with poor outcomes after one year. The incidence of GBS varies over time but is, on average, similar in similar demographics. The decreased prevalence of triggering infections due to social restrictions led to a decrease in the incidence of GBS during the COVID-19 pandemic. The serum NfL Z-score is a promising biomarker for prognosis, while the NfL ratio and the NfL index have potential as diagnostic biomarkers. BD-tau is a potential biomarker for long-term outcomes, which indicates that the degree of CNS involvement is crucial for long-term recovery.
Functioning after COVID-19 – A long term follow-up of hospitalized patients using qualitative and quantitave methods
(2025-04-09) Larsson, Alexandra C
ABSTRACT Background: In 2020, the novel SARS-CoV-2 virus triggered the COVID-19 pandemic, overwhelming healthcare systems worldwide and causing significant suffering. At the time, the long-term consequences of COVID-19 on affected individuals were unknown. Aim: This thesis aims to describe functioning during the first year after hospitalization for COVID-19 from a biopsychosocial perspective, using both qualitative and quantitative methods. Methods: Three quantitative studies and one qualitative study were conducted with a cohort of 211 participants who were assessed at hospital discharge, three months, and one-year after hospitalization using patient-reported outcome measures and clinical assessments. Additionally, 11 out of the 211 participants were interviewed, and their experiences were analyzed using thematic analysis. Results: In Study I, participants exhibited impairments in body functions and limitations in daily activities at hospital discharge, with older individuals and those who had received intensive care treatment being more affected. In Study II, three months after discharge, participants reported persistent challenges in body functions, activities, and participation. However, no major differences in functioning were observed based on age, sex, or prior hospital care level. One year after discharge, Study IV found that participants continued to experience functional impairments due to COVID-19, although some assessments, such as muscle strength, showed improvement. Older age, female sex, and early fatigue at three months were associated with lower functioning at one year. In Study III, four themes were developed from interviews describing daily life experiences in the year following hospitalization. Patients described using familiar strategies but in new ways when managing COVID-19, as well as highlighting the support from employers and colleagues in the return-to-work process. Participants struggled with lacking energy and persistent fatigue, which impacted various aspects of life, and encountered difficulties accessing healthcare and rehabilitation. Conclusion: After hospitalization for COVID-19, many individuals were discharged with impairments requiring rehabilitation and follow-up care, particularly older adults and those individuals who had been treated in intensive care. Recovery was complex and varied, with the heterogeneous findings of Study II suggesting that rehabilitation should be individualized. Study IV highlights the need for in-depth assessments to identify functional impairments and rehabilitation needs. Considering factors such as age, sex, and fatigue may facilitate long-term rehabilitation planning. Study III revealed that some support could be found from colleagues and employers when returning to work along with one’s own strategies for managing COVID-19 symptoms. Still persistent fatigue and challenges in accessing healthcare and rehabilitation shaped life after COVID-19. This emphasizes the need for ongoing healthcare and rehabilitation support throughout the first year of recovery after hospitalization due to COVID-19.
Sex-specific modulation of neurobehavioral outcomes - The intersection of sex steroids, gut peptides, and behavior
(2025-04-09) Börchers, Stina
Despite ample evidence indicating that psychiatric disorders and their symptoms exhibit significant differences based on sex, research on their underlying mechanisms in females has historically been limited. This thesis examines how sex steroids and gut peptides like ghrelin regulate anxiety and aggression, with an emphasis on sex-specific mechanisms. In Paper I, we found that standard tests of anxiety-like behavior lack predictive validity for human sex differences. While female rats appeared less anxious in standard tests of anxiety-like behavior, they exhibited heightened startle responses, better aligning with human data and suggesting limitations in existing models. In Paper II, we found that the ghrelin system is sexually dimorphic. Female rats had higher circulating ghrelin levels, lower Leap-2 expression, and increased ghrelin receptor expression in key brain regions involved in anxiety and feeding. Increased ghrelin signaling via fasting and exogenous application also reduced anxiety more effectively in females. In Paper III we demonstrated that both male and female rats developed conditioned place preference for winning aggressive encounters, with aggression-induced dopamine release in the nucleus accumbens more pronounced in females. Blocking dopamine D1 receptors abolished this effect in both sexes, overall suggesting that male and female rats experience winning aggressive interactions as rewarding. Finally, we explored the role of central estrogen synthesis in aggression in Paper IV. Aromatase knockdown in the central amygdala increased aggression in females but not males, specifically after loss of circulating ovarian hormones via gonadectomy. It also increased anxiety-like behavior, suggesting a dampening effect of estrogen on both behaviors. Overall, the findings of this thesis highlight critical sex differences in neurobehavioral regulation and underscore the need for sex-specific considerations in preclinical research and therapeutic development.
Post-traumatic epilepsy: Risk factors, Clinical insights, Socioecinomic aspects and prognosis
(2025-04-03) Karlander, Markus
Traumatic brain injury (TBI) is a common cause of acquired epilepsy, and the risk of post-traumatic epilepsy (PTE) increases with the severity of the TBI. The risk of PTE varies in the literature, and following a post-traumatic seizure (PTS), it is uncertain when an individual fulfills the diagnostic criteria for PTE, as the risk of seizure recurrence varies, and most studies are based on smaller cohorts. Additionally, drug resistant epilepsy, medical retirement and unemployment seem to be more common among war-veterans with PTE, compared to other types of epilepsy. In general, individuals with PTE do also have an increased risk of death compared to individuals with a TBI without subsequent epilepsy. However, it remains unclear if this is due to the epilepsy itself or related to other factors. The results from this thesis, including nation-wide data, showed that individuals with a TBI in Sweden had a risk of 4.0% for epilepsy within ten years. The risk increased to 12.9% after the most severe TBI. Acute symptomatic seizures were a strong risk factor. The risk of seizure recurrence after a first post-traumatic seizure increased with the severity of the TBI and was additionally increased if the first seizure occurred <2 years after the TBI. However, the risk of seizure recurrence after milder TBI was comparable to that in individuals without prior TBI. Individuals with PTE were more frequently unemployed than those with epilepsy of unknown etiology. They were also less likely to hold a university degree, but did not seem to have a more severe epilepsy. They also had an increased risk of death, with an unadjusted hazard ratio of 2.3, compared to individuals with a TBI without later epilepsy. Epilepsy was a contributing factor in 18.4% of deaths. The thesis highlights a considerable risk of epilepsy among individuals following a more severe TBI, particularly when acute symptomatic seizures occur after the trauma. In most cases, PTE should be diagnosed after two unprovoked epileptic seizures, similar to epilepsy without a prior brain injury. The results also emphasize the need for proper epilepsy care and rehabilitation following the trauma.
Epidemiology of Humanpapilloma Virus in East Africa
(2025-03-28) Uwamungu, Schifra; Uwamungu, Schifra
ABSTRACT Background: Human papillomavirus (HPV) infection is a well-known etiological factor in cervical, anogenital, and head and neck malignancies. East Africa has the highest global prevalence of HPV infections and the highest cervical cancer mortality rate. However, the prevalence of HPV infections in mucous membranes other than the uterine cervix in this region remains limited. Additionally, the prevalence of co-infections across different mucosal sites is unknown. It is also unclear whether vaginal HPV screening could use be to identify women at risk of developing cervical cancer in East Africa. Furthermore, potential genetic variants associated with the susceptibility to HPV infection and the progression to cervical cancer in this population have yet to be identified. Aims: 1. To assess the prevalence and co-infection patterns of HPV in different mucous membranes among HIV-concordant couples living in Rwanda (Cohort B; Paper I). 2. To evaluate the prevalence of oral HPV infections in Zambia's general urban and rural populations (Paper II). 3. To determine the prevalence of HPV infections in the vaginal and cervical mucosa of women living with HIV (WLWH; Cohort A) in Rwanda (Paper III). 4. To investigate the prevalence of chronic HPV infections among women from Cohorts A and B and to examine whether single nucleotide polymorphisms (SNPs) are associated with the risk of HPV acquisition and the development of chronic HPV infections (Paper IV). Methods: Swab samples were collected from the oral cavity, oropharynx, vagina (both self-collected and physician-collected), uterine cervix, penis, and anus, along with Pap smears from the uterine cervix, from 50 HIV-positive concordant couples (cohort B) in Rwanda (Paper I). Vaginal and cervical swabs for HPV detection were collected from WLWH in cohort A (Paper III). WLWH from cohorts A and B were reassessed two years later (Paper IV), with follow-up swab samples for HPV and biomarker analysis, alongside blood tests. Male and female participants residing in Ndola (urban area) and Mansa (rural area) underwent oral swabs and oral clinical examinations (Paper II). Real-time polymerase chain reaction (RT-PCR) was conducted to detect 12 high-risk HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) and two low-risk types (HPV6 and 11) across all studies (Papers I–IV). Pap smears were cytologically examined in Papers I and III. Single nucleotide polymorphisms (SNPs) were also analyzed in baseline blood samples using the Illumina Global Screening Array–Multi Disease version 3 (Paper IV). Participants were also interviewed regarding demographics and risk factors associated with HPV acquisition (Papers I–IV). Results: In Rwandan men and women living with HIV, high-risk HPV (HR-HPV) was detected in the oral cavity in 10% and 12% of cases, respectively, and in the oropharynx in 10% of men but not in women (Paper I). In contrast, HPV prevalence in Zambia’s urban and rural populations was low (<1%; Paper II). Among Rwandan women, HPV58, HPV52, HPV51, and HPV16 were the most common vaginal and cervical types, with one-third of WLWH co-infected with multiple types (Paper III). HR-HPVs were found in the cervix of 24% (Cohort B) and 38% (Cohort A) of women and vaginal samples collected by physicians in 30% and 39% of women, respectively. HR-HPV status showed high concordance between self-collected and physician-collected vaginal samples (κ = 0.70) and between vaginal and cervical samples (κ = 0.54–0.83). Anal HR-HPV infections were higher in women than men (24% vs. 2%, p = 0.002), while only 22% of HR-HPV infections were shared between partners (Paper I). Lastly, rs13158830 in PPARGC1B was the most significant SNP linked to chronic HR-HPV infection (Paper IV). Conclusions: HPV infections are prevalent among women and men living with HIV in Rwanda. Self-collected HPV screening has proven to be both feasible and representative of cervical HPV status, offering a promising approach to increasing cervical cancer screening rates among women in Rwanda. Additionally, we have identified unique SNPs associated with an elevated risk of developing chronic HPV infections. These genetic markers may potentially be used in the future to identify individuals at higher risk of cervical cancer, enabling more targeted prevention strategies. Keywords: HPV, screening, biomarker, single nucleotide polymorphism, Rwanda, Zambia
Long-term Mental Health and Multimorbidity Outcomes in 22q11.2 deletion syndrome - A Comprehensive Study from Childhood to Adulthood
(2025-03-17) Wallin, Lena
22q11.2 deletion syndrome (22q11.2DS) is a genetic disorder with a markedly diverse phenotype. Aims: Examine mental health and multimorbidity in adults with 22q11.2DS followed prospectively from childhood/young adult age focusing on i) neurodevelopmental disorder (NDD) and other psychiatric conditions in adulthood; ii) associations between self-reported eye-contact sensitivity and face processing; iii) stability in cognitive functioning and link to psychosis in adulthood, and iv) long-term physical health outcomes. Methods: The study involved 79 individuals with 22q11.2DS from an original cohort of 100, first examined at ages 1-35 years and followed up after 12-23 years at ages 18-50 years, with psychiatric and neuropsychological assessments, eye-tracking examinations, and blood sampling for amino acid analysis. Results: High rates of NDDs, psychiatric and physical disorders were found, and multimorbidity was very common. Even though rates of psychotic disorders were high, prevalence was lower than in other studies. Individual intellectual decline was observed in some cases despite stable group performance. Regarding psychosis, a possible link to declines in full-scale intelligence quotient (IQ), particularly verbal IQ, was found. Adult functioning correlated positively with baseline IQ but negatively with psychosis. Hyperprolinemia was not associated with any NDD, or psychiatric disorder. Self-reported discomfort with eye contact may indicate social challenges.. Conclusions: Findings underscore the complexity of 22q11.2DS and the necessity for long-term clinical follow-up to prevent severe psychiatric morbidity, including psychosis. Coordinated multidisciplinary care is essential for providing tailored interventions to promote health and development in this population.
Health improvement in chronic widespread pain. Outcomes and experiences
(2025-03-04) Sofia, Juhlin
Aim: The purpose of this thesis was to investigate changes in health outcomes and experiences of improvement over time and the effect of person-centred physical activity delivered with digital e-health support on health outcomes in participants with chronic widespread pain (CWP), as well as predictors of improvements. Methods: The thesis includes four studies. Study I is a long-term follow-up study investigating health changes in women with CWP (n=126) after ten to twelve years. Study II is an interview study exploring experiences of improvement among women with CWP (n=17) that had improved over time. Study III is a randomised controlled trial investigating the health effects of a person-centred health plan co-created with a physiotherapist and supported by a digital e-health platform compared to support by one telephone call in participants with CWP (n=139). Study IV investigates the effect of person-centred health plans, including physical activity, after twelve months in participants with CWP (n=102). Results: The results showed significant improvements in pain, fatigue, depression, overall health, health-related quality of life and stress after ten to twelve years among the participants in Study I. Also, participants who reported less stress symptoms ten to twelve years earlier had a higher chance of substantial improvement in pain intensity at follow-up. The analysis in Study II yielded three categories describing participants’ thoughts of their improvement: experiences of improvement, developed strategies for better health and the meaning of contextual factors for improvement. Study III found no significant benefits when the person-centred health plan was supported with the digital e-health platform compared to support by the telephone call. There was a significant difference in global fatigue in favour of the group receiving support by telephone. The results in Study IV showed no significant change in level of physical activity twelve months after the participants had co-created the health plan. A positive experience of physical activity at baseline was associated with a higher likelihood of reaching a level of physical activity sufficient to receive health-enhancing effects. Conclusion: Many people with CWP seem to experience a reduction in several symptoms over time. Experienced life stressors and clinical manifestations of stress impact the potential for improvement over time. The results of this thesis also support multifactorial reasons for improvement, highlighting the importance of individual factors. This underscores the value of stress-reducing interventions and rehabilitation based on a person-centred approach. Additionally, the results emphasise the importance of considering patients' own experiences and perceptions of physical activity before planning rehabilitation to enhance their level of physical activity.

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