Imaging of cognitive outcomes in patients with autoimmune encephalitis

Die Autoimmunenzephalitis ist eine kürzlich beschriebene entzündliche Erkrankung des zentralen Nervensystems, die Gedächtnisdefizite, Psychosen, oder epileptische Anfälle hervorrufen kann. Derzeit ist hingegen noch nicht ausreichend verstanden, welche pathologischen Veränderungen zu den kognitiven Defiziten führen und welche neuropsychologischen und bildgebenden Langzeitoutcomes zu erwarten sind. Anhand von strukturellen und funktionellen Bildgebungsanalysen zeigt diese Dissertation, dass kognitive Defizite auch nach der akuten Phase der Autoimmunenzephalitis fortbestehen können. Bei der LGI1-Enzephalitis gehen Gedächtnisdefizite mit fokalen strukturellen Läsionen im Hippocampus einher. Durch eine funktionelle Störung der Resting-State-Konnektivität des Default-Mode- und Salienznetzwerkes beeinträchtigen diese Hippocampusläsionen auch Hirnregionen außerhalb des limbischen Systems. Bei Patient:innen mit NMDA-Rezeptor-Enzephalitis finden sich in der longitudinalen neuropsychologischen Untersuchung trotz guter allgemeiner Genesung auch noch mehrere Jahre nach der Akutphase persistierende Defizite des Gedächtnisses und exekutiver Funktionen. Zuletzt zeigt eine transdiagnostische Analyse, dass der anteriore Hippocampus eine erhöhte Vulnerabilität gegenüber immunvermittelten pathologischen Prozessen aufweist. Diese Ergebnisse legen nahe, dass kognitive Symptome auch noch nach der Entlassung aus der stationären Behandlung fortbestehen können. Sowohl umschriebene strukturelle Hippocampusläsionen als auch Veränderungen in makroskopischen funktionellen Hirnnetzwerken tragen zur pathophysiologischen Erklärung dieser Symptome bei. Zudem erlauben diese Ergebnisse einen Einblick in neuroplastische Veränderungen des Gehirns und haben weitreichende Implikationen für die Langzeitversorgung und das Design zukünftiger klinischer Studien.Autoimmune encephalitis is a recently described inflammatory disease of the central nervous system that can cause memory deficits, psychosis, or seizures. The trajectory of cognitive dysfunction and the underlying long-term imaging correlates are, however, not yet fully understood. By using advanced structural and functional neuroimaging, this thesis shows that cognitive deficits persist beyond the acute phase. In LGI1 encephalitis, MRI postprocessing revealed that memory deficits are related to focal structural hippocampal lesions. These hippocampal lesions propagate to brain areas outside the limbic system through aberrant resting-state connectivity of the default mode network (DMN) and the salience network. In NMDA receptor encephalitis, a longitudinal analysis of neuropsychological data describes persistent cognitive deficits, especially in the memory and executive domains, despite good physical recovery several years after the acute disease. Lastly, a transdiagnostic analysis reveals that the anterior hippocampus is particularly vulnerable to immune-mediated damage. In conclusion, these results demonstrate that cognitive symptoms in autoimmune encephalitis can persist beyond discharge from neurological care. Both discrete structural hippocampal damage and changes in macroscopic functional networks shed light on the pathophysiological basis of these symptoms. These findings help to explain how the brain responds to pathological damage and have substantial implications for long-term patient care and the design of future clinical studies

9‐cis Retinoic acid and 1.25‐dihydroxyvitamin D 3 drive differentiation into IgA + secreting plasmablasts in human naïve B cells

Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells, controlled by their corresponding nuclear receptors, VDR and RAR. Herein, after the establishment of a plasmablast differentiation culture, we investigated how both ligands modulate human naïve B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified naïve B cells resulted in a strong differentiation of CD27+ CD38+ plasmablasts and antibody secretion. The significant IgA response was preceded by a strong induction of α-germline transcription (GLT). Induction of αGLT and consecutively IgA secretion driven by calcitriol is a novel observation and we show by magnetic chromatin IP that this was mediated by recruitment of the VDR to the TGF-β promoter thus inducing TGF-β expression. Finally, as revealed by transcriptomic profiling calcitriol and 9cRA modulate several signals required for differentiation and isotype switching in a noncompeting but rather additive manner. Calcitriol and 9cRA participate in the control of the IgA response in human activated naïve B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction

Long‐Term Cognitive Outcome in Anti–N‐Methyl‐D‐Aspartate Receptor Encephalitis

Objective: Cognitive dysfunction is a core symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but detailed studies on prevalence, characteristics of cognitive deficits, and the potential for recovery are missing. Here, we performed a prospective longitudinal study to assess cognitive long-term outcome and identify clinical predictors. Methods: Standardized comprehensive neuropsychological assessments were performed in 43 patients with NMDAR encephalitis 2.3 years and 4.9 years (median) after disease onset. Cognitive assessments covered executive function, working memory, verbal/visual episodic memory, attention, subjective complaints, and depression and anxiety levels. Cognitive performance of patients was compared to that of 30 healthy participants matched for age, sex, and education. Results: All patients had persistent cognitive deficits 2.3 years after onset, with moderate or severe impairment in >80% of patients. Core deficits included memory and executive function. After 4.9 years, significant improvement of cognitive function was observed, but moderate to severe deficits persisted in two thirds of patients, despite favorable functional neurological outcomes (median modified Rankin Scale = 1). Delayed treatment, higher disease severity, and longer duration of the acute phase were predictors for impaired cognitive outcome. The recovery process was time dependent, with greater gains earlier after the acute phase, although improvements were possible for several years after disease onset. Interpretation: Cognitive deficits are the main contributor to long-term morbidity in NMDAR encephalitis and persist beyond functional neurological recovery. Nonetheless, cognitive improvement is possible for several years after the acute phase and should be supported by continued cognitive rehabilitation. Cognition should be included as an outcome measure in future clinical studies

Long‐Term Cognitive Outcome in Anti–N‐Methyl‐D‐Aspartate Receptor Encephalitis

Objective Cognitive dysfunction is a core symptom of anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis, but detailed studies on prevalence, characteristics of cognitive deficits, and the potential for recovery are missing. Here, we performed a prospective longitudinal study to assess cognitive long‐term outcome and identify clinical predictors. Methods Standardized comprehensive neuropsychological assessments were performed in 43 patients with NMDAR encephalitis 2.3 years and 4.9 years (median) after disease onset. Cognitive assessments covered executive function, working memory, verbal/visual episodic memory, attention, subjective complaints, and depression and anxiety levels. Cognitive performance of patients was compared to that of 30 healthy participants matched for age, sex, and education. Results All patients had persistent cognitive deficits 2.3 years after onset, with moderate or severe impairment in >80% of patients. Core deficits included memory and executive function. After 4.9 years, significant improvement of cognitive function was observed, but moderate to severe deficits persisted in two thirds of patients, despite favorable functional neurological outcomes (median modified Rankin Scale = 1). Delayed treatment, higher disease severity, and longer duration of the acute phase were predictors for impaired cognitive outcome. The recovery process was time dependent, with greater gains earlier after the acute phase, although improvements were possible for several years after disease onset. Interpretation Cognitive deficits are the main contributor to long‐term morbidity in NMDAR encephalitis and persist beyond functional neurological recovery. Nonetheless, cognitive improvement is possible for several years after the acute phase and should be supported by continued cognitive rehabilitation. Cognition should be included as an outcome measure in future clinical studies. ANN NEUROL 2021;90:949–961Bundesministerium für Bildung und Forschung http://dx.doi.org/10.13039/501100002347Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Peer Reviewe

Vitamin A controls the allergic response through T follicular helper cell as well as plasmablast differentiation

Background Vitamin A regulates the adaptive immune response and a modulatory impact on type I allergy is discussed. The cellular mechanisms are largely unknown. Objective To determine the vitamin A-responding specific lymphocyte reaction in vivo. Methods Antigen-specific B and T lymphocytes were analyzed in an adoptive transfer airway inflammation mouse model in response to 9-cis retinoic acid (9cRA) and after lymphocyte-specific genetic targeting of the receptor RAR alpha. Flow cytometry, quantitative PCR, next-generation sequencing, and specific Ig-ELISA were used to characterize the cells functionally. Results Systemic 9cRA profoundly enhanced the specific IgA-secreting B-cell frequencies in the lung tissue and serum IgA while reducing serum IgE concentrations. RAR alpha overexpression in antigen-specific B cells promoted differentiation into plasmablasts at the expense of germinal center B cells. In antigen-specific T cells, RAR alpha strongly promoted the differentiation of T follicular helper cells followed by an enhanced germinal center response. Conclusions 9cRA signaling via RAR alpha impacts the allergen-specific immunoglobulin response directly by the differentiation of B cells and indirectly by promoting T follicular helper cells

Blood pressure trajectories over 35 years and dementia risk: A retrospective study: The HUNT study

High blood pressure is a well-established risk factor of dementia. However, the timing of the risk remains controversial. The aim of the present study was to compare trajectories of systolic blood pressure (SBP) over a 35-year follow-up period in the Health Survey in Trøndelag (HUNT) from study wave 1 to 4 in people with and without a dementia diagnosis at wave 4 (HUNT4). This is a retrospective cohort study of participants aged ≥ 70 years in HUNT4, where 9,720 participants were assessed for dementia. In the HUNT study all residents aged ≥ 20 years have been invited to four surveys: HUNT1 1984–86, HUNT2 1995–97, HUNT3 2006–08 and HUNT4 2017–19. The study sample was aged 70–102 years (mean 77.6, SD 6.0) at HUNT4, 54% were women and 15.5% had dementia, 8.8% had Alzheimer’s disease (AD), 1.6% had vascular dementia (VaD) and 5.1% had other types of dementia. Compared to those without dementia at HUNT4, those with dementia at HUNT4 had higher SBP at HUNT1 and HUNT2, but lower SBP at HUNT4. These differences at HUNT1 and 2 were especially pronounced among women. Results did not differ across birth cohorts. For dementia subtypes at HUNT4, the VaD group had a higher SBP than the AD group at HUNT2 and 3. Age trajectories in SBP showed that the dementia group experienced a steady increase in SBP until 65 years of age and a decrease from 70 to 90 years. SBP in the no- dementia group increased until 80 years before it leveled off from 80 to 90 years. Frontiers in Aging Neuroscience. The present study confirms findings of higher midlife SBP and lower late-life SBP in people with dementia. This pattern may have several explanations and it highlights the need for close monitoring of BP treatment in older adults, with frequent reappraisal of treatment needs.publishedVersio

Blood pressure trajectories over 35 years and dementia risk: A retrospective study: The HUNT study

High blood pressure is a well-established risk factor of dementia. However, the timing of the risk remains controversial. The aim of the present study was to compare trajectories of systolic blood pressure (SBP) over a 35-year follow-up period in the Health Survey in Trøndelag (HUNT) from study wave 1 to 4 in people with and without a dementia diagnosis at wave 4 (HUNT4). This is a retrospective cohort study of participants aged ≥ 70 years in HUNT4, where 9,720 participants were assessed for dementia. In the HUNT study all residents aged ≥ 20 years have been invited to four surveys: HUNT1 1984–86, HUNT2 1995–97, HUNT3 2006–08 and HUNT4 2017–19. The study sample was aged 70–102 years (mean 77.6, SD 6.0) at HUNT4, 54% were women and 15.5% had dementia, 8.8% had Alzheimer’s disease (AD), 1.6% had vascular dementia (VaD) and 5.1% had other types of dementia. Compared to those without dementia at HUNT4, those with dementia at HUNT4 had higher SBP at HUNT1 and HUNT2, but lower SBP at HUNT4. These differences at HUNT1 and 2 were especially pronounced among women. Results did not differ across birth cohorts. For dementia subtypes at HUNT4, the VaD group had a higher SBP than the AD group at HUNT2 and 3. Age trajectories in SBP showed that the dementia group experienced a steady increase in SBP until 65 years of age and a decrease from 70 to 90 years. SBP in the no- dementia group increased until 80 years before it leveled off from 80 to 90 years. The present study confirms findings of higher midlife SBP and lower late-life SBP in people with dementia. This pattern may have several explanations and it highlights the need for close monitoring of BP treatment in older adults, with frequent reappraisal of treatment needs

Distinct Functional Connectivity Signatures of Impaired Social Cognition in Multiple Sclerosis

Objective: Multiple sclerosis (MS) is characterized by impairments in basic cognitive functions such as information processing speed as well as in more complex, higher-order domains such as social cognition. However, as these deficits often co-occur, it has remained challenging to determine whether they have a specific pathological basis or are driven by shared biology. Methods: To identify neural signatures of social cognition deficits in MS, data were analyzed from n = 29 patients with relapsing-remitting MS and n = 29 healthy controls matched for age, sex, and education. We used neuropsychological assessments of information processing speed, attention, learning, working memory, and relevant aspects of social cognition (theory of mind, emotion recognition (ER), empathy) and employed neuroimaging of CNS networks using resting-state functional connectivity. Results: MS patients showed significant deficits in verbal learning and memory, as well as implicit ER. Performance in these domains was uncorrelated. Functional connectivity analysis identified a distinct network characterized by significant associations between poorer ER and lower connectivity of the fusiform gyrus (FFG) with the right lateral occipital cortex, which also showed lower connectivity in patients compared to controls. Moreover, while ER was correlated with MS symptoms such as fatigue and motor/sensory functioning on a behavioral level, FFG connectivity signatures of social cognition deficits showed no overlap with these symptoms. Conclusions: Our analyses identify distinct functional connectivity signatures of social cognition deficits in MS, indicating that these alterations may occur independently from those in other neuropsychological functions

Multiple sclerosis-related fatigue: Altered resting-state functional connectivity of the ventral striatum and dorsolateral prefrontal cortex

OBJECTIVE Since recent studies suggested a role of the striatum and prefrontal cortex for multiple sclerosis (MS)-related fatigue, we investigated resting-state functional connectivity alterations of striatal subdivisions and the dorsolateral prefrontal cortex (dlPFC). METHODS Resting-state functional magnetic resonance imaging was acquired in 77 relapsing-remitting MS patients (38 fatigued (F-MS), 39 non-fatigued (NF-MS)) and 41 matched healthy controls (HC). Fatigue severity was assessed using the fatigue severity scale. Seed-based connectivity analyses were performed using subregions of the striatum and the dlPFC as regions of interest applying non-parametric permutation testing. RESULTS Compared to HC and NF-MS patients, F-MS patients showed reduced caudate nucleus and ventral striatum functional connectivity with the sensorimotor cortex (SMC) and frontal, parietal, and temporal cortex regions. Fatigue severity correlated negatively with functional connectivity of the caudate nucleus and ventral striatum with the SMC and positively with functional connectivity of the dlPFC with the rostral inferior parietal gyrus and SMC. CONCLUSION MS-related fatigue is associated with reduced functional connectivity between the striatum and sensorimotor as well as attention and reward networks, in which the ventral striatum might be a key integration hub. Together with increased connectivity between the dlPFC and sensory cortical areas, these connectivity alterations shed light on the mechanisms of MS-related fatigue