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Abstract Background Neurogenic dysphagia is a frequent complication of stroke and is associated with aspiration pneumonia and poor outcomes. Although ischaemic lesion location and size are major determinants of the presence and severity of post‐stroke dysphagia, little is known about the contribution of other acute stroke‐unrelated factors. We aimed to analyse the impact of swallowing and non‐swallowing muscles measurements on swallowing function after large vessel occlusion stroke. Methods This retrospective study was based on a prospective registry of consecutive ischaemic stroke patients. Patients who underwent mechanical thrombectomy between July 2021 and June 2022 and received a flexible endoscopic evaluation of swallowing (FEES) within 5 days after admission were included. Demographic, anthropometric, clinical, and imaging data were collected from the registry. The cross‐sectional areas (CSA) of selected swallowing muscles (as a surrogate marker for swallowing muscle mass) and of cervical non‐swallowing muscles were measured in computed tomography. Skeletal muscle index (SMI) was calculated and used as a surrogate marker for whole body muscle mass. FEES parameters, namely, Functional Oral Intake Scale (FOIS, as a surrogate marker for dysphagia presence and severity), penetration aspiration scale, and the presence of moderate‐to‐severe pharyngeal residues were collected from the clinical records. Univariate and multivariate ordinal and logistic regression analyses were performed to analyse if total CSA of swallowing muscles and SMI were associated with FEES parameters. Results The final study population consisted of 137 patients, 59 were female (43.1%), median age was 74 years (interquartile range 62–83), median baseline National Institutes of Health Stroke Scale score was 12 (interquartile range 7–16), 16 patients had a vertebrobasilar occlusion (11.7%), and successful recanalization was achieved in 127 patients (92.7%). Both total CSA of swallowing muscles and SMI were significantly correlated with age (rho = −0.391, P

Abstract We developed a video-based tool to quantitatively assess the Glabellar Tap Reflex (GTR) in patients with idiopathic Parkinson’s disease (iPD) as well as healthy age-matched participants. We also video-graphically assessed the effect of dopaminergic medication on the GTR in iPD patients, as well as the frequency and blinking duration of reflex and non-reflex blinks. The Glabellar Tap Reflex is a clinical sign seen in patients e.g. suffering from iPD. Reliable tools to quantify this sign are lacking. Methods: We recorded the GTR in 11 iPD patients and 12 healthy controls (HC) with a consumer-grade camera at a framerate of at least 180 images/s. In these videos, reflex and non-reflex blinks were analyzed for blink count and blinking duration in an automated fashion. Results: With our setup, the GTR can be extracted from high-framerate cameras using landmarks of the MediaPipe face algorithm. iPD patients did not habituate to the GTR; dopaminergic medication did not alter that response. iPD patients’ non-reflex blinks were higher in frequency and higher in blinking duration (width at half prominence); dopaminergic medication decreased the median frequency (Before medication—HC: p

Abstract Post-COVID-19 syndrome is a serious complication following SARS-CoV-2 infection, characterized primarily by fatigue and cognitive complaints. Although first metabolic and structural imaging alterations in Post-COVID-19 syndrome have been identified, their functional consequences remain unknown. Thus, we explored the impact of Post-COVID-19 syndrome on the functional connectome of the brain providing a deeper understanding of pathophysiological mechanisms. In a cross-sectional observational study, resting-state functional magnetic resonance imaging data of 66 patients with Post-COVID-19 syndrome after mild infection (mean age 42.3 years, 57 female) and 57 healthy controls (mean age 42.1 years, 38 female) with a mean time of seven months after acute COVID-19 were analysed using a graph theoretical approach. Network features were quantified using measures including mean distance, nodal degree, betweenness and Katz centrality, and compared between both groups. Graph measures were correlated with clinical measures quantifying fatigue, cognitive function, affective symptoms and sleep disturbances. Alterations were mainly found in the brainstem, olfactory cortex, cingulate cortex, thalamus and cerebellum on average seven months after SARS-CoV-2 infection. Additionally, strong correlations between fatigue severity, cognitive functioning and daytime sleepiness from clinical scales and graph measures were observed. Our study confirms functional relevance of brain imaging changes in Post-COVID-19 syndrome as mediating factors for persistent symptoms and improves our pathophysiological understanding.

Abstract Background In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts. Methods An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented. Results 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy. Conclusions This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

Abstract Objective Communication skills can deteriorate in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD); however, their clinical assessment and treatment in patient care can be challenging. In the present study, we aimed to quantify the distinctive communication resources and barriers reported by patients and their relatives in AD and FTD and associated these communicative characteristics with clinical parameters, such as the degree of cognitive impairment and atrophy in language‐associated brain areas. Methods We assessed self‐reported communication barriers and resources in 33 individuals with AD and FTD through an interview on daily‐life communication, using the Aachener KOMPASS questionnaire. We correlated reported communication barriers and resources with atrophy from high‐resolution 3T brain magnetic resonance imaging, neuropsychological assessment, and neurodegenerative markers from cerebrospinal fluid. Results Communicative impairment was higher in FTD compared to AD. Increased reported communication barriers in our whole sample were associated with the atrophy rate in the left middle temporal lobe, a critical site within the neuronal language network, and with depressive symptoms as well as the semantic word fluency from neuropsychological assessment. The best model for prediction of communicative impairment included the diagnosis (AD or FTD), semantic word fluency, and depressive symptoms. Conclusions Our study demonstrates that communication barriers and resources can be successfully assessed via a structured interview based on self‐report and report of patients’ relatives in practice and are reflected in neuroimaging specific for AD and FTD as well as in further clinical parameters specific for these neurodegenerative diseases. This can potentially open new treatment options for clinical practice and patient care.

Abstract Background The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). Methods To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical‐onset FA (

Abstract Background The AT(N) research framework for Alzheimer's disease (AD) remains unclear on how to best deal with borderline cases. Our aim was to characterise patients with suspected AD with a borderline Aß1-42/Aß1-40 ratio in cerebrospinal fluid. Methods We analysed retrospective data from two cohorts (memory clinic cohort and ADNI) of patients (n = 63) with an Aß1-42/Aß1-40 ratio within a predefined borderline area—Q1 above the validated cut-off value(grey zone). We compared demographic, clinical, neuropsychological and neuroimaging features between grey zone patients and patients with low Aß1-42 (normal Aß ratio but pathological Aß1-42, n = 42) and patients with AD (pathological Aß, P-Tau, und T-Tau, n = 80). Results Patients had mild cognitive impairment or mild dementia and a median age of 72 years. Demographic and general clinical characteristics did not differ between the groups. Patients in the grey zone group were the least impaired in cognition. However, they overlapped with the low Aß1-42 group in verbal episodic memory performance, especially in delayed recall and recognition. The grey zone group had less severe medial temporal atrophy, but mild posterior atrophy and mild white matter hyperintensities, similar to the low Aß1-42 group. Conclusions Patients in the Aß ratio grey zone were less impaired, but showed clinical overlap with patients on the AD continuum. These borderline patients may be at an earlier disease stage. Assuming an increased risk of AD and progressive cognitive decline, careful consideration of clinical follow-up is recommended when using dichotomous approaches to classify Aß status.

Introduction: The inclusion of non-haemorrhagic imaging markers, namely a severe burden of enlarged perivascular spaces (EPVS) in the centrum semiovale (CSO) and a multispot pattern of white matter hyperintensities, improved the diagnostic accuracy of the recently updated diagnostic criteria for cerebral amyloid angiopathy (CAA, Boston Criteria 2.0). However, the prevalence of non-haemorrhagic markers in patients presenting with cognitive impairment remains unclear. Our objective was to determine the prevalence of newly proposed non-haemorrhagic imaging markers for CAA in a memory clinic cohort and to investigate possible associations with other clinical features Methods: A total of 622 patients from a memory clinic cohort who had undergone MRI and had available cerebrospinal fluid (CSF) neurodegeneration biomarkers. Severe EPVS in CSO and the presence of a multispot pattern were determined visually by two independent raters, blinded to clinical information, using validated Methods: Through multivariate analyses, we investigated the correlation between non-haemorrhagic imaging markers and various demographic, clinical, and neurodegeneration biomarker features. Results: The average age at diagnosis was 71 years, and 50% of patients were female. Most patients had mild cognitive impairment (56%). By applying the updated Boston criteria 2.0, the number of patients with possible CAA increased from 51 to 306. Severe EPVS in CSO was found in 53% of the sample and a multispot pattern was found in 38%. Factors such as age (OR 1.04 95%CI 1.01-1.07), female sex (OR 1.68 95%CI 1.11-2.54), and CAA diagnosis (Boston criteria 1.5, OR 2.11 95%CI 1.02-4.35) were independently associated with an increased likelihood of non-haemorrhagic CAA markers. However, the ASCVD 10-year risk (OR 1.01 95%CI 0.99-1.03), CSF Aβ1-42 levels (OR 1.00 95%CI 0.99-1.00) and clinical severity (CDR OR 1.19 95%CI 0.76-1.85) did not have a significant impact (Fig. 1). Discussion: More than half of the patients in our memory clinic cohort exhibited non-haemorrhagic markers of CAA, resulting in a notable rise in the number of patients who met the updated criteria for possible CAA. In this cohort, non-haemorrhagic markers were not specific of CAA, but the association between non-haemorrhagic and haemorrhagic markers of CAA supports a link between non- haemorrhagic markers and Aβ vascular deposition.

Summary: Background: People with complex symptomatology but unclear diagnosis presenting to a centre for rare diseases (CRD) may present with mental (co-)morbidity. We hypothesised that combining an expert in somatic medicine with a mental health specialist working in tandem will improve the diagnostic outcome. Methods: Patients aged 12 years and older who presented to one of the 11 participating German CRDs with an unknown diagnosis were recruited into this prospective cohort trial with a two-phase cohort design. From October 1, 2018 to September 30, 2019, participants were allocated to standard care (SC, N = 684), and from October 1, 2019 to January 31, 2021 to innovative care (IC, N = 695). The cohorts consisted mainly of adult participants with only a minority of children included (N = 67). IC included the involvement of a mental health specialist in all aspects of care (e.g., assessing medical records, clinic visits, telehealth care, and case conferences). Clinicaltrials.gov identifier: NCT03563677. Findings: The proportion of patients with diagnoses established within 12 months after the first visit to the CRD explaining the entire symptomatology (primary outcome) was 19% (N = 131 of 672) in the SC and 42% (N = 286 of 686) in the IC cohort (OR adjusted for centre effects 3.45 [95% CrI: 1.99–5.65]). The difference was mainly due to a higher prevalence of mental disorders and non-rare somatic diseases in the IC cohort. The median time to explaining diagnoses was one month shorter with IC (95% CrI: 1–2), and significantly more patients could be referred to local regular care in the IC (27.5%; N = 181 of 659) compared to the SC (12.3%; N = 81 of 658) cohort (OR adjusted for centre effects 2.70 [95% CrI: 2.02–3.60]). At 12-month follow-up, patient satisfaction with care was significantly higher in the IC compared to the SC cohort, while quality of life was not different between cohorts. Interpretation: Our findings suggested that including a mental health specialist in the entire evaluation process of CRDs for undiagnosed adolescents and adults should become an integral part of the assessment of individuals with a suspected rare disease. Funding: The study was funded by the Global Innovation Fund from the Joint Federal Committee in Germany (Innovationsfonds des Gemeinsamen Bundesausschusses), grant number 01NVF17031.

IntroductionAssessment methods for physical activity and fitness are of upmost importance due to the possible beneficial effect of physical conditioning on neurodegenerative diseases. The implementation of these methods can be challenging when examining elderly or cognitively impaired participants. In the presented study, we compared three different assessment methods for physical activity from the Dementia-MOVE trial, a 6-months intervention study on physical activity in Alzheimer’s disease. The aim was to determine the comparability of physical activity assessments in elderly participants with cognitive impairment due to Alzheimer’s disease.Material or methods38 participants (mean age 70 ± 7 years) with early-stage Alzheimer’s disease (mean MoCA 18.84 ± 4.87) were assessed with (1) fitness trackers for an average of 12 (± 6) days, (2) a written diary on daily activities and (3) a questionnaire on physical activity at three intervention timepoints. For comparison purposes, we present a transformation and harmonization method of the physical assessment output parameters: Metabolic equivalent of task (MET) scores, activity intensity minutes, calorie expenditure and moderate-to-vigorous physical activity (MVPA) scores were derived from all three modalities. The resulting parameters were compared for absolute differences, correlation, and their influence by possible mediating factors such as cognitive state and markers from cerebrospinal fluid.ResultsParticipants showed high acceptance and compliance to all three assessment methods. MET scores and MVPA from fitness trackers and diaries showed high overlap, whilst results from the questionnaire suggest that participants tended to overestimate their physical activity in the long-term retrospective assessment. All activity parameters were independent of the tested Alzheimer’s disease parameters, showing that not only fitness trackers, but also diaries can be successfully applied for physical activity assessment in a sample affected by early-stage Alzheimer’s disease.DiscussionOur results show that fitness trackers and physical activity diaries have the highest robustness, leading to a highly comparable estimation of physical activity in people with Alzheimer’s disease. As assessed parameters, it is recommendable to focus on MET, MVPA and on accelerometric sensor data such as step count, and less on activity calories and different activity intensities which are dependent on different variables and point to a lower reliability.

Abstract We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA.

Abstract Background Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data. Methods A panel representing international clinical experts, stakeholders and consumer groups provided oversight to guideline development within the GRADE framework. Invited expert authors generated the Patient, Intervention, Comparison, Outcome (PICO) questions to guide the literature search (2014 to June 2020). Evidence profiles in tandem with feedback from individuals living with FRDA, natural history registry data and expert clinical observations contributed to the final recommendations. Authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process. Results Seventy clinical experts contributed to fifteen topic-specific chapters with clinical recommendations and/or best practice statements. New topics since 2014 include emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence was evaluated according to GRADE criteria and 130 new recommendations and 95 best practice statements were generated. Discussion and conclusion Evidence-based CMGs are required to ensure the best clinical care for people with FRDA. Adopting the GRADE rare-disease framework enabled the development of higher quality CMGs for FRDA and allows individual topics to be updated as new evidence emerges. While the primary goal of these guidelines is better outcomes for people living with FRDA, the process of developing the guidelines may also help inform the development of clinical guidelines in other rare diseases.

Abstract Epicardial adipose tissue is involved in the pathophysiology of atrial fibrillation (AF). This study aimed to analyze its relevance as a stroke etiology marker. A retrospective study of acute ischemic stroke patients with large vessel occlusion was conducted, periatrial epicardial adipose tissue thickness (pEATT) on admission computed tomography angiography was measured. One hundred and twenty‐one patients with AF‐related stroke and 94 patients with noncardioembolic stroke were included. Patients with AF‐related stroke had increased pEATT. CT‐measured left‐sided pEATT was an independent predictor of AF‐related stroke (adjusted odds ratio per 1 mm increase = 1.27, 95% CI = 1.05–1.53, p = 0.012). pEATT is an independent marker of AF‐related stroke.

Abstract Background Several non-motor symptoms are present in Parkinson's disease (PD), including increasing prevalence rates of cognitive impairment during disease progression. Due to its multifaceted nature, PD management involves pharmacotherapy and non-pharmacotherapies, ideally in a multidisciplinary manner. Evidence regarding the impact of multidisciplinary interventions on motor and non-motor symptoms, as well as its impact on quality of life and daily activities of living, is limited. Methods The aim of this real-life exploratory study was to investigate the effectiveness of a three-week clinical multidisciplinary Parkinson complex therapy (Parkinson-Komplexbehandlung, PKB), which is available as standard care for PD in the German health care system. Especially, the effect of neuropsychological attention training of 40 patients with PD was analyzed concerning their impact on motor abilities (UPDRS-III ON state), cognitive profiles and reported depressive symptoms and psychosocial function. Results Neuropsychological data showed an improvement in response inhibition after intervention (z = − 2.611, p = 0.009). Additionally, improvements in verbal memory (z = − 2.318, p = 0.020), motor functions (UPDRS-III-score; z = − 5.163, p

Abstract Seizure Related 6 Homolog Like 2 (SEZ6L2) protein has been shown to have implications in neuronal and especially motor function development. In oncology, overexpression of SEZ6L2 serves as a negative prognostic marker in several tumor entities. Recently, few cases of anti-SEZ6L2 antibody mediated cerebellar syndromes were reported. In this article, we present a case of a 70-year-old woman with subacute onset of gait disturbance, dysarthria and limb ataxia. Serum anti-SEZ6L2 antibodies were markedly increased, and further diagnostic workup revealed left sided breast cancer. Neurological symptoms and SEZ6L2 titer significantly improved after curative tumor therapy. This is a very rare and educationally important report of anti-SEZ6L2 autoimmune cerebellar syndrome with a paraneoplastic etiology. Additionally, we performed a review of the current literature for SEZ6L2, focusing on comparing the published cases on autoimmune cerebellar syndrome.

Abstract By whole-exome sequencing, we found the heterozygous POLG variant c.3542G>A; p.Ser1181Asn in a family of four affected individuals, presenting with a mixed neuro-myopathic phenotype. The variant is located within the active site of polymerase gamma, in a cluster region associated with an autosomal dominant inheritance. In adolescence, the index developed distal atrophies and weakness, sensory loss, afferent ataxia, double vision, and bilateral ptosis. One older sister presented with Charcot-Marie-Tooth-like symptoms, while the youngest sister and father reported exercise-induced muscle pain and proximal weakness. In none of the individuals, we observed any involvement of the central nervous system. Muscle biopsies obtained from the father and the older sister showed ragged-red fibers, and electron microscopy confirmed mitochondrial damage. We conclude that this novel POLG variant explains this family’s phenotype.

Abstract Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. Trial registration ClinicalTrials.gov; Identifier: NCT03563677; First posted: June 20, 2018, https://clinicaltrials.gov/ct2/show/NCT03563677 .

Abstract Objectives We aimed to objectify and compare persisting self‐reported symptoms in initially hospitalized and non‐hospitalized patients after infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by applying clinical standardized measures. Methods We conducted a cross‐sectional study of adult patients with confirmed SARS‐CoV‐2 infection including medical history, neurological examination, blood markers, neuropsychological testing, patient‐reported outcome measures (PROMs), and brain magnetic resonance imaging (MRI). Results Fifty patients with persisting symptoms for at least 4 weeks were included and classified by initial hospitalization status. Median time from SARS‐CoV‐2 detection to investigation was 29.3 weeks (range 3.3–57.9). Although individual cognitive performance was generally within the normative range in both groups, mostly mild deficits were found in attention, executive functions, and memory. Hospitalized patients performed worse in global cognition, logical reasoning, and processes of verbal memory. In both groups, fatigue severity was associated with reduced performance in attention and psychomotor speed tasks (rs = −0.40, p

Polyglutamine (polyQ) diseases are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in Drosophila melanogaster. This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases in humans. Computer-aided drug discovery was implemented to identify human TRMT2A inhibitors. Additionally, the crystal structure of one protein domain, the RNA recognition motif (RRM), was determined, and Biacore experiments with the RRM were performed. The identified molecules were validated for their potency to reduce polyQ aggregation and polyQ-induced cell death in human HEK293T cells and patient derived fibroblasts. Our work provides a first step towards pharmacological inhibition of this enzyme and indicates TRMT2A as a viable drug target for polyQ diseases.

Recombinant human erythropoietin (rhEPO) has been shown to exert anti-apoptotic and anti-inflammatory effects after cerebral ischemia. Inflammatory cytokines interleukin-1β and -18 (IL-1β and IL-18) are crucial mediators of apoptosis and are maturated by multiprotein complexes termed inflammasomes. Microglia are the first responders to post-ischemic brain damage and are a main source of inflammasomes. However, the impact of rhEPO on microglial activation and the subsequent induction of inflammasomes after ischemia remains elusive. To address this, we subjected human microglial clone 3 (HMC-3) cells to various durations of oxygen-glucose-deprivation/reperfusion (OGD/R) to assess the impact of rhEPO on cell viability, metabolic activity, oxidative stress, phagocytosis, migration, as well as on the regulation and activation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes. Administration of rhEPO mitigated OGD/R-induced oxidative stress and cell death. Additionally, it enhanced metabolic activity, migration and phagocytosis of HMC-3. Moreover, rhEPO attenuated post-ischemic activation and regulation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes as well as their downstream effectors CASPASE1 and IL-1β. Pharmacological inhibition of NLRP3 via MCC950 had no effect on the activation of CASPASE1 and maturation of IL-1β after OGD/R, but increased protein levels of NLRP1, NLRC4, and AIM2, suggesting compensatory activities among inflammasomes. We provide evidence that EPO-conveyed anti-inflammatory actions might be mediated via the regulation of the inflammasomes.

Abstract Background The SARS-Coronavirus-2 (SARS-CoV-2) invades the respiratory system, causing acute and sometimes severe pulmonary symptoms, but turned out to also act multisystematically with substantial impact on the brain. A growing number of studies suggests a diverse spectrum of neurological manifestations. To investigate the spectrum of symptoms, we here describe the neurological manifestations and complications of patients with proven SARS-CoV-2 infection who have been hospitalized at the RWTH University Hospital Aachen, Germany. Methods Between March and September 2020, we evaluated common symptoms, clinical characteristics, laboratory (including cerebrospinal fluid (CSF) analysis), radiological, and electroencephalography (EEG) data from 53 patients admitted with a positive SARS-CoV-2 polymerase chain reaction (PCR). We used the Montreal Cognitive Assessment Test (MoCA) to screen for cognitive impairment, when feasible. We compared critically ill and non-critically ill patients categorized according to the presence of Acute Respiratory Distress Syndrome (ARDS). Results Major clinical neurological features of hospitalized COVID-19 patients were coordination deficits (74%), cognitive impairment (61.5%), paresis (47%), abnormal reflex status (45%), sensory abnormalities (45%), general muscle weakness and pain (32%), hyposmia (26%), and headache (21%). Patients with ARDS were more severely affected than non-ADRS patients. 29.6% of patients with ARDS presented with subarachnoid bleedings, and 11.1% showed ischemic stroke associated with SARS-CoV-2 infection. Cognitive deficits mainly affected executive functions, attention, language, and delayed memory recall. We obtained cerebrospinal fluid (CSF) by lumbar puncture in nine of the 53 patients, none of which had a positive SARS-CoV-2 PCR. Conclusions In line with previous findings, our results provide evidence for a range of SARS-CoV-2-associated neurological manifestations. 26% of patients reported hyposmia, emphasizing the neuro-invasive potential of SARS-CoV-2, which can enter the olfactory bulb. It can therefore be speculated that neurological manifestations may be caused by direct invasion of the virus in the CNS; however, PCR did not reveal positive intrathecal SARS-CoV-2. Therefore, we hypothesize it is more likely that the para-infectious severe pro-inflammatory impact of COVID-19 is responsible for the neurological deficits including cognitive impairment. Future studies with comprehensive longitudinal assessment of neurological deficits are required to determine potential long-term complications of COVID-19.

Human NEET proteins, such as NAF-1 and mitoNEET, are homodimeric, redox iron-sulfur proteins characterized by triple cysteine and one histidine-coordinated [2Fe-2S] cluster. They exist in an oxidized and reduced state. Abnormal release of the cluster is implicated in a variety of diseases, including cancer and neurodegeneration. The computer-aided and structure-based design of ligands affecting cluster release is of paramount importance from a pharmaceutical perspective. Unfortunately, experimental structural information so far is limited to only one ligand/protein complex. This is the X-ray structure of furosemide bound to oxidized mitoNEET. Here we employ an enhanced sampling approach, Localized Volume-based Metadynamics, developed by some of us, to identify binding poses of furosemide to human mitoNEET protein in solution. The binding modes show a high variability within the same shallow binding pocket on the protein surface identified in the X-ray structure. Among the different binding conformations, one of them is in agreement with the crystal structure’s one. This conformation might have been overstabilized in the latter because of the presence of crystal packing interactions, absent in solution. The calculated binding affinity is compatible with experimental data. Our protocol can be used in a straightforward manner in drug design campaigns targeting this pharmaceutically important family of proteins.

Abstract Background In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich’s Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. Methods Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. Results In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n = 57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR = 2–9) years and it improved significantly after the introduction of genetic testing (2(IQR = 1–5) years, p

Introduction Drug development for neurodegenerative diseases such as Friedreich’s ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. Methods 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich’s Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. Discussion Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. Clinical trial registration ClinicalTrails.gov Identifier: NCT04349514.

Introduction: Application of MRI in clinical routine mainly addresses structural alterations. However, pathological changes at a cellular level are expected to precede the occurrence of brain atrophy clusters and of clinical symptoms. In this context, 23Na-MRI examines sodium changes in the brain as a potential metabolic parameter. Recently, we have shown that 23Na-MRI at ultra-high-field (7 T) was able to detect increased tissue sodium concentration (TSC) in Alzheimer’s disease (AD). In this work, we aimed at assessing AD-pathology with 23Na-MRI in a larger cohort and on a clinical 3T MR scanner. Methods: We used a multimodal MRI protocol on 52 prodromal to mild AD patients and 34 cognitively healthy control subjects on a clinical 3T MR scanner. We examined the TSC, brain volume, and cortical thickness in association with clinical parameters. We further compared TSC with intra-individual normalized TSC for the reduction of inter-individual TSC variability resulting from physiological as well as experimental conditions. Normalized TSC maps were created by normalizing each voxel to the mean TSC inside the brain stem. Results: We found increased normalized TSC in the AD cohort compared to elderly control subjects both on global as well as on a region-of-interest-based level. We further confirmed a significant association of local brain volume as well as age with TSC. TSC increase in the left temporal lobe was further associated with the cognitive state, evaluated via the Montreal cognitive assessment (MoCA) screening test. An increase of normalized TSC depending on disease stage reflected by the Clinical Dementia Rating (CDR) was found in our AD patients in temporal lobe regions. In comparison to classical brain volume and cortical thickness assessments, normalized TSC had a higher discriminative power between controls and prodromal AD patients in several regions of the temporal lobe. Discussion: We confirm the feasibility of 23Na-MRI at 3T and report an increase of TSC in AD in several regions of the brain, particularly in brain regions of the temporal lobe. Furthermore, to reduce inter-subject variability caused by physiological factors such as circadian rhythms and experimental conditions, we introduced normalized TSC maps. This showed a higher discriminative potential between different clinical groups in comparison to the classical TSC analysis. In conclusion, 23Na-MRI represents a potential translational imaging marker applicable e.g. for diagnostics and the assessment of intervention outcomes in AD even under clinically available field strengths such as 3T. Implication of 23Na-MRI in association with other metabolic imaging marker needs to be further elucidated.

In patients with Friedreich ataxia, structural MRI is typically used to detect abnormalities primarily in the brainstem, cerebellum, and spinal cord. The aim of the present study was to additionally investigate possible metabolic changes in Friedreich ataxia using in vivo sodium MRI that may precede macroanatomical alterations, and to explore potential associations with clinical parameters of disease progression.Tissue sodium concentration across the whole brain was estimated from sodium MRI maps acquired at 3 T and compared between 24 patients with Friedreich ataxia (21–57 years old, 13 females) and 23 controls (21–60 years old, 12 females). Tensor-based morphometry was used to assess volumetric changes. Total sodium concentrations and volumetric data in brainstem and cerebellum were correlated with clinical parameters, such as severity of ataxia, activity of daily living and disability stage, age, age at onset, and disease duration.Compared to controls, patients showed reduced brain volume in the right cerebellar lobules I-V (difference in means: −0.039% of total intracranial volume [TICV]; Cohen’s d = 0.83), cerebellar white matter (WM) (-0.105%TICV; d = 1.16), and brainstem (-0.167%TICV; d = 1.22), including pons (-0.102%TICV; d = 1.00), medulla (-0.036%TICV; d = 1.72), and midbrain (-0.028%TICV; d = 1.05). Increased sodium concentration was additionally detected in the total cerebellum (difference in means: 2.865 mmol; d = 0.68), and in several subregions with highest effect sizes in left (5.284 mmol; d = 1.01) and right cerebellar lobules I-V (5.456 mmol; d = 1.00), followed by increases in the vermis (4.261 mmol; d = 0.72), and in left (2.988 mmol; d = 0.67) and right lobules VI-VII (2.816 mmol; d = 0.68). In addition, sodium increases were also detected in all brainstem areas (3.807 mmol; d = 0.71 to 5.42 mmol; d = 1.19). After controlling for age, elevated total sodium concentrations in right cerebellar lobules IV were associated with younger age at onset (r = -0.43) and accordingly with longer disease duration in patients (r = 0.43).Our findings support the potential of in vivo sodium MRI to detect metabolic changes of increased total sodium concentration in the cerebellum and brainstem, the key regions in Friedreich ataxia. In addition to structural changes, sodium changes were present in cerebellar hemispheres and vermis without concomitant significant atrophy. Given the association with age at disease onset or disease duration, metabolic changes should be further investigated longitudinally and in larger cohorts of early disease stages to determine the usefulness of sodium MRI as a biomarker for early neuropathological changes in Friedreich ataxia and efficacy measure for future clinical trials.

Abstract Lambert-Eaton myasthenic syndrome (LEMS) is a rare, autoimmune or paraneoplastic condition characterized by muscle weakness and fatigability. In cancer therapy, immune checkpoint inhibitors (ICI) sensitize the immune system for tumor antigens. We report a 62-year-old, female patient with paraneoplastic LEMS as first manifestation of Merkel cell carcinoma. Under avelumab, the LEMS exacerbated with worsening of limb weakness and a severely reduced vital capacity (

Tremor is one of the common symptoms of Parkinson’s disease (PD). Thanks to the recent evolution of digital technologies, monitoring of PD patients’ hand movements employing contactless methods gained momentum. Objective: We aimed to quantitatively assess hand movements in patients suffering from PD using the artificial intelligence (AI)-based hand-tracking technologies of MediaPipe. Method: High-frame-rate videos and accelerometer data were recorded from 11 PD patients, two of whom showed classical Parkinsonian-type tremor. In the OFF-state and 30 Minutes after taking their standard oral medication (ON-state), video recordings were obtained. First, we investigated the frequency and amplitude relationship between the video and accelerometer data. Then, we focused on quantifying the effect of taking standard oral treatments. Results: The data extracted from the video correlated well with the accelerometer-based measurement system. Our video-based approach identified the tremor frequency with a small error rate (mean absolute error 0.229 (±0.174) Hz) and an amplitude with a high correlation. The frequency and amplitude of the hand movement before and after medication in PD patients undergoing medication differ. PD Patients experienced a decrease in the mean value for frequency from 2.012 (±1.385) Hz to 1.526 (±1.007) Hz and in the mean value for amplitude from 8.167 (±15.687) a.u. to 4.033 (±5.671) a.u. Conclusions: Our work achieved an automatic estimation of the movement frequency, including the tremor frequency with a low error rate, and to the best of our knowledge, this is the first paper that presents automated tremor analysis before/after medication in PD, in particular using high-frame-rate video data.

Reducing α-synuclein pathology constitutes a plausible strategy against Parkinson’s disease. As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein, interferes with fibril nucleation, and reduces α-synuclein aggregation in vitro and in a fruit fly model of α-synuclein toxicity. The aim of this study was to investigate whether AS69 also reduces α-synuclein pathology in mammalian neurons. To induce α-synuclein pathology, primary mouse neurons were exposed to pre-formed fibrils (PFF) of human α-synuclein. PFF were also injected into the striatum of A30P-α-synuclein transgenic mice. The extent of α-synuclein pathology was determined by phospho-α-synuclein staining and by Triton X-100 solubility. The degeneration of neuronal somata, dendrites, and axon terminals was determined by immunohistochemistry. AS69 and PFF were taken up by primary neurons. AS69 did not alter PFF uptake, but AS69 did reduce PFF-induced α-synuclein pathology. PFF injection into mouse striatum led to α-synuclein pathology and dystrophic neurites. Co-injection of AS69 abrogated PFF-induced pathology. AS69 also reduced the PFF-induced degeneration of dopaminergic axon terminals in the striatum and the degeneration of dopaminergic dendrites in the substantia nigra pars reticulata. AS69 reduced the activation of astroglia but not microglia in response to PFF injection. Collectively, AS69 reduced PFF-induced α-synuclein pathology and the associated neurodegeneration in primary neurons and in mouse brain. Our data therefore suggest that small proteins binding the N-terminus of α-synuclein monomers are promising strategies to modify disease progression in Parkinson’s disease.

Progressive multifocal leukoencephalopathy (PML) is a subacute brain infection by the opportunistic John Cunningham (JC) virus. Herein, we describe seven patients with PML, lymphopenia, and sarcoidosis, in three of whom PML was the first manifestation of sarcoidosis. At onset, the clinical picture comprised rapidly progressive spastic hemi- or limb pareses as well as disturbances of vision, speech, and orientation. Cerebral magnetic resonance imaging showed T2-hyperintense, confluent, mainly supratentorial lesions. Four patients developed punctate contrast enhancement as a radiological sign of an immune reconstitution inflammatory syndrome (IRIS), three of them having a fatal course. In the cerebrospinal fluid, the initial JC virus load (8–25,787 copies/ml) did not correlate with interindividual severity; however, virus load corresponded to clinical dynamics. Brain biopsies ( n = 2), performed 2 months after symptom onset, showed spotted demyelination and microglial activation. All patients had lymphopenia in the range of 270–1150/µl. To control JC virus, three patients received a combination of mirtazapine and mefloquine, another two patients additionally took cidofovir. One patient was treated with cidofovir only, and one patient had a combined regimen with mirtazapine, mefloquine, cidofovir, intravenous interleukin 2, and JC capsid vaccination. To treat sarcoidosis, the four previously untreated patients received prednisolone. Three patients had taken immunosuppressants prior to PML onset, which were subsequently stopped as a potential accelerator of opportunistic infections. After 6–54 months of follow up, three patients reached an incomplete recovery, one patient progressed, but survived so far, and two patients died. One further patient was additionally diagnosed with lung cancer, which he died from after 24 months. We conclude that the combination of PML and sarcoidosis is a diagnostic and therapeutic challenge. PML can occur as the first sign of sarcoidosis without preceding immunosuppressive treatment. The development of IRIS might be an indicator of poor outcome.

Abstract Introduction Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown. Methods The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1–4) to the individually highest tolerated dose of 2–4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5–104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician’s and patient’s global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death. Perspective The NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia. Trial registration EudraCT-No.: 2017-002163-17, ClinicalTrials.gov NCT03761511.

Abstract Background IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment. Methods NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics. Results The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients. Conclusion It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.

Abstract Introduction Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD‐MCI) compared to Parkinson's disease (PD‐MCI) are rare. Methods Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were compared using scores derived from the Consortium to Establish a Registry for Alzheimer's Disease battery. Results Patients with AD‐MCI showed lower standardized scores on all memory test scores and a language test. Patients with PD‐MCI showed lower standardized scores in a set‐shifting measure as an executive task. A cross‐validated logistic regression with test scores as predictors was able to classify 72% of patients correctly to AD‐MCI versus PD‐MCI. Discussion The applied test battery successfully discriminated between AD‐MCI and PD‐MCI. Neuropsychological test batteries in clinical practice should always include a broad spectrum of cognitive domains to capture any cognitive changes.

Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against αSyn is altered in patients with PD. In this work, we biophysically characterized nAbs against αSyn (nAbs-αSyn) and determined their biological effects. nAbs-αSyn were isolated from commercial intravenous immunoglobulins using column affinity purification. Biophysical properties were characterized using a battery of established in vitro assays. Biological effects were characterized in HEK293T cells transiently transfected with fluorescently tagged αSyn. Specific binding of nAbs-αSyn to monomeric αSyn was demonstrated by Dot blot, ELISA, and Surface Plasmon Resonance. nAbs-αSyn did not affect viability of HEK293T cells as reported by Cell Titer Blue and LDH Assays. nAbs-αSyn inhibited fibrillation of αSyn reported by the Thioflavin T aggregation assay. Altered fibril formation was confirmed with atomic force microscopy. In cells transfected with EGFP-tagged αSyn we observed reduced formation of aggresomes, perinuclear accumulations of αSyn aggregates. The results demonstrate that serum of healthy individuals contains nAbs that specifically bind αSyn and inhibit aggregation of αSyn in vitro. The addition of nAbs-αSyn to cultured cells affects intracellular αSyn aggregates. These findings help understanding the role of the innate immune systems for the pathogenesis of PD and suggest that systemic αSyn binding agents could potentially affect neuronal αSyn pathology.

Abstract Background Physical activity has shown a positive impact on aging and neurodegeneration and represents a possible treatment option in cognitive decline. However, its underlying mechanisms and influences on brain pathology remain unclear. Dementia‐MOVE (Multi‐Objective Validation of Exercise) is a randomized‐controlled pilot trial, including 50 patients with amnestic cognitive impairment associated with Alzheimer's pathology, aiming to analyze the effect of physical activity and fitness on disease progression. Methods Dementia‐MOVE is divided into two arms, of either an intervention comprising physical activity, for at least twice a week, combined with a psychoeducational program, or a sole psychoeducational program. Physical activity intervention includes a supervised and unsupervised multimodal concept combining resistance, endurance, coordinative, and aerobic training. The primary outcome is the change of brain metabolism due to physical interventional treatment. Besides metabolic magnetic resonance imaging (MRI) including sodium and phosphorus imaging, resting state functional MRI, T1‐, T2‐weighted and fluid‐attenuated inversion recovery (FLAIR), as well as diffusion‐weighted imaging (DWI) of the brain and whole‐body fat MRI are performed before and after intervention, and will be compared in their sensitivity for the detection of intervention effects. We further assess cognitive performance, neuropsychiatric symptoms, quality of life, fitness, and sleep via questionnaires/interviews and/or fitness trackers, as well as microbiome, under the aspect of Alzheimer's pathology. Discussion The aim of Dementia‐MOVE is to investigate the effect of a multimodal exercise program on Alzheimer's pathology under different aspects of the disease. In this context, one of the main aims is the comparison of different MRI methods regarding their responsiveness for the detection of alterations induced by physical activity. As an underlying goal, new treatment and diagnostic options, as well as the exploration of fitness effects on brain structure and metabolism within a whole‐body perspective of Alzheimer's disease are envisaged.

Introduction: Mild cognitive impairment (MCI) is a heterogenous syndrome considered as a risk factor for developing dementia. Previous work examining morphological brain changes in MCI has identified a temporo-parietal atrophy pattern that suggests a common neuroanatomical denominator of cognitive impairment. Using functional connectivity analyses of structurally affected regions in MCI, we aimed to investigate and characterize functional networks formed by these regions that appear to be particularly vulnerable to disease-related disruptions.Methods: Areas of convergent atrophy in MCI were derived from a quantitative meta-analysis and encompassed left and right medial temporal (i.e., hippocampus, amygdala), as well as parietal regions (precuneus), which were defined as seed regions for connectivity analyses. Both task-based meta-analytical connectivity modeling (MACM) based on the BrainMap database and task-free resting-state functional MRI in a large cohort of older adults from the 1000BRAINS study were applied. We additionally assessed behavioral characteristics associated with the seed regions using BrainMap meta-data and investigated correlations of resting-state connectivity with age.Results: The left temporal seed showed stronger associations with a fronto-temporal network, whereas the right temporal atrophy cluster was more linked to cortico-striatal regions. In accordance with this, behavioral analysis indicated an emphasis of the left temporal seed on language generation, and the right temporal seed was associated with the domains of emotion and attention. Task-independent co-activation was more pronounced in the parietal seed, which demonstrated stronger connectivity with a frontoparietal network and associations with introspection and social cognition. Correlation analysis revealed both decreasing and increasing functional connectivity with higher age that may add to pathological processes but also indicates compensatory mechanisms of functional reorganization with increasing age.Conclusion: Our findings provide an important pathophysiological link between morphological changes and the clinical relevance of major structural damage in MCI. Multimodal analysis of functional networks related to areas of MCI-typical atrophy may help to explain cognitive decline and behavioral alterations not tractable by a mere anatomical interpretation and therefore contribute to prognostic evaluations.

Abstract Background Neuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer’s disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1β (IL-1β) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid β1–42 (Aβ1–42) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD. The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aβ1–42-induced inflammation in microglial cells. In this study, we investigated the effect of Aβ1–42-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT. Methods Primary cortical astrocytes from BALB/c mice were stimulated with Aβ1–42 and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components. Results Our study revealed that A1AT reduces Aβ1–42-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1β in Aβ1–42-stimulated astrocytes. Conclusion We conclude that Aβ1–42-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aβ1–42-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer’s disease.

Background: Parkinson's disease (PD) has been suggested to affect males and females differently. Neuropsychiatric symptoms are common and disabling in PD. However, previous studies focusing on emotion recognition in PD have neglected the confounder of gender and lack evidence on the underlying endocrinal and genetic mechanisms. Moreover, while there are many imaging studies on emotion processing in PD, gender-related analyses of neural data are scarce. We therefore aimed at exploring the interplay of the named factors on emotion recognition and processing in PD. Methods: 51 non-demented PD patients (26 male) and 44 age- and gender-matched healthy controls (HC; 25 male) were examined clinically and neuropsychologically including an emotion recognition task (Ekman 60faces test). A subsample of 25 patients and 31 HC underwent task-based functional magnetic resonance imaging (fMRI) comprised of videos of emotional facial expressions. To examine the impact of hormones and genetics on emotion processing, blood samples were taken for endocrinal (testosterone, estradiol, progesterone) and genetic testing (5-HTTLPR, Val158Met COMT polymorphisms). Results: No group or gender differences emerged regarding cognitive abilities. Male but not female PD patients exhibited confined impairments in recognizing the emotion anger accompanied by diminished neural response to facial expressions (e.g. in the putamen and insula). Endocrinologically, fear recognition was positively correlated with estrogen levels in female patients, while on the genetic level we found an effect of Val158Met COMT genotype on the recognition of fear in PD patients. Conclusions: Our study provides evidence that impaired emotion processing in PD specifically affects male patients, and that hormones and genetics contribute to emotion recognition performance. Further research on the underlying neural, endocrinological and genetic mechanisms of specific symptoms in PD is of clinical relevance, as it can improve our understanding of the phenomenology and pathobiology of the disease and may allow a more personalized medicine. Keywords: Parkinson's disease (PD), Emotion, Gender, Genetics, Functional magnetic resonance imaging (fMRI)

Abstract Background Anterior sacral meningoceles are rare, and usually occur with other malformations of the posterior lower spine. While these are more frequently reported in pediatric cohorts, we report a case in an elderly woman. Case presentation We report on a 71 year-old woman with a recently diagnosed colorectal adenocarcinoma who presented with a severe bacterial meningitis. The cerebrospinal fluid cell count revealed a pleocytosis of 80,000 cells/μl and a severe disturbance of the blood-brain-barrier. Fusobacterium nucleatum was cultured as the causing pathogen. A lumbar MRI showed, in addition to contrast-enhancing meninges as sign of inflammation, a presacral mass. In the next step, the mass was diagnosed as an anterior sacral meningocele connected to the gut. An adequate antibiotic was used to treat the leptomeningitis. The connection between gut and meningocele was closed surgically and the patient recovered well and underwent further treatment of her colorectal adenocarcinoma. Conclusion We report on a case of meningitis with an anterior sacral meningocele that was connected to the gut in a patient with a infiltrative colorectal adenocarcinoma. Anatomic variants have to be considered as rare causes of meningitis with typical intestinal germs.

Hypoxia is known to impair mitochondrial and endoplasmic reticulum (ER) homeostasis. Post-hypoxic perturbations of the ER proteostasis result in the accumulation of misfolded/unfolded proteins leading to the activation of the Unfolded Protein Response (UPR). Mitochondrial chaperone TNF receptor-associated protein 1 (TRAP1) is reported to preserve mitochondrial membrane potential and to impede reactive oxygen species (ROS) production thereby protecting cells from ER stress as well as oxidative stress. The first-line antidiabetic drug Metformin has been attributed a neuroprotective role after hypoxia. Interestingly, Metformin has been reported to rescue mitochondrial deficits in fibroblasts derived from a patient carrying a homozygous TRAP1 loss-of-function mutation. We sought to investigate a putative link between Metformin, TRAP1, and the UPR after hypoxia. We assessed post-hypoxic/reperfusion longevity, mortality, negative geotaxis, ROS production, metabolic activity, gene expression of antioxidant proteins, and activation of the UPR in Trap1-deficient flies. Following hypoxia, Trap1 deficiency caused higher mortality and greater impairments in negative geotaxis compared to controls. Similarly, post-hypoxic production of ROS and UPR activation was significantly higher in Trap1-deficient compared to control flies. Metformin counteracted the deleterious effects of hypoxia in Trap1-deficient flies but had no protective effect in wild-type flies. We provide evidence that TRAP1 is crucially involved in the post-hypoxic regulation of mitochondrial/ER stress and the activation of the UPR. Metformin appears to rescue Trap1-deficiency after hypoxia mitigating ROS production and downregulating the pro-apoptotic PERK (protein kinase R-like ER kinase) arm of the UPR.

Abstract Sleep disordered breathing (SDB) is known for fluctuating heart rates and an increased risk of developing arrhythmias. The current reference for heartbeat analysis is an electrocardiogram (ECG). As an unobtrusive alternative, we tested a sensor foil for mechanical vibrations to perform a ballistocardiography (BCG) and applied a novel algorithm for beat-to-beat cycle length detection. The aim of this study was to assess the correlation between beat-to-beat cycle length detection by the BCG algorithm and simultaneously recorded ECG. In 21 patients suspected for SDB undergoing polysomnography, we compared ECG to simultaneously recorded BCG data analysed by our algorithm. We analysed 362.040 heartbeats during a total of 93 hours of recording. The baseline beat-to-beat cycle length correlation between BCG and ECG was r s = 0.77 (n = 362040) with a mean absolute difference of 15 ± 162 ms (mean cycle length: ECG 923 ± 220 ms; BCG 908 ± 203 ms). After filtering artefacts and improving signal quality by our algorithm, the correlation increased to r s = 0.95 (n = 235367) with a mean absolute difference in cycle length of 4 ± 72 ms (ECG 920 ± 196 ms; BCG 916 ± 194 ms). We conclude that our algorithm, coupled with a BCG sensor foil provides good correlation of beat-to-beat cycle length detection with simultaneously recorded ECG.

Abstract Many new strategies for the reconstruction of peripheral nerve injuries have been explored for their effectiveness in supporting nerve regeneration. However only a few of these materials were actually clinically evaluated and approved for human use. This open, mono-center, non-randomized clinical study summarizes the 12-month follow-up of patients receiving reconstruction of the sural nerve biopsy defect by the collagen-based nerve guide Neuromaix. Neuromaix was implanted as a micro-structured, two-component scaffold bridging 20–40 mm nerve defects after sural nerve biopsy in twenty patients (eighteen evaluated, two lost in follow-up). Safety of the material was evaluated by clinical examination of wound healing. Performance was assessed by sensory testing of modalities, pain assessment, and palpation for the Hoffmann–Tinel’s sign as well as demarcating the asensitive area at each follow-up visit. Every patient demonstrated uneventful wound healing during the complete 12-month time course of the study. Two patients reported complete return of sensation, whereas eleven out of eighteen patients reported a positive Hoffmann–Tinel’s sign at the lower leg with simultaneous reduction of the asensitive area by 12 months. Our data show that Neuromaix can be implanted safely in humans to bridge sural nerve gaps. No procedure-related, adverse events, or severe adverse events were reported. These first clinical data on Neuromaix provide promising perspectives for the bridging of larger nerve gaps in combined nerves, which should be investigated more through extensive, multi-center clinical trials in the near future.

Abstract Background Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset muscle disorder, characterized by the presence of nemaline rods in muscle fibers. Phenotypic characterization in a large cohort and a comprehensive overview of SLONM are lacking. Methods We studied the clinico-pathological features, treatment and outcome in a large cohort of 76 patients with SLONM, comprising 10 new patients and 66 cases derived from a literature meta-analysis (PubMed, 1966–2016), and compared these with 15 reported HIV-associated nemaline myopathy (HIV-NM) cases. In 6 SLONM patients, we performed a targeted next-generation sequencing (NGS) panel comprising 283 myopathy genes. Results SLONM patients had a mean age at onset of 52 years. The predominant phenotype consisted of weakness and atrophy of proximal upper limbs in 84%, of proximal lower limbs in 80% and both in 67%. Other common symptoms included axial weakness in 68%, as well as dyspnea in 55% and dysphagia in 47% of the patients. In 53% a monoclonal gammopathy of unknown significance (MGUS) was detected in serum. The mean percentage of muscle fibers containing rods was 28% (range 1–63%). In 2 cases ultrastructural analysis was necessary to detect the rods. The most successful treatment in SLONM patients (all with MGUS) was autologous peripheral blood stem cell therapy. A targeted NGS gene panel in 6 SLONM patients (without MGUS) did not reveal causative pathogenic variants. In a comparison of SLONM patients with and without MGUS, the former comprised significantly more males, had more rapid disease progression, and more vacuolar changes in muscle fibers. Interestingly, the muscle biopsy of 2 SLONM patients with MGUS revealed intranuclear rods, whereas this feature was not seen in any of the biopsies from patients without paraproteinemia. Compared to the overall SLONM cohort, significantly more HIV-NM patients were male, with a lower age at onset (mean 34 years). In addition, immunosuppression was more frequently applied with more favorable outcome, and muscle biopsies revealed a significantly higher degree of inflammation and necrosis in this cohort. Similar to SLONM, MGUS was present in half of the HIV-NM patients. Conclusions SLONM presents a challenging, but important differential diagnosis to other neuromuscular diseases of adult onset. Investigations for MGUS and HIV should be performed, as they require distinct but often effective therapeutic approaches. Even though SLONM and HIV-NM show some differences, there exists a large clinico-pathological overlap between the 2 entities.

Current treatment in late-life cognitive impairment and dementia is still limited, and there is no cure for brain tissue degeneration or reversal of cognitive decline. Physical activity represents a promising non-pharmacological interventional approach in many diseases causing cognitive impairment, but its effect on brain integrity is still largely unknown. Especially research of cerebral alterations in disease state that goes beyond observations of clinical improvement is crucial to understand disease processes and possible effective treatments. In this systematic review, we address the question how physical activity and fitness in mild cognitive impairment (MCI) and Alzheimer's disease (AD) influences brain architecture compared to cognitively healthy elderly. We review both interventional studies comprising aerobic, coordinative and resistance exercises and observational studies on fitness and physical activity combined with Magnetic Resonance imaging (MRI). Different MRI approaches were included such as volumetric and structural analyses, Diffusion Tensor Imaging (DTI), functional MRI and Cerebral Blood Flow (CBF). We evaluate MRI results for different exercise modalities and performed a methodological evaluation of interventional studies in cognitive decline compared to normal aging. According to our results, among 12 interventions in AD/MCI, aerobic exercise is most frequently applied (9 studies). Interventions in AD/MCI altogether reveal a higher methodological quality compared to interventions in healthy elderly (8.33 ± 2.19 vs. 6.25 ± 2.36 out of 13 points), with most frequent missing aspects related to descriptions of complications, lack of intention-to-treat and statistical power analyses. Effects of aerobic exercise and fitness seem to mainly impact brain structures sensitive to neurodegeneration, which especially comprise frontal, temporal and parietal regions, such as the hippocampal/parahippocampal region, precuneus, anterior cingulate and prefrontal cortex, which are reported by several studies. General fitness measured via an objective fitness assessment and questionnaires seems to have a more global cerebral effect, probably due to its long-term application, whereas distinct intervention effects of durations between 3 and 6 months seem to concentrate on more local brain regions as the hippocampus, which can also be influenced by region of interest analyses. There is still a lack of evidence on other or combined types of intervention modalities, such as resistance, coordinative as well as multicomponent exercise during cognitive decline, and complex interventions as dancing. Future research should examine their beneficial effect on brain integrity, since several non-MRI studies already point to their advantageous impact. As a further future prospect, combination and application of newly developed imaging methods such as metabolic imaging should be envisaged to understand physical activity and its cerebral influence under its many-sided facets. Keywords: Physical activity, Exercise, Fitness, MRI, Neuroimaging, Dementia

With emerging treatment approaches, it is crucial to correctly diagnose and monitor hereditary and acquired polyneuropathies. This study aimed to assess the validity and accuracy of magnet resonance imaging (MRI)-based muscle volumetry.Using semi-automatic segmentations of upper- and lower leg muscles based on whole-body MRI and axial T1-weighted turbo spin-echo sequences, we compared and correlated muscle volumes, and clinical and neurophysiological parameters in demyelinating Charcot-Marie-Tooth disease (CMT) (n = 13), chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 27), and other neuropathy (n = 17) patients.The muscle volumes of lower legs correlated with foot dorsiflexion strength (p < 0.0001), CMT Neuropathy Score 2 (p < 0.0001), early gait disorders (p = 0.0486), and in CIDP patients with tibial nerve conduction velocities (p = 0.0092). Lower (p = 0.0218) and upper (p = 0.0342) leg muscles were significantly larger in CIDP compared to CMT patients. At one-year follow-up (n = 15), leg muscle volumes showed no significant decrease.MRI muscle volumetry is a promising method to differentiate and characterize neuropathies in clinical practice.

Background: Though Todd’s phenomenon (TP) is a relatively rare occurrence, its correct identification is of key diagnostic and therapeutic importance as a stroke mimic. Here we describe a case of isolated gaze palsy as a manifestation of TP, discuss periictal gaze abnormalities as lateralizing sign involving the frontal eye field (FEF), and present a narrative literature review. Methods: We reviewed the main features of the case and conducted a structured literature search of TP and gaze palsy using PubMed. We restricted the search to publications in English, Spanish, French, and German. Case presentation: A 71-year-old male with a history of right frontotemporal subarachnoid hemorrhage was admitted to the Emergency Department of our institution after suffering a first unprovoked focal to bilateral tonic-clonic seizure with ictal gaze deviation to the left. Cranial imaging showed no signs of ischemia, intracerebral hemorrhage, or tumor. The patient presented the following postictal features: involuntary eye deviation to the right due to left-sided gaze palsy and disorientation in time with preserved responsiveness. Eye movements were normal three days later. We concluded that the patient suffered from new-onset epilepsy due to sequelae following the right frontotemporal subarachnoid hemorrhage, affecting the FEF with contralateral ictal gaze deviation, and postictal gaze palsy with ipsilateral eye deviation as an unusual Todd’s phenomenon. Conclusion: Unusual manifestations of TP are uncommon but clinically highly relevant, as they can mimic stroke or epileptic status and are decisive in the diagnostic and therapeutic decision-making process. Though postictal gaze palsy has been reported associated with other deficits, this constitutes, to our knowledge, the first report of isolated gaze palsy as a form of TP. Further research into the underlying causes is needed. Ictal contralateral gaze and head deviation, and probably postictal ipsilateral gaze deviation if present, are very helpful for the lateralization of the seizure-onset zone.

Inclusions containing Fused in Sarcoma (FUS) are found in familial and sporadic cases of the incurable progressive motor neuron disease amyotrophic lateral sclerosis and in a common form of dementia, frontotemporal dementia. Most disease-associated mutations are located in the C-terminal proline–tyrosine nuclear localization sequence (PY-NLS) of FUS and impair its nuclear import. It has been shown in cell culture that the nuclear import of FUS is mediated by transportin, which binds the PY-NLS and the last arginine/glycine/glycine-rich (RGG) domain of FUS. Methylation of this last RGG domain by protein arginine methyltransferases (PRMTs) weakens transportin binding and therefore impairs nuclear translocation of FUS. To investigate the requirements for the nuclear import of FUS in an in vivo model, we generated different transgenic Drosophila lines expressing human FUS wild type (hFUS wt) and two disease-related variants P525L and R495X, in which the NLS is mutated or completely absent, respectively. To rule out effects caused by heterologous hFUS expression, we analysed the corresponding variants for the Drosophila FUS orthologue Cabeza (Caz wt, P398L, Q349X). Expression of these variants in eyes and motor neurons confirmed the PY-NLS-dependent nuclear localization of FUS/Caz and caused neurodegenerative effects. Surprisingly, FUS/Caz toxicity was correlated to the degree of its nuclear localization in this overexpression model. High levels of nuclear FUS/Caz became insoluble and reduced the endogenous Caz levels, confirming FUS autoregulation in Drosophila. RNAi-mediated knockdown of the two transportin orthologues interfered with the nuclear import of FUS/Caz and also enhanced the eye phenotype. Finally, we screened the Drosophila PRMT proteins (DART1-9) and found that knockdown of Dart1 led to a reduction in methylation of hFUS P525L and aggravated its phenotype.These findings show that the molecular mechanisms controlling the nuclear import of FUS/Caz and FUS autoregulation are conserved between humans and Drosophila. In addition to the well-known neurodegenerative effects of FUS loss-of function, our data suggest toxic potential of overexpressed FUS in the nucleus and of insoluble FUS.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG). For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1) and inferior frontal junction (IFJ). The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM). MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments activating the MOG or IFJ in conjunction with the striatum were associated with cognitive functions, while the network formed by M1 and the striatum was driven by motor-related tasks. Thus, based on morphological changes in HD, we identified functionally distinct cortico-striatal networks resembling a cognitive and motor loop, which may be prone to early disruptions in different stages of the disease and underlie HD-related cognitive and motor symptom profiles. Our findings provide an important link between morphometrically defined seed-regions and corresponding functional circuits highlighting the functional and ensuing clinical relevance of structural damage in HD.

BackgroundCognitive decline is characteristic for Alzheimer’s disease (AD) and also for healthy ageing. As a proof-of-concept study, we examined whether this decline can be counteracted using real-time fMRI neurofeedback training. Visuospatial memory and the parahippocampal gyrus (PHG) were targeted.MethodsSixteen healthy elderly subjects (mean age 63.5 years, SD = 6.663) and 10 patients with prodromal AD (mean age 66.2 years, SD = 8.930) completed the experiment. Four additional healthy subjects formed a sham-feedback condition to validate the paradigm. The protocol spanned five examination days (T1–T5). T1 contained a neuropsychological pre-test, the encoding of a real-world footpath, and an anatomical MRI scan of the brain. T2–T4 included the fMRI neurofeedback training paradigm, in which subjects learned to enhance activation of the left PHG while recalling the path encoded on T1. At T5, the neuropsychological post-test and another anatomical MRI brain scan were performed. The neuropsychological battery included the Montreal Cognitive Assessment (MoCA); the Visual and Verbal Memory Test (VVM); subtests of the Wechsler Memory Scale (WMS); the Visual Patterns Test; and Trail Making Tests (TMT) A and B.ResultsHealthy elderly and patients with prodromal AD showed improved visuospatial memory performance after neurofeedback training. Healthy subjects also performed better in a working-memory task (WMS backward digit-span) and in the MoCA. Both groups were able to elicit parahippocampal activation during training, but no significant changes in brain activation were found over the course of the training. However, Granger-causality-analysis revealed changes in cerebral connectivity over the course of the training, involving the parahippocampus and identifying the precuneus as main driver of activation in both groups. Voxel-based morphometry showed increases in grey matter volumes in the precuneus and frontal cortex. Neither cognitive enhancements, nor parahippocampal activation were found in the control group undergoing sham-feedback.ConclusionThese findings suggest that cognitive decline, either related to prodromal AD or healthy ageing, could be counteracted using fMRI-based neurofeedback. Future research needs to determine the potential of this method as a treatment tool.