A Neurological Outpatient Clinic for Patients With Post-COVID-19 Syndrome — A Report on the Clinical Presentations of the First 100 Patients

Background and Objectives: Neurological and psychiatric symptoms are frequent in patients with post-COVID-19 syndrome (PCS). Here, we report on the clinical presentation of the first 100 patients who presented to our PCS Neurology outpatient clinic ≥ 12 weeks after the acute infection with SARS-CoV-2. To date, PCS is only defined by temporal connection to SARS-CoV-2 infection. Identification of clinical phenotypes and subgroups of PCS is urgently needed. Design: We assessed clinical data of our first 100 ambulatory patients regarding clinical presentations; self-questionnaires focusing on daytime sleepiness, mood, and fatigue; and a screening assessment for detecting cognitive impairment. Results: A total of 89% of the patients presenting to the Neurology outpatient clinic had an initially mild course of COVID-19 and had not been hospitalized. The majority of the patients were female (67 vs. 33% male). The most frequent symptom reported was cognitive impairment (72%). There were 30% of patients who reported cognitive deficits and scored below 26 points on the Montreal Cognitive Assessment Scale. Fatigue (67%), headache (36%), and persisting hyposmia (36%) were also frequently reported; 5.5% of all patients showed signs of severe depression. Discussion: To our knowledge, this is the first report of patient data of a PCS Neurology outpatient clinic. Neurological sequelae also exist for more than 3 months after mainly mild SARS-CoV-2 acute infections. The reported symptoms are in accordance with recently published data of hospitalized patients

Genome-wide characterization of circulating metabolic biomarkers

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases

The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity

Genome-wide characterization of circulating metabolic biomarkers

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8,9,10,11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases

Delirium in idiopathic Parkinson’s disease

Hintergrund: Die Entwicklung eines Delirs im Rahmen eines idiopathischen Parkinson-Syndrom (IPS) ist eine gefürchtete Komplikation, die mit einem hohen Risiko für langanhaltende Verschlechterungen von Motorik und Psychopathologie einhergeht. Bisher liegen nur unzureichende Kenntnisse zu Prävalenz, Inzidenz, Verlauf und Prognose vor. Ebenso fehlen klinische Studien, aus denen sich Empfehlungen zum evidenzbasierten Management des Delirs bei IPS ableiten lassen. Ziel der Arbeit/Fragestellung: Darstellung des aktuellen wissenschaftlichen Kenntnisstandes des Delirs beim IPS und Sensibilisierung für diese wichtige Krankheitsentität. Methoden: Die Literatursuche wurde in PubMed durchgeführt. Ergebnisse: Das IPS ist ein unabhängiger Risikofaktor für die Entwicklung eines Delirs. IPS-Patienten zeigen nach einem Delir anhaltende Verschlechterungen sowohl der Kognition als auch der motorischen Symptomatik. Diskussion: Bislang existieren keine validierten Bewertungsskalen zur Erkennung und Verlaufsbeurteilung des Delirs beim IPS. Präventive und nichtpharmakologische Maßnahmen sollten konsequent und strukturiert angewandt werden. Die medikamentöse Behandlung mit Quetiapin und Clozapin ist bisher noch unzureichend untersucht, während andere Neuroleptika aufgrund ihrer dopaminantagonistischen Wirkung zur Behandlung des Delirs beim IPS kontraindiziert sind.Background: The development of delirium in patients with idiopathic Parkinson’s disease (IPD) is a feared complication, which is often associated with sustained worsening of motor symptoms and psychopathological sequelae. Little is known regarding the prevalence and incidence rates, course and prognosis. Clinical studies from which recommendations for evidence-based management of delirium in IPD can be derived are lacking. Objective: To summarize the state of the art regarding epidemiological and clinical features of delirium in IPD. Discussion of prevention strategies and non-pharmacological and pharmacological treatment options. Methods: A literature search was carried out in PubMed. Results: The IPD is an independent risk factor for the development of delirium. Patients with IPD show poorer clinical outcome frequently with cognitive worsening and motor complications following development of delirium. Conclusion: So far no validated rating scales for recognition and course evaluation of delirium in IPD are available. Preventive strategies and non-pharmacological measures should be consistently implemented to improve management. There are insufficient data concerning pharmacotherapy with quetiapine and clozapine, whereas other neuroleptics are contraindicated for delirium in IPD due to antidopaminergic side effects

Reflections on Addiction in Students Using Stimulants for Neuroenhancement: A Preliminary Interview Study

The use of stimulants for the purpose of pharmacological neuroenhancement (NE) among students is a subject of increasing public awareness. The risk of addiction development by stimulant use for NE is still unanswered. Therefore, face-to-face interviews were carried out among 18 university students experienced in the nonmedical use of methylphenidate and amphetamines for NE assessing aspects of addiction. Interviews were tape-recorded, verbatim-transcribed, and analyzed using a qualitative approach. The interviews showed that participants—the majority had current or lifetime diagnoses of misuse or addiction to alcohol or cannabis—reported an awareness of the risk of addiction development associated with stimulant use and reported various effects which may increase their likelihood of future stimulant use, for example, euphoric effects, increase of self-confidence, and motivation. They also cited measures to counteract the development of addiction as well as measures taken to normalize again after stimulant use. Students were convinced of having control over their stimulant use and of not becoming addicted to stimulants used for NE. We can conclude that behavior and beliefs of the students in our sample appear to be risky in terms of addiction development. However, long-term empirical research is needed to estimate the true risk of addiction

Pharmacological neuroenhancement and the ability to recover from stress – a representative cross-sectional survey among the German population

BACKGROUND: Pharmacological neuroenhancement (PNE) refers to the use of psychoactive substances without doctor’s prescription to enhance cognitive performance or to improve mood. Although some studies have reported that drugs for PNE are also being used to cope with stressful life situations, nothing is known about the relationship of PNE and resilience, i.e. the ability to recover from stress. This study aimed at investigating the relationship of PNE and resilience in the first representative population sample. METHODS: A cross-sectional survey in a representative sample of 1128 adults (age ≥ 18 yrs.) living in Germany was conducted. The use of PNE and related attitudes, perceptions and behaviours were assessed by structured interviews and self-report questionnaires. Stepwise logistic regression with backward elimination was conducted to identify potential risk factors for PNE use. RESULTS: Lifetime prevalence for the use of stimulating prescription drugs without medical indication was 4.3%, 10.2% for stimulating illicit drugs, 20.3% for mood modulating prescription drugs, and 23.4% for cannabis. Coping with stressful situations was more frequently reported as underlying motive for using stimulant or mood modulating prescription drugs than stimulating illicit drugs or cannabis. The individual perceived stress increased the risk of using stimulating prescription drugs (OR: 2.86; 95% Cl: 1.49–5.46) and the individual ability to recover from stress decreased the risk of using any substance for PNE and especially mood modulating prescription drugs (OR: .62; 95% Cl: .47–.81). CONCLUSIONS: The non-medical use of prescription drugs for PNE appears to be more prevalent in subjects who are less resilient to stress. Tailored resilience interventions that improve the ability to adapt to and recover from stressors may prevent the use of prescription medication for PNE. Further research should disentangle the association between psychological resilience and PNE as well as examine the efficacy of resilience interventions in the prevention of PNE

Neuro-COVID-19 is more than anosmia: clinical presentation, neurodiagnostics, therapies, and prognosis

Purpose of review To provide an overview on current knowledge of neurological symptoms and complications of COVID-19, and to suggest management concepts. Recent findings Headache, dizziness, excessive tiredness, myalgia, anosmia/hyposmia, and ageusia/dysgeusia are common nonspecific neurological manifestations during early COVID-19 disease found in the majority of patients. Less frequent but more severe and specific neurological manifestations include Guillain--Barre syndrome, encephalopathy, encephalitis/meningitis, epileptic seizures, and cerebrovascular events. Beyond standard neurological examination, these require a more extensive work-up, including cerebrospinal fluid assessment, neurophysiological evaluation, neuroimaging, and cognitive testing. Symptomatic treatment is advisable unless the neurological complication's immune pathogenesis is proven. Summary Neurological manifestations of COVID-19 occur during the acute, para-infectious, and 'recovery' phase. Therapeutic management depends on the clinical presentation and neurological work-up

Use of illicit and prescription drugs for cognitive or mood enhancement among surgeons

BACKGROUND: Surgeons are usually exposed to high workloads leading to fatigue and stress. This not only increases the likelihood of mistakes during surgery but also puts pressure on surgeons to use drugs to counteract fatigue, distress, concentration deficits, burnout or symptoms of depression. The prevalence of surgeons taking pharmacological cognitive enhancement (CE) or mood enhancement (ME) drugs has not been systematically assessed so far. METHODS: Surgeons who attended five international conferences in 2011 were surveyed with an anonymous self-report questionnaire (AQ) regarding the use of prescription or illicit drugs for CE and ME and factors associated with their use. The Randomized Response Technique (RRT) was used in addition. The RRT guarantees a high degree of anonymity and confidentiality when a person is asked about stigmatizing issues, such as drug abuse. RESULTS: A total of 3,306 questionnaires were distributed and 1,145 entered statistical analysis (response rate: 36.4%). According to the AQ, 8.9% of all surveyed surgeons confessed to having used a prescription or illicit drug exclusively for CE at least once during lifetime. As one would expect, the prevalence rate assessed by RRT was approximately 2.5-fold higher than that of the AQ (19.9%; 95% confidence interval (CI), 15.9% to 23.9%, N = 1,105). An even larger discrepancy between the RRT and AQ was observed for the use of antidepressants with a 6-fold higher prevalence (15.1%; 95% CI, 11.3% to 19.0%, N = 1,099) as compared to 2.4% with the AQ. Finally, logistic regression analysis revealed that pressure to perform at work (odds ratio (OR): 1.290; 95% CI, 1.000 to 1.666; P = 0.05) or in private life (OR: 1.266; 95% CI, 1.038 to 1.543; P = 0.02), and gross income (OR: 1.337; 95% CI, 1.091 to 1.640; P = 0.005), were positively associated with the use of drugs for CE or ME. CONCLUSIONS: The use of illicit and prescription drugs for CE or ME is an underestimated phenomenon among surgeons which is generally attributable to high workload, perceived workload, and private stress. Such intake of drugs is associated with attempts to counteract fatigue and loss of concentration. However, drug use for CE may lead to addiction and to overestimation of one's own capabilities, which can put patients at risk. Coping strategies should be taught during medical education