Remdesivir shifts circadian rhythmicity to eveningness; similar to the most prevalent chronotype in ADHD.

Circadian clocks control immunity and virus replication, as well as pharmacokinetics and efficacy therapeutics. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after remdesivir exposure. In the current study, we analysed circadian gene expression in a cohort of participants without a neuropsychiatric diagnosis. After ex vivo exposure to remdesivir to human dermal fibroblast (HDF) cultures and dexamethasone synchronization, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analysed via qRT-PCR. In this study, D-MEQ scores indicated that participants without a neuropsychiatric diagnosis had no evening preference. Remdesivir leads to a slight phase-shift in Clock, Per1 and Per2. Significant different expressions of Bmal1 and Per3 were detected after remdesivir exposure: Bmal1 at ZT8 (t(22) = 3.26, p = 0.004), ZT24 (t(22) = - 2.66, p = 0.015), ZT28 (t(20) = - 2.14, p = 0.045) and Per3 at ZT8 (t(22) = - 4.27, p < 0.001) and ZT12 (t(22) = - 2.61, p = 0.016). A significant difference between chronotype and circadian gene expression for Bmal1, Cry1 and Per3 was observed. The present study shows that remdesivir has an impact on circadian function. It is well known that the circadian rhythm effects sleep and, moreover, sleep quality. The results suggest that remdesivir medication may alter sleep quality in participants without a neuropsychiatric diagnosis and shifts chronotype to eveningness; similar as prevalent in ADHD.

The development of the Screening of Visual Complaints questionnaire for patients with neurodegenerative disorders: Evaluation of psychometric features in a community sample.

BACKGROUND AND OBJECTIVES: Patients with neurodegenerative disorders often experience impairments in visual function. In research and clinical care, visual problems are primarily understood as objective visual impairments. Subjective complaints, referring to complaints from a patient's perspective, receive less attention, while they are of utmost clinical importance to guide assessment and rehabilitation. A 21-item Screening of Visual Complaints questionnaire (SVC) was developed for the assessment of subjective visual complaints in patients with neurodegenerative disorders. This prospective study aims to evaluate the psychometric properties of the SVC in a large community sample. METHODS: A stratified convenience sample of 1,461 healthy Dutch participants (18-95 years) without severe self-reported neurological, ophthalmological or psychiatric conditions completed the SVC, Cerebral Visual Complaints questionnaire (CVC-q), National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), Behavior Rating Inventory of Executive Function-A (BRIEF-A), Questionnaire for Experiences of Attention Deficits (Fragebogen erlebter Defizite der Aufmerkzamkeit; FEDA), Depression Anxiety Stress Scale-21 (DASS-21) and the Structured Inventory for Malingered Symptomatology (SIMS) online. After two weeks, 66 participants completed the SVC again. We evaluated the factor structure, internal consistency, convergent and divergent validity, and test-retest reliability of the SVC. RESULTS: The sample was split in two subsamples to perform exploratory and confirmatory factor analyses. In the first subsample, the exploratory factor analysis extracted three factors from the SVC: diminished visual perception, altered visual perception and ocular discomfort. The confirmatory factor analysis showed this model to be valid in the second subsample. The SVC showed satisfactory convergent validity (NEI-VFQ-25: r = -0.71; CVC-q: r = 0.84) and divergent validity (SIMS: r = 0.26; BRIEF-A: r = 0.29; FEDA: r = 0.40; DASS-21: r = 0.34) and good internal consistency (Cronbach's alpha = 0.85) and test-retest reliability (ICC = 0.82). CONCLUSIONS: The SVC is a valid and reliable tool for the assessment of subjective visual complaints in a community sample and appears promising for clinical use in patients with neurodegenerative disorders.

Social competence in newly diagnosed pediatric brain tumor patients.

Brain tumors (BTs) are a common pediatric malignancy. Improved treatment has resulted in higher survival rates. There is, however, increasing concern about adverse effects of the disease and its treatment, including effects on social competence (i.e. effective social functioning in everyday life). The aim of this study is to examine multiple levels of social competence (i.e. social skills and social adjustment) in newly diagnosed pediatric BT patients. Thirty newly diagnosed BT patients aged 5-12 years were assessed shortly after diagnosis with a neuropsychological test battery focusing on social competence, including tests for IQ, social skills (i.e. social-affective and executive functioning) and social adjustment (rated by parents and teachers). Their performance was compared to 95 healthy controls who completed the same assessment. Patients and healthy controls were largely comparable with regard to demographic and environmental factors and did not differ on measures of IQ, social skills and social adjustment. Furthermore, age was found to have a positive significant effect on social skills independent of group. Shortly after diagnosis, pediatric BT patients did not perform different from healthy controls on IQ and measures of social skills and social adjustment. This is an encouraging finding. However, because of potentially neurotoxic adjuvant therapy and the ongoing development of social skills, longitudinal follow-up studies are needed to investigate long-term outcome regarding social competence in BT survivors.

Screening for Cognitive Impairment in Parkinson's Disease: Improving the Diagnostic Utility of the MoCA through Subtest Weighting.

BACKGROUND: Given the high prevalence of cognitive impairment in Parkinson's disease (PD), cognitive screening is important in clinical practice. The Montreal Cognitive Assessment (MoCA) is a frequently used screening test in PD to detect mild cognitive impairment (PD-MCI) and Parkinson's disease dementia (PD-D). However, the proportion in which the subtests are represented in the MoCA total score does not seem reasonable. We present the development and preliminary evaluation of an empirically based alternative scoring system of the MoCA which aims at increasing the overall diagnostic accuracy. METHODS: In study 1, the MoCA was administered to 40 patients with PD without cognitive impairment (PD-N), PD-MCI, or PD-D, as defined by a comprehensive neuropsychological test battery. The new MoCA scoring algorithm was developed by defining Areas under the Curve (AUC) for MoCA subtests in a Receiver Operating Characteristic (ROC) and by weighting the subtests according to their sensitivities and specificities. In study 2, an independent sample of 24 PD patients (PD-N, PD-MCI, or PD-D) was tested with the MoCA. In both studies, diagnostic accuracy of the original and the new scoring procedure was calculated. RESULTS: Diagnostic accuracy increased with the new MoCA scoring algorithm. In study 1, the sensitivity to detect cognitive impairment increased from 62.5% to 92%, while specificity decreased only slightly from 77.7% to 73%; in study 2, sensitivity increased from 68.8% to 81.3%, while specificity stayed stable at 75%. CONCLUSION: This pilot study demonstrates that the sensitivity of the MoCA can be enhanced substantially by an empirically based weighting procedure and that the proposed scoring algorithm may serve the MoCA's actual purpose as a screening tool in the detection of cognitive dysfunction in PD patients better than the original scoring of the MoCA. Further research with larger sample sizes is necessary to establish efficacy of the alternate scoring system.

Cognition and brain abnormalities on MRI in pituitary patients.

PURPOSE: The extent to which cognitive dysfunction is related to specific brain abnormalities in patients treated for pituitary macroadenoma is unclear. Therefore, we compared brain abnormalities seen on Magnetic Resonance Imaging (MRI) in patients treated for nonfunctioning pituitary macroadenoma (NFA) with or without impairments in cognitive functioning. METHODS: In this cross-sectional design, a cohort of 43 NFA patients was studied at the University Medical Center Groningen. White matter lesions (WMLs), cerebral atrophy, (silent) brain infarcts and abnormalities of the temporal lobes and hippocampi were assessed on pre-treatment and post-treatment MRI scans. Post-treatment cognitive examinations were performed using a verbal memory and executive functioning test. We compared our patient cohort with large reference populations representative of the Dutch population. RESULTS: One or more impairments on both cognitive tests were frequently observed in treated NFA patients. No treatment effects were found with regard to the comparison between patients with and without impairments in executive functioning. Interestingly, in patients with one or more impairments on verbal memory function, treatment with radiotherapy had been given more frequently (74% in the impaired group versus 40% in the unimpaired group, P=0.025). Patients with or without any brain abnormality on MRI did not differ in verbal memory or executive functioning. CONCLUSIONS: Brain abnormalities on MRI are not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning. Conversely, the absence of brain abnormalities on MRI does not exclude impairments in cognition.

The effects of nutritional polyunsaturated fatty acids on locomotor activity in spontaneously hypertensive rats.

The present study investigated the effects of nutritional omega-3 polyunsaturated fatty acids on locomotor activity in spontaneously hypertensive rats (SHRs), which are used as an animal model of attention-deficit/hyperactivity disorder (ADHD). For 6 weeks, two groups of randomly assigned SHRs received food either enriched with or deficient in omega-3 fatty acids (based on the American Institute of Nutrition-93 G/AIN93G). Using an open field, locomotor activity was subsequently assessed for 6 days. A marked difference in locomotor activity as assessed by the distance travelled in the open field was found between the two groups of rats. In comparison with rats fed with omega-3 fatty acid-enriched food, the animals on the omega-3 fatty acid-deficient diet showed a significantly higher locomotor activity. The present findings demonstrated that nutritional enrichment with omega-3 fatty acids was associated with reduced motor activity in an established animal model of ADHD and support the notion that omega-3 polyunsaturated fatty acids may play a role in the pathophysiology of ADHD.

Effects of previous growth hormone excess and current medical treatment for acromegaly on cognition.

BACKGROUND: In untreated acromegaly patients, decreased cognitive functioning is reported to be associated with the degree of growth hormone (GH) and IGF-1 excess. Whether previous GH excess or current medical treatment for acromegaly specifically affects cognition remains unclear. The aim of this study was to compare cognitive functioning of patients who are treated for acromegaly with patients with non-functioning pituitary adenomas (NFA). In addition, we assessed the influence of prolonged medical treatment after initial transsphenoidal surgery on cognition. DESIGN: In this cross-sectional study, 74 patients participated, who were treated for acromegaly (n = 50; median [interquartile range] age: 53 [45-65] years) or NFA (n = 24; age: 63 [59-70] years). The NFA patients were selected for a high likelihood of normal GH secretion based on an IGF-1 z-score within the normal range (> -2) and zero or one axis substituted. Of the acromegaly patients, 28 had achieved remission, while 22 were biochemically controlled with long-acting somatostatin analogues and/or pegvisomant. Memory and executive functioning were assessed by the 15 Words Test and the Ruff Figural Fluency Test, and reported as z-scores. RESULTS: The total patient group scored significantly poorer than the reference population on memory and executive functioning (P < 0·001). However, cognitive test performance was not significantly different between acromegaly patients with a persistent disease, acromegaly patients in remission and NFA patients. CONCLUSION: The total patient group scored worse compared with reference populations. We found no association between previous GH excess and cognition. In addition, current medical treatment for GH excess in acromegaly was not related to memory and executive functioning.

Cognitive performance after postoperative pituitary radiotherapy: a dosimetric study of the hippocampus and the prefrontal cortex.

OBJECTIVE: The hippocampus and prefrontal cortex (PFC) are important for memory and executive functioning and are known to be sensitive to radiotherapy (RT). Radiation dosimetry relates radiation exposure to specific brain areas. The effects of various pituitary RT techniques were studied by relating detailed dosimetry of the hippocampus and PFC to cognitive performance. METHODS: In this cross-sectional design, 75 non-functioning pituitary macroadenoma (NFA) patients (61±10 years) participated and were divided into irradiated (RT+, n=30) and non-irradiated (RT-, n=45) groups. The RT+ group (who all received 25 fractions of 1.8 Gy; total dose: 45 Gy) consisted of three RT technique groups: three-field technique, n=10; four-field technique, n=15; and five-field technique, n=5. Memory and executive functioning were assessed by standardized neuropsychological tests. A reconstruction of the dose distributions for the three RT techniques was made. The RT doses on 30, 50, and 70% of the volume of the left and right hippocampus and PFC were calculated. RESULTS: Cognitive test performance was not different between the four groups, despite differences in radiation doses applied to the hippocampi and PFC. Age at RT, time since RT, and the use of thyroid hormone varied significantly between the groups; however, they were not related to cognitive performance. CONCLUSION: This study showed that there were no significant differences on cognitive performance between the three-, four-, and five-field RT groups and the non-irradiated patient group. A dose-response relationship could not be established, even with a radiation dose that was higher on most of the volume of the hippocampus and PFC in case of a four-field RT technique compared with the three- and five-field RT techniques.

Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy.

CONTEXT AND OBJECTIVE: Cognitive deterioration is reported in patients with a nonfunctioning pituitary macroadenoma (NFA) and after pituitary radiotherapy. However, reported results are inconsistent and are potentially confounded by different underlying pituitary disorders. The aim of this study was to examine cognitive functions in patients previously treated for NFA with or without radiotherapy. DESIGN: Verbal memory was assessed with the Dutch equivalent to the Rey Auditory Verbal Learning Test (15 Words Test, 15 WT). Executive functioning was examined using the Ruff Figural Fluency Test (RFFT). We compared our patient cohort with large reference populations representative of the Dutch population. PATIENTS: Eighty-four patients (62±10 years) who underwent transsphenoidal surgery 8.6±6.3 years earlier participated. Patients who underwent radiotherapy (n=39) were compared to those who received surgery alone (n=45). All patients were on stable hormonal replacement therapy. RESULTS: The total patient group scored significantly below the reference sample on all 15 WT z-scores (95%CI): short-term memory, -0.3 (-0.5 to -0.1); total memory, -0.8 (-1.1 to -0.5); learning score, -0.3 (-0.5 to -0.1); delayed memory, -0.8 (-1.1 to -0.5), all P<0.01. The total patient group scored significantly below the reference sample on RFFT z-scores (95%CI): unique designs, -0.7 (-0.9 to -0.5) and perseverative errors, -0.5 (-0.8 to -0.2), both P<0.001. Patients who underwent radiotherapy showed no significant differences on cognition when compared to those who received surgery alone. CONCLUSION: Patients with NFA score significantly worse on cognition compared to reference populations. Radiotherapy does not appear to have a major influence on cognition.

Effects of nicotine chewing gum on a real-life motor task: a kinematic analysis of handwriting movements in smokers and non-smokers.

RATIONALE: In laboratory tasks nicotine has consistently been shown to improve psychomotor performance. OBJECTIVES: The aim of the present experiment was to assess the effects of nicotine on a skilled task of everyday life in smoking and non-smoking healthy adults. METHODS: Assessment of handwriting movements of 38 non-deprived smokers and 38 non-smokers was performed following the chewing of gum containing 0 mg, 2 mg or 4 mg of nicotine. A digitising tablet was used for the assessment of fine motor movements. Subjects were asked to perform a simple writing task. Movement time, velocity and acceleration of the handwriting movements were measured. Furthermore, every writing specimen was independently rated by two examiners regarding the quality of handwriting. RESULTS: Kinematic analysis of writing movements revealed that nicotine could produce absolute improvements in handwriting. Following nicotine administration, reduced movement times, increased velocities and more fluent handwriting movements were observed. These improvements were more striking in smokers than in non-smokers. No effects of nicotine were found with regard to the quality of handwriting. CONCLUSION: The results suggest that nicotine can enhance psychomotor performance to a significant degree in a real-life motor task.

Preoperative and postoperative cognitive functioning in patients with frontal meningiomas.

OBJECT: There is presently no specific information available concerning the nature and course of cognitive deficits caused by intracranial meningiomas. In this prospective study the authors examined the cognitive functioning of patients with frontal meningiomas. METHODS: Fifty-four patients with frontal meningiomas were examined neuropsychologically before and after neurosurgery. The test battery consisted of standardized instruments including those assessing memory, attention, visuoconstructive abilities, and executive functions. The time period between pre-and postoperative assessment ranged from 4 to 9 months. The patients' performance was compared with the results in 54 healthy adults who were also assessed twice by using the same test battery in a period ranging from 4 to 9 months. In addition, the effect on cognition of meningioma lateralization, localization, lesion size, edema, brain compression, time course, and the occurrence of preoperative seizures was analyzed. CONCLUSIONS: Except in the case of working memory, comparisons of pre- and postoperative assessments of cognition revealed no differences in memory, visuoconstructive abilities, or executive functions, although a postoperative improvement in attentional functions was observed. The results of this study indicate that the surgical removal of frontal meningiomas does not impair patients' cognitive functioning. Furthermore, improvements in attentional functions may occur in these patients.

Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury.

BACKGROUND: Patients with Parkinson disease characteristically exhibit an increased echogenicity of the substantia nigra (SN) on transcranial sonography, a new neuroimaging technique. The same echo feature of the SN can be identified in 9% of healthy adults. OBJECTIVE: To evaluate the relevance of the echogenic SN in healthy adults. DESIGN: In the first part of the study, 10 healthy subjects younger than 40 years with a distinct SN hyperechogenicity underwent extensive neurological, motor, neuropsychological, and fluorine 18-dopa positron emission tomographic ([18F]-dopa PET) examinations. Results were compared with those of 10 subjects with a low echogenic SN. In the second part of the study, the postmortem brains of 20 patients without extrapyramidal disorders during their lifetime were sonographically examined with a particular focus on SN echogenicity. Subsequently, one half of the brain was prepared for heavy metal analysis, the other for a histological examination. RESULTS: Healthy subjects with SN hyperechogenicity exhibited a significant reduction of the [18F]-dopa uptake, especially in the putamen (Wilcoxon matched pair test: left side, P =.006; right side, P =.009), whereas their neuropsychological and motor performance were normal. Postmortem studies showed that the echogenicity of the SN correlated with its iron content. CONCLUSIONS: Increased echogenicity of the SN, characteristically seen in Parkinson disease, is related to a functional impairment of the nigrostriatal system (even in young healthy adults) that can be revealed by [18F]-dopa PET studies. Substantia nigra hyperechogenicity is related to a higher tissue iron level, which is known to enhance the cells' generation of reactive oxygen specimens. Therefore, we hypothesize that transcranial sonography may identify a susceptibility marker for the development of nigral injury that can be detected early in life, prior to the onset of Parkinson disease.