No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies.

The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.

Psychosocial Well-Being of Siblings of Pediatric Patients in Palliative Home Care.

CONTEXT: Despite the proposed high burden of siblings of children and adolescents with life-limiting conditions receiving pediatric palliative care (PPC) at home, little is known about their psychosocial well-being. METHODS: In this prospective, cross-sectional trial siblings of patients of a large pediatric palliative home care team were asked to answer the KINDL survey of health-related quality of life, the strengths and difficulties questionnaire (SDQ) to assess problems and resources of children and adolescents as well as the LARES questionnaire, a potential tool for early screening of distress in siblings of chronically ill children. The results of the KINDL total and subdomains as well of the SDQ-subdomains were compared to recent German normative data using multiple t-tests. RESULTS: In total, 44 siblings (28 female; age 7-18 years, mean 11.8 ± 3.03) of 29 families participated in this study. The subgroup which matches the age range of current normative data of 11-17 years old siblings (n = 25) reported a significant lower total quality of life as measured by KINDL in comparison to normative data. Subscale analyses revealed a significant lower physical and psychological well-being and self-esteem. Siblings of PPC patients yielded significant higher scores in the subdomain prosocial behavior compared to normative data as measured by the SDQ. CONCLUSIONS: Siblings of children receiving PPC in a home care setting are at risk for a relevant impairment of their health-related quality of life. Future studies should address the potential for possible interventions specific for this population-at-risk.

Case report: Life threatening hyponatremia in infants with urinary tract infections: two cases of type III pseudohypoaldosteronism and review of the literature.

We describe two female infants at the age of five and six months with urinary tract infections presenting with vomiting and reduced drinking behavior. On laboratory analysis, severe hyponatremia (106 mmol/L and 109 mmol/L) was seen with hyperkalemia and compensated metabolic acidosis. Endocrinological analyses revealed massively increased levels of aldosterone and renin, leading to the diagnosis of type III pseudohypoaldosteronism (PHA). A review of the current literature 2013-2023 revealed 26 type III PHA cases aged up to ten months with reduced drinking behavior, weight loss and/or failure to thrive being the most common clinical presentations. Given the severe presentation of PHA electrolyte measurements in infants with urinary tract infections and/or in infants with congenital anomalies of the kidney and urinary tract (CAKUT) are strongly recommended.

Advance care planning and the parental geographical background in pediatric palliative home care: a retrospective chart review.

The relevance to acknowledge the parental migration history in pediatric palliative care is widely recognized. However, its influence on integral parts of advance care planning (ACP) is unknown. In this non-interventional cohort study, we aimed at identifying systematic differences between pediatric palliative patients with varying parental countries of origin regarding medical orders for life-sustaining treatment and the location of patients' death. Two hundred eighty-eight pediatric cases in an ambulant pediatric palliative care setting in Germany were retrospectively analyzed using multinomial logistic regression models. Agreements on medical orders for life-sustaining treatment (MOLST) differed significantly between patients with varying parental countries of origin. Full code orders for life-sustaining treatment were made more often in Turkish families than in German families. There were no significant associations between the patients' location of death and the parental countries of origin. However, confounder-analysis revealed a strong association between the patients' underlying disease and the orders for life-sustaining treatment as well as the location of death.Conclusions: Even this study indicates that the parental geographical background as an important sociocultural aspect might have an impact on ACP decisions for children and adolescents with life-limiting conditions, other factors as the patients' underlying disease can be more crucial for decision making in pediatric palliative care. The reason for the differences found might lay in cultural preferences or barriers to appropriate care. The inclusion of sociocultural aspects in decision-making is crucial to guarantee culture-sensitive, patient-centered pediatric palliative care.

Regional changes of brain structure during progression of idiopathic Parkinson's disease - A longitudinal study using deformation based morphometry.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder with a broad spectrum of motor and non-motor symptoms. The neuropathological characteristics of idiopathic PD are the degeneration of dopaminergic neurons in the striatum, and the propagation of aggregates of misfolded α-synuclein in the brain following a specific pattern (Braak et al., 2006). The relationship of this pattern with motor and cognitive symptoms is still equivocal. Therefore, we investigated longitudinally the spatio-temporal patterns of atrophy propagation in PD, their inter-individual variability and associations with clinical symptoms. Magnetic resonance (MR) images of 37 PD patients and 27 controls were acquired at up to 15 time-points per subject, and over observation periods of up to 8.8 years (mean: 3.7 years). MR images were analyzed by Deformation-based Morphometry to measure region volumes and their longitudinal changes. Differences of these regional volume data between patients and controls and their associations with clinical symptoms were calculated. At baseline, group differences in the regional volumes were found mainly in areas of the sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, and in the substantia nigra, among others. The longitudinal analysis yielded more widespread and more pronounced group differences, with significantly accelerated volume decreases in PD patients in the occipital and temporal lobes, the inferior parietal lobule, as well as in the insula, putamen and nucleus basalis Meynert. The white matter was less affected than the gray matter. Worse clinical scores (MMSE, PDQ-39, UPDRS-III) were in particular associated with volume decreases of cortical areas, amygdala and basal forebrain nuclei, but not of the basal ganglia. The observed longitudinal patterns of accelerated volume decrease in PD patients largely coincide with the pattern of α-synuclein pathology in PD stages 3-5 as proposed by Braak and colleagues. Thus, longitudinal DBM appears to depict already in-vivo the progression of neuropathological changes.

Brain volume patterns in corticobasal syndrome versus idiopathic Parkinson's disease.

BACKGROUND AND PURPOSE: Patients with a corticobasal syndrome (CBS) present a rare form of atypical parkinsonism characterized by asymmetric clinical symptoms and progressive motor and nonmotor impairment, such as apraxia, alien limb phenomenon, aphasia, myoclonus, dystonia, and cognitive impairment. At early stages, clinical differentiation between CBS and idiopathic Parkinson's disease (IPD) can be challenging. METHODS: Using high-resolution T1-weighted images and voxel-based morphometry (VBM), we sought to identify disease-specific patterns of brain atrophy in a small sample of CBS and IPD patients at early stages of disease. We acquired MR images of 17 patients diagnosed with CBS and compared them with MR images of 17 subjects affected by IPD. Images were preprocessed and analyzed using VBM. RESULTS: When compared to each other, the CBS and IPD patients of our cohort showed differences in regional gray and white matter volume depending on the diagnosis, specifically in the superior longitudinal fascicle. CONCLUSIONS: In our small patients' group, VBM was able to detect changes in regional gray and white matter volume between patients affected by CBS and patients with IPD as early as 1.5-2 years after the onset of the first motor symptoms.

High rate of clinically unrecognized SARS-CoV-2 infections in pediatric palliative care patients.

Little is known about the frequency and clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in pediatric patients with severe comorbidities. In this prospective cross-sectional trial, the seroprevalence of SARS-CoV-2-IgG in patients with life-limiting conditions being treated by a large specialized pediatric palliative home-care team was determined. In order to gain insight into the infection chain, close contacts of seropositive patients were also included in the study. We analyzed the sera of 39 patients and found a 25.6% seroprevalence for SARS-CoV-2. No SARS-CoV-2 infections were known prior to the study. No significant difference was found in the symptom load between seropositive and seronegative patients during the risk period for SARS-CoV-2 infections. Of the 20 close contacts tested, only one was seropositive for SARS-CoV-2.Conclusions: Our results indicate a substantially high prevalence of silent SARS-CoV-2 infections in pediatric palliative care patients. Surprisingly, no severe outcomes were seen in this fragile patient collective with severe comorbidities. The chain of infection and thus the reason for the high frequency of SARS-CoV-2 infections in pediatric palliative care patients remain unclear. What is Known: •Even though severe disease courses of COVID-19 have been reported in children, there are yet no established risk factors for SARS-CoV-2 in pediatric patients. What is New: •In this cross-sectional seroprevalence study of palliative pediatric patients with severe life-limiting conditions, a high rate of seropositive patients (25.6%) was found. •Surprisingly, all seropositive patients were previously unrecognized, despite the severe comorbidities of our collective.

The Effect of Transcranial Random Noise Stimulation on Cognitive Training Outcome in Healthy Aging.

Background and Objective: Aging is associated with a decline in attentional and executive abilities, which are linked to physiological, structural, and functional brain changes. A variety of novel non-invasive brain stimulation methods have been probed in terms of their neuroenhancement efficacy in the last decade; one that holds significant promise is transcranial random noise stimulation (tRNS) that delivers an alternate current at random amplitude and frequency. The aim of this study was to investigate whether repeated sessions of tRNS applied as an add-on to cognitive training (CT) may induce long-term near and far transfer cognitive improvements. Methods: In this sham-controlled, randomized, double-blinded study forty-two older adults (age range 60-86 years) were randomly assigned to one of three intervention groups that received 20 min of 0.705 mA tRNS (N = 14), 1 mA tRNS (N = 14), or sham tRNS (N = 19) combined with 30 min of CT of executive functions (cognitive flexibility, inhibitory control, working memory). tRNS was applied bilaterally over the dorsolateral prefrontal cortices for five sessions. The primary outcome (non-verbal logical reasoning) and other cognitive functions (attention, memory, executive functions) were assessed before and after the intervention and at a 1-month follow-up. Results: Non-verbal logical reasoning, inhibitory control and reaction time improved significantly over time, but stimulation did not differentially affect this improvement. These changes occurred during CT, while no further improvement was observed during follow-up. Performance change in logical reasoning was significantly correlated with age in the group receiving 1 mA tRNS, indicating that older participants profited more from tRNS than younger participants. Performance change in non-verbal working memory was significantly correlated with age in the group receiving sham tRNS, indicating that in contrast to active tRNS, older participants in the sham group declined more than younger participants. Interpretation: CT induced cognitive improvements in all treatment groups, but tRNS did not modulate most of these cognitive improvements. However, the effect of tRNS depended on age in some cognitive functions. We discuss possible explanations leading to this result that can help to improve the design of future neuroenhancement studies in older populations.

Investigating the 1-year decline in midbrain-to-pons ratio in the differential diagnosis of PSP and IPD.

BACKGROUND: A reliable measure of PSP-specific midbrain atrophy, the midbrain-to-pons ratio (MTPR) has been reported to support the differential diagnosis of progressive supranuclear palsy (PSP) from idiopathic Parkinson's disease (IPD). Since longitudinal analyses are lacking so far, the present study aimed to evaluate the diagnostic value of the relative change of MTPR (relΔt_MTPR) over a 1-year period in patients with PSP, IPD, and healthy controls (HC). METHODS: Midsagittal individual MRIs of patients with PSP (n = 15), IPD (n = 15), and healthy controls (HC; n = 15) were assessed and the MTPR at baseline and after 1 year were defined. The diagnostic accuracy of the MTPR and its relative change were evaluated using ROC curve analyses. RESULTS: PSP-patients had a significantly lower MTPR at baseline (M = 0.45 ± 0.06), compared to both non-PSP groups (F (2, 41) = 62.82, p < 0.001), with an overall predictive accuracy of 95.6% for an MTPR ≤ 0.54. PSP-patients also presented a significantly stronger 1-year decline in MTPR compared to IPD (p < 0.001). Though predictive accuracy of relΔt_MTPR for PSP (M = - 4.74% ± 4.48) from IPD (M = + 1.29 ± 3.77) was good (76.6%), ROC analysis did not reveal a significant improvement of diagnostic accuracy by combining the MTPR and relΔt_MTPR (p = 0.670). Still, specificity for PSP increased, though not significantly (p = 0.500). CONCLUSION: The present results indicate that the relΔt_MTPR is a potentially useful tool to support the differential diagnosis of PSP from IPD. For its relative 1-year change, still, more evaluation is needed.

Acquired undescended testis: When does the ascent occur?

BACKGROUND: Little is known about the timeframe in which acquired undescended testes occur. To guide recommendations for screening examinations, we aimed to (1) specify the ratio of acquired undescended testes in orchiopexy cases and to (2) identify a predisposing age for the development of acquired undescended testis. METHODS: Three-hundred-forty cases of orchiopexy were retrospectively analyzed and classified as congenital or acquired cases of undescended testis. In acquired cases, the time of the last documented physiological testicular position was obtained. The time of testicular ascent was approximated by calculating the mean between the last physiological finding and orchiopexy. RESULTS: In 151 cases (44.4%) prior physiological position of testes was documented and acquired undescended testis was assumed. In 115 of these cases (76.2%) details on the age at last physiological position were available. Ascent occurred between the age of one and fourteen. The 50th, 75th, 85th, 90th and 95th percentile for the estimated age at ascent was 5.8, 7.3, 8.4, 8.7 and 11.1 years, respectively. CONCLUSIONS: Acquired undescended testes are a common cause of cryptorchidism. Ascent occurs throughout all prepubertal ages, emphasizing the need to regular follow-up of testicular position until puberty. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level II.

Somatosensory area 3b is selectively unaffected in corticobasal syndrome: combining MRI and histology.

An increasing number of neuroimaging studies addressing patients with corticobasal syndrome use macroscopic definitions of brain regions. As a closer link to functionally relevant units, we aimed at identifying magnetic resonance-based atrophy patterns in regions defined by probability maps of cortical microstructure. For this purpose, three analyses were conducted: (1) Whole-brain cortical thickness was compared between 36 patients with corticobasal syndrome and 24 controls. A pattern of pericentral atrophy was found, covering primary motor area 4, premotor area 6, and primary somatosensory areas 1, 2, and 3a. Within the central region, only area 3b was without atrophy. (2) In 18 patients, longitudinal measures with follow-ups of up to 59 months (mean 21.3 ± 15.4) were analyzed. Areas 1, 2, and 6 showed significantly faster atrophy rates than primary somatosensory area 3b. (3) In an individual autopsy case, longitudinal in vivo morphometry and postmortem pathohistology were conducted. The rate of magnetic resonance-based atrophy was significantly correlated with tufted-astrocyte load in those cytoarchitectonically defined regions also seen in the group study, with area 3b being selectively unaffected.

How to improve patient education on deep brain stimulation in Parkinson's disease: the CARE Monitor study.

BACKGROUND: The introduction of deep brain stimulation (DBS) about 25 years ago provided one of the major breakthroughs in the treatment of Parkinson's disease (PD). However, a high percentage of patients are reluctant to undergo DBS. Previous research revealed that the critical step on the patient's path to DBS is the decision whether to undergo further diagnostic assessment for surgery at a specialized DBS-center. The aims of the current study were to evaluate how effective the combination of an outpatient DBS screening tool, STIMULUS, with specially developed educational material was to enhance patient education on DBS and to identify motivational aspects which influenced the patients' willingness to undergo further assessment. METHODS: In total, 264 patients were identified as appropriate candidates for DBS by general neurologists using the electronic preselection tool STIMULUS. Patient-centered information material was designed and handed out to support education on DBS. Further, several clinical characteristics and details of the patient counseling were documented. Refusal or consent to show up at a DBS center was registered over the following 16 months. RESULTS: 114 (43.2%) patients preselected as eligible for DBS (STIMULUS Score ≥ 6) agreed to show up at a specialized DBS center to undergo further diagnostic assessment. The patients' ages, PD classification as an akinetic-rigid type and the talks' topics side-effects of dopaminergic medication and the optimal time frame had a significant influence on the patients' decisions. CONCLUSIONS: The combination of preselection tools as STIMULUS with comprehensive information material is effective to increase DBS-acceptance rate in PD patients. Important topics of the information about DBS cover the optimal time frame for DBS surgery, the side-effects of dopaminergic medication as well as side-effects and complications of DBS surgery.

Non-invasive brain stimulation in Parkinson's disease: Exploiting crossroads of cognition and mood.

Cognitive impairments and depression are common non-motor manifestations in Parkinson's disease (PD). Recent evidence suggests that both partially arise via the same frontostriatal network, opening the opportunity for concomitant treatment with non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). In this systematic review, we evaluate the effects of NIBS on cognition and/or mood in 19 placebo-controlled studies involving 561 PD patients. Outcomes depended on the area stimulated and the technique used. rTMS over the dorsolateral-prefrontal cortex (DLPFC) resulted in significant reductions in scores of depressive symptoms with moderate to large effect sizes along with increased performance in several tests of cognitive functions. tDCS over the DLPFC improved performance in several cognitive measures, including executive functions with large effect sizes. Additional effects of tDCS on mood were not detectable; however, only non-depressed patients were assessed. Further confirmatory research is needed to clarify the contribution that NIBS could make in the care of PD patients.

FP-CIT- and IBZM-SPECT in Corticobasal Syndrome: Results from a Clinical Follow-Up Study.

OBJECTIVE: To evaluate the striatal presynaptic dopamine transporter (FP-CIT-SPECT) and postsynaptic D2 receptor (IBZM-SPECT) binding in patients with corticobasal syndrome (CBS). BACKGROUND: FP-CIT and IBZM are commercially available and approved SPECT tracers for in vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration, but only few data for CBS are available. METHODS: 23 patients meeting clinical criteria for early- to mid-stage CBS (disease duration ≤4 years) were examined with SPECT radiotracers FP-CIT and IBZM. All suspected CBS patients underwent a clinical follow-up examination and were re-evaluated after 19.7 ± 15.2 months (mean ± SD). Postmortem diagnosis was available for 2 patients. In patients who met research criteria for probable CBS at the final follow-up visit (n = 19; disease duration: 1.95 ± 0.91 years), SPECT binding values were compared to those of age- and gender-matched Parkinson's disease (PD) patients (n = 18, disease duration: 1.92 ± 0.91 years; clinical follow-up: 32 ± 29.6 months) and neurologically normal control subjects (n = 19). RESULTS: In comparison to the healthy control subjects, both patient groups showed significant and asymmetric reduction of the striatal presynaptic dopamine transporter binding, but PD patients had significantly lower FP-CIT binding ratios than probable-CBS patients. FP-CIT binding values of probable-CBS patients and healthy controls demonstrated marked overlaps, and in 7 patients (39%) scans revealed no dopaminergic deficit. IBZM uptake did not show significant between-group differences. CONCLUSION: Our data indicate that in the early- to mid-stage CBS the degree of nigrostriatal impairment is only mild with a significant proportion of preserved dopamine transporter binding.

Beta Band Transcranial Alternating (tACS) and Direct Current Stimulation (tDCS) Applied After Initial Learning Facilitate Retrieval of a Motor Sequence.

The primary motor cortex (M1) contributes to the acquisition and early consolidation of a motor sequence. Although the relevance of M1 excitability for motor learning has been supported, the significance of M1 oscillations remains an open issue. This study aims at investigating to what extent retrieval of a newly learned motor sequence can be differentially affected by motor-cortical transcranial alternating (tACS) and direct current stimulation (tDCS). Alpha (10 Hz), beta (20 Hz) or sham tACS was applied in 36 right-handers. Anodal or cathodal tDCS was applied in 30 right-handers. Participants learned an eight-digit serial reaction time task (SRTT; sequential vs. random) with the right hand. Stimulation was applied to the left M1 after SRTT acquisition at rest for 10 min. Reaction times were analyzed at baseline, end of acquisition, retrieval immediately after stimulation and reacquisition after eight further sequence repetitions. Reaction times during retrieval were significantly faster following 20 Hz tACS as compared to 10 Hz and sham tACS indicating a facilitation of early consolidation. tDCS yielded faster reaction times, too, independent of polarity. No significant differences between 20 Hz tACS and tDCS effects on retrieval were found suggesting that 20 Hz effects might be associated with altered motor-cortical excitability. Based on the behavioral modulation yielded by tACS and tDCS one might speculate that altered motor-cortical beta oscillations support early motor consolidation possibly associated with neuroplastic reorganization.

Cognitive outcome of pallidal deep brain stimulation for primary cervical dystonia: One year follow up results of a prospective multicenter trial.

BACKGROUND: Pallidal deep brain stimulation (DBS) is effective in alleviating motor symptoms of medication refractory cervical dystonia, but little is known about effects on cognitive functions. METHODS: As part of the first randomized, sham-controlled multicenter trial on DBS in medication-refractory primary cervical dystonia (ClinicalTrials.gov, number NCT00148889), a subgroup of 13 patients aged 39 to 69 underwent prospective neuropsychological long-term follow-up assessments. Various cognitive domains (memory, executive functions, attention, visual perception, mental arithmetic and verbal intelligence) were examined before and after 12 months of continuous DBS. RESULTS: Only the number of produced words in a verbal fluency task which included alternating categories decreased after stimulation (p = 0.020). All other cognitive domains remained unchanged. CONCLUSIONS: These findings indicate that long-term pallidal DBS for the treatment of primary cervical dystonia seems to be safe regarding global cognitive functioning.

Cervical dystonia caused by focal putaminal ischemia.

We describe a 48-year-old woman with putaminal gliosis and a sphenoid wing meningioma at the left, who developed dystonia restricted to cervical regions. We propose the following causal chain: the meningioma led to an occlusion of a lenticulo-striatal branch of the middle cerebral artery that caused ventral putaminal ischemia and finally resulting in symptomatic dystonia. The previously reported relevance of the infarcted regions to the pathophysiology of dystonia supports this assumption. Implications for the diagnostic procedure of dystonia will be discussed.