Theory of mind deficits in Parkinson’s disease are not modulated by dopaminergic medication

IntroductionPatients with Parkinson’s disease (PD) exhibit deficits in social cognition, particularly with respect to Theory of Mind (ToM) capacities. It is unclear whether they are associated with PD-related dopamine deficiency and modulated by levodopa replacement therapy.MethodsA total of 15 persons with PD and 13 healthy controls (HC) participated in the study. They performed different neuropsychological tasks, including the Faux Pas Recognition Test (FPRT), assessing different dimensions of cognitive ToM (e.g., detection, inappropriateness, intentions), and the Reading the Mind in the Eyes Test (RMET) as an index of affective ToM. Persons with PD were tested twice, once under their regular treatment and another time after at least 18 h of levodopa withdrawal (MED-ON and MED-OFF, respectively). On either occasion, serum drug levels and motor symptom severity [Unified Parkinson’s Disease Rating Scale (UPDRS)] were measured.ResultsMED-ON and MED-OFF conditions in patients with PD were confirmed by higher serum drug levels in the former than in the latter state and a corresponding amelioration of the motor deficit. In so doing, no performance difference in any ToM-related task was identified as a function of the levodopa therapy. Generally, patients performed worse than controls in both affective and cognitive ToM tests.ConclusionPatients with PD have deficits in cognitive and affective ToM. Dopamine replacement, effective for improving the motor condition, does not appear to counteract these dysfunctions

Early recurrent ischemic lesions in patients with cryptogenic stroke and patent foramen ovale: an observational study

Background: Randomized controlled trials indicate that patent foramen ovate (PFO) closure reduces risk of stroke recurrence in patients with cryptogenic stroke and PFO. However, the optimal time point for PFO closure is unknown and depends on the risk of stroke recurrence. Objective: We aimed to investigate risk of early new ischemic lesions on cerebral magnetic resonance imaging (MRI) in cryptogenic stroke patients with and without PFO. Methods: Cryptogenic stroke patients underwent serial MRI examinations within 1 week after symptom onset to detect early new ischemic lesions. Diffusion-weighted imaging (DWI) lesions were delineated, co-registered, and analyzed visually for new hyperintensities by raters blinded to clinical details. A PFO was classified as stroke-related in patients with PFO and a Risk of Paradoxical Embolism (RoPE) score >5 points. Results: Out of 80 cryptogenic stroke patients, risk of early recurrent DWI lesions was not significantly different in cryptogenic stroke patients with and without PFO. Similar results were observed in patients <= 60 years of age. Patients with a stroke-related PFO even had a significantly lower risk of early recurrent ischemic lesions compared to all other patients with cryptogenic stroke (unadjusted odds ratio 0.23 [95% confidence interval 0.06-0.87], P = 0.030). Conclusion: Our data argue against a high risk of early stroke recurrence in patients with cryptogenic stroke and PFO

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol:Deep Phenotyping of an International Genetic Cohort

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions.Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data.Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants.Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &amp;Yahr, and Schwab &amp; England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021).Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivityClinical Trial Registration:ClinicalTrials.gov, NCT04214509

Neurale Substrate der Verarbeitung sozialer und selbst-referentieller Stimuli bei Manie in der fMRT

Introduction: Patients with mania show alterations of social behaviour, characterized by excessive involvement in pleasurable social activities and inappropriate social communication and interaction. These deficits in social competence may be caused by underlying impairments in social cognitive functions. Manic patients also exhibit feeling of grandiosity, that hint at an impaired processing of self-referential stimuli. Based on clinical observations and previous behavioural findings of social deficits in mania, we studied the neural substrates of (1) impaired social cognition and (2) self- referential processsing for the first time in patients with mania in their acute phase. We focused on areas such as the medial prefrontal cortex and the temporo-parietal junction, which are involved in social cognition in healthy subjects, and the cortical midline structures, especially the medial prefrontal cortex, which is implicated in self-referential processing. Methods: In the first paradigm the neuronal response to standardized pictures with social and non-social content was compared in 14 patients with bipolar 1 disorder in mania to healthy controls using BOLD-fMRI as a surrogate marker of neuronal activity. In the second paradigm we investigated the self-referential processing in the same design, by asking the patients to indicate, whether the presented pictures personally related to them or not. In the group analysis the results of both experiments were contrasted with those of 14 matched healthy volunteers. Results: The study (1) found in the group contrast diminished response in patients with mania in the dorsomedial prefrontal cortex and increased response in the temporo-parietal junction in response to social stimuli. The response in the temporo-parietal junction correlated positively with the score of delusional ideation. The study (2) found decreased activation to self-referential stimuli in mania in ventromedial prefrontal cortex and increased response in precuneus/posterior cingulate cortex. Discussion: The finding of decreased activation to social stimuli in patients with mania in the dorsomedial prefrontal cortex may be related to deficits in making cognitive inferences about others’ mental states. The finding of increased activation of the temporo-parietal junction in manic patients is likely related to exaggerated attribution of meaning to social stimuli. The pattern of increased activation in precuneus/posterior cingulate cortex and decreased activation in ventromedial prefrontal cortex to self- referential stimuli in mania may reflect the clinical presentation of increased focus on external content, resulting in increased distractibility and flight of ideas in mania.Hintergrund: Patienten mit Manie zeigen Veränderungen des sozialen Verhaltens, die durch übermäßige Einbindung in angenehme soziale Aktivitäten und unangemessene soziale Kommunikation und Interaktion geprägt sind. Diese Beeinträchtigungen der sozialen Kompetenz gründen in Störungen der sozialen kognitiven Funktionen. Ebenso kann das Gefühl der Grandiosität bei Patienten mit Manie als Hinweis auf eine gestörte Verarbeitung von selbst-referenziellen Stimuli verstanden werden. Basierend auf klinischen Beobachtungen und früheren Verhaltensstudien zu sozialen Defiziten bei Manie adressiert die vorliegende Arbeit das mögliche neuronale Substrat (1) gestörter sozialer Kognition und (2) selbst-referenzieller Verarbeitung erstmals bei Patienten mit Manie in ihrer manischen Phase. Dabei wird ein Schwerpunkt auf die Untersuchung von Arealen gelegt, die wie der mediale präfrontale Kortex und temporo-parietaler Übergang ausgehend von bildgebenden Untersuchungen bei Gesunden in sozialer Kognition beteiligt sind, während kortikale Mittellinienstrukturen - hier insbesondere der mediale präfrontale Kortex - bei selbst-referenzieller Verarbeitung eine Rolle zu spielen scheinen. Methoden: Bei 14 Patienten mit einer bipolaren 1 Erkrankung wurde im ersten Paradigma zur sozialen Kognition die neuronale Antwort auf standardisierte Bilder mit sozialen und nicht- sozialen Inhalt mittels BOLD-fMRI als Surrogatparameter neuronaler Aktivität in einem ereigniskorrelierten Design verglichen. In einem zweiten Paradigma untersuchten wir selbst-referenzielle Verarbeitung im gleichen Design, indem die Patienten angaben, ob die präsentierten Bilder für sie einen persönlichen Bezug hatten oder nicht. In einer Gruppenanalyse wurden die Ergebnisse beider Untersuchungen dann mit denen von 14 gleichaltrigen Gesunden kontrastiert. Ergebnisse: In Studie (1) zeigte sich im Gruppenkontrast eine verminderte Aktivierung bei Patienten mit Manie im dorsomedialen präfrontalen Kortex und eine erhöhte Aktivität im temporo-parietalen Übergang in Antwort auf soziale Stimuli. Die Aktivierung im temporo-parietalen Übergang korrelierte dabei positiv mit den skalierten wahnhaften Vorstellungen. Studie (2) ergab eine verminderte Aktivierung in Antwort auf selbst-referenzielle Stimuli bei den manischen Patienten im ventromedialen präfrontalen Kortex, während sie im Precuneus / posterioren cingulären Cortex vermehrt aktivierten. Diskussion: Die verminderte Aktivierung auf soziale Stimuli im dorsomedialen präfrontalen Kortex bei Patienten mit Manie kann zu Defiziten bei Rückschlüssen auf mentale Zustände anderer in Beziehung gesetzt werden. Die vermehrte Aktivierung des temporo-parietalen Übergangs bei manischen Patienten spiegelt wahrscheinlich eine übertriebene Bedeutungsattribution zu den sozialen Stimuli wider. Ebenso kann das Muster der erhöhten Aktivierung in Precuneus / posterioren cingulären Cortex und die verminderte Aktivierung im ventromedialen präfrontalen Kortex auf selbst-referenzielle Stimuli den verstärkten Fokus auf externe Inhalte reflektieren, was klinisch mit einer erhöhten Ablenkbarkeit und Ideenflucht korreliert

Early New Ischemic Lesions Located Outside the Initially Affected Vascular Territory Appear More Often in Stroke Patients with Elevated Glycated Hemoglobin (HbA1c)

Background: Early new ischemic lesions are common in patients with an acute ischemic stroke. These new ischemic lesions may represent the natural course of the initial stroke or de novo events. Objective: We hypothesized that early new ischemic lesions located outside the initially affected vascular territory would point at de novo events. Therefore, we differentiated new ischemic lesions located outside the initially affected vascular territory from those occurring only inside the initially affected vascular territory to identify risk factors that are associated with de novo events. Methods: Stroke patients underwent three magnetic resonance imaging examinations (at 3-T): on admission, on the next day and 4–7 days after symptom onset (clinicaltrials.gov: NCT00715533). Diffusion-weighted imaging (DWI) lesions were delineated, coregistered, and then analyzed for new hyperintensities on follow-up examinations by raters blinded to clinical details. Patients were classified as having “new distant lesions” if new DWI lesions appeared outside or both outside and inside the initially affected vascular territory or “new local lesions” if they were only inside. Results: 115 patients with early new DWI lesions constitute the study population. Sixteen patients (14%) had new distant lesions and 99 patients (86%) had new local lesions. In comparison between patients with new distant and new local lesions, patients with new distant lesions had significantly more often elevated glycated hemoglobin (HbA1c ≥ 6.5%; p = 0.022). Conclusion: Our data indicate that patients with elevated HbA1c have an increased risk for new, de novo ischemic lesions in the acute phase after an ischemic stroke

Early New Ischemic Lesions Located Outside the Initially Affected Vascular Territory Appear More Often in Stroke Patients with Elevated Glycated Hemoglobin (HbA1c)

BackgroundEarly new ischemic lesions are common in patients with an acute ischemic stroke. These new ischemic lesions may represent the natural course of the initial stroke or de novo events.ObjectiveWe hypothesized that early new ischemic lesions located outside the initially affected vascular territory would point at de novo events. Therefore, we differentiated new ischemic lesions located outside the initially affected vascular territory from those occurring only inside the initially affected vascular territory to identify risk factors that are associated with de novo events.MethodsStroke patients underwent three magnetic resonance imaging examinations (at 3-T): on admission, on the next day and 4–7 days after symptom onset (clinicaltrials.gov: NCT00715533). Diffusion-weighted imaging (DWI) lesions were delineated, coregistered, and then analyzed for new hyperintensities on follow-up examinations by raters blinded to clinical details. Patients were classified as having “new distant lesions” if new DWI lesions appeared outside or both outside and inside the initially affected vascular territory or “new local lesions” if they were only inside.Results115 patients with early new DWI lesions constitute the study population. Sixteen patients (14%) had new distant lesions and 99 patients (86%) had new local lesions. In comparison between patients with new distant and new local lesions, patients with new distant lesions had significantly more often elevated glycated hemoglobin (HbA1c ≥ 6.5%; p = 0.022).ConclusionOur data indicate that patients with elevated HbA1c have an increased risk for new, de novo ischemic lesions in the acute phase after an ischemic stroke

Validity and Prognostic Value of a Polygenic Risk Score for Parkinson’s Disease

Idiopathic Parkinson’s disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the risk for a disease like PD in a single quantity. However, reassessment of the performance of a given PRS in independent data sets is a precondition for establishing the PRS as a valid tool to this end. We studied a previously proposed PRS for PD in a separate genetic data set, comprising 1914 PD cases and 4464 controls, and were able to replicate its ability to differentiate between cases and controls. We also assessed theoretically the prognostic value of the PD-PRS, i.e., its ability to predict the development of PD in later life for healthy individuals. As it turned out, the PD-PRS alone can be expected to perform poorly in this regard. Therefore, we conclude that the PD-PRS could serve as an important research tool, but that meaningful PRS-based prognosis of PD at an individual level is not feasible