ABSTRACT
Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (â¼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that â¼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.
Subject(s)
Genetic Testing , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Parkinson Disease , Humans , Parkinson Disease/genetics , Male , Female , Middle Aged , Aged , Genetic Testing/methods , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Glucosylceramidase/genetics , alpha-Synuclein/genetics , Genetic Predisposition to Disease , Ubiquitin-Protein Ligases/genetics , Cohort Studies , Protein Kinases/genetics , Mutation , AdultSubject(s)
Antiparkinson Agents , Levodopa , Parkinsonian Disorders , Humans , Levodopa/therapeutic use , Levodopa/administration & dosage , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/genetics , Antiparkinson Agents/therapeutic use , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/pharmacology , Male , Female , Middle AgedABSTRACT
Introduction: Patients 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. Methods: A 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. Results: MED-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. Conclusion: Patients with PD have deficits in cognitive and affective ToM. Dopamine replacement, effective for improving the motor condition, does not appear to counteract these dysfunctions.
ABSTRACT
Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.
ABSTRACT
Depressive symptoms in Parkinson's disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit. However, at least a subset of PD patients may exhibit an unspecific depressive reaction to chronic illness. Here, we compared the prevalence and severity of depressive symptoms in PD patients and disease controls (DC). PD patients reported depressive symptoms at similar frequencies as DC but were on antidepressants, especially Mirtazapine, more frequently. Still, in both groups, a high proportion of patients with clinically significant depressive symptoms was not receiving medication. Diagnosis and treatment of depressive symptoms both in PD and DC should be improved.
ABSTRACT
Glucosylceramidase beta 1 (GBA1) variants have attracted enormous attention as the most promising and important genetic candidates for precision medicine in Parkinson's disease (PD). A substantial correlation between GBA1 genotypes and PD phenotypes could inform the prediction of disease progression and promote the development of a preventive intervention for individuals at a higher risk of a worse disease prognosis. Moreover, the GBA1-regulated pathway provides new perspectives on the pathogenesis of PD, such as dysregulated sphingolipid metabolism, impaired protein quality control, and disrupted endoplasmic reticulum-Golgi trafficking. These perspectives have led to the development of novel disease-modifying therapies for PD targeting the GBA1-regulated pathway by repositioning treatment strategies for Gaucher's disease. This review summarizes the current hypotheses on a mechanistic link between GBA1 variants and PD and possible therapeutic options for modulating GBA1-regulated pathways in PD patients.
ABSTRACT
Patients with Parkinson's disease (PD) carrying variants in the Glucocerebrosidase (GBA) gene (GBA-PD) suffer from orthostatic symptoms more frequently than idiopathic PD patients (IPD). Systematic measurements of the blood pressure have not yet been performed. In the present study, a prospective analysis of 33 GBA-PD and 313 IPD patients was carried out. Systolic blood pressure upon changing from the supine to the upright position dropped more strongly in GBA-PD compared to IPD patients. Diastolic blood pressure and heart rate did not differ between groups. This study provides further evidence for a pronounced involvement of the autonomic nervous system in GBA-PD.
Subject(s)
Hypotension, Orthostatic , Parkinson Disease , Autonomic Nervous System , Blood Pressure , Glucosylceramidase/genetics , Humans , Hypotension, Orthostatic/etiology , Mutation , Parkinson Disease/complications , Parkinson Disease/diagnosis , Parkinson Disease/geneticsABSTRACT
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.
Subject(s)
Genetic Predisposition to Disease/genetics , Multifactorial Inheritance/genetics , Parkinson Disease/genetics , Parkinson Disease/pathology , Aged , Female , Genome-Wide Association Study/methods , Humans , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide/genetics , Prognosis , Risk FactorsABSTRACT
Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.
ABSTRACT
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 &Yahr, and Schwab & 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 expressivity Clinical Trial Registration:ClinicalTrials.gov, NCT04214509.
ABSTRACT
BACKGROUND: Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants. METHODS: Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing. RESULTS: Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers. CONCLUSIONS: The ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Subject(s)
Parkinson Disease , Cohort Studies , Glucosylceramidase/genetics , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Mutation , Observational Studies as Topic , Parkinson Disease/diagnosis , Parkinson Disease/epidemiology , Parkinson Disease/geneticsABSTRACT
Background: Randomized controlled trials indicate that patent foramen ovale (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.
ABSTRACT
Aims: Therapeutic oral anticoagulation on hospital admission reduces morbidity and mortality after acute ischaemic stroke in patients with atrial fibrillation (AF). The underlying mechanism is not fully understood. In order to assess the impact of INR-level on admission on stroke volume, lesion pattern and the frequency of intracranial arterial occlusion, we analysed serial MRI measurements in AF patients suffering acute ischaemic stroke. Methods and results: This subgroup analysis of the prospective '1000Plus' study included patients with acute ischaemic stroke and known AF or a first episode of AF in hospital. All patients underwent serial brain magnetic resonance imaging. Stroke patients were categorized as follows: Group1, phenprocoumon intake, international normalized ratio (INR) ≥1.7 on admission, no thrombolysis; Group2, INR < 1.7 on admission, thrombolysis; and Group3, INR < 1.7, no thrombolysis. In 98 AF patients {77 ± 9 years, 60% male; median National Institute of Health Stroke Scale [NIHSS] score on admission 5 (interquartile range [IQR] 2-8)} with known AF before admission, territorial infarction was less often found in Group 1 (n = 20) compared with Group 2 + 3 (20% vs. 47%, P = 0.022). Arterial occlusion rate on admission differed among groups (30%, 75%, and 35%, respectively, P = 0.004) but not between Group 1 vs. Group 2 + 3 (30% vs. 45%, P = 0.31). Median FLAIR volume on Days 5-7 was lower in Group1 compared with Group 2 (n = 20) [3.2 cm3 (IQR 1.1-11.3) vs. 18.6 cm3 (IQR 8.2-49.4); P = 0.009] but not compared with Group 2 + 3 [7.8 cm3 (IQR 1.6-25.9); P = 0.23]. An INR ≥ 1.7 on admission was not associated with smaller stroke volume in multivariable regression analysis. Adding 57 patients with a first AF episode during the in-hospital stay, similar results were observed in 155 AF patients. Conclusion: In this AF cohort, an INR ≥ 1.7 at stroke onset affects lesion pattern but does not affect significantly lower stroke volume and the frequency of arterial occlusion on admission.
Subject(s)
Arterial Occlusive Diseases , Atrial Fibrillation , Brain Ischemia/diagnostic imaging , Stroke , Warfarin/administration & dosage , Administration, Oral , Aged , Aged, 80 and over , Anticoagulants/administration & dosage , Arterial Occlusive Diseases/diagnosis , Arterial Occlusive Diseases/prevention & control , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Atrial Fibrillation/epidemiology , Cerebral Arteries/diagnostic imaging , Cerebral Arteries/pathology , Female , Germany/epidemiology , Humans , International Normalized Ratio/methods , Length of Stay , Magnetic Resonance Imaging/methods , Male , Prospective Studies , Severity of Illness Index , Stroke/diagnosis , Stroke/epidemiology , Stroke/etiology , Stroke/prevention & controlABSTRACT
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.
ABSTRACT
BACKGROUND: Patients with bipolar disorder in mania exhibit symptoms pointing towards altered self-referential processing, such as decreased self-focus, flight of ideas and high distractibility. In depression, the opposite pattern of symptoms has been connected to increased activation of medial prefrontal cortex (mPFC) during self-referential processing. In this study, we hypothesized that (1) patients with mania will exhibit decreased activation in the mPFC during self-referential processing and (2) will be more alexithymic and that levels of alexithymia will correlate negatively with mPFC activation. METHODS: The neural response to standardized pictures was compared in 14 patients with bipolar I disorder in mania to 14 healthy controls using blood oxygen level dependent contrast magnetic resonance imaging. Participants were asked to indicate with button press during the scanning session for each picture whether the pictures personally related to them or not. Toronto alexithymia scale (TAS) scores were recorded from all participants. RESULTS: In the group analysis, patients with mania exhibited decreased activation in a predefined region of interest in the mPFC during self-referential processing compared to healthy controls. Patients with mania showed significantly higher levels of alexithymia, attributable to difficulties in identifying and describing emotions. Activation in the mPFC correlated negatively with levels of alexithymia. LIMITATIONS: Results presented here should be replicated in a larger group, potentially including unmedicated patients. CONCLUSIONS: The finding of decreased mPFC activation during self-referential processing in mania may reflect decreased self-focus and high distractibility. Support for this view comes from the negative correlation between higher alexithymia scores and decreased mPFC activation. These findings represent an opposite clinical and neuroimaging pattern to findings in depression.
Subject(s)
Bipolar Disorder/physiopathology , Mental Processes/physiology , Prefrontal Cortex/physiopathology , Self Concept , Adult , Bipolar Disorder/diagnostic imaging , Bipolar Disorder/psychology , Brain Mapping , Case-Control Studies , Emotions/physiology , Female , Humans , Magnetic Resonance Imaging/methods , Male , Prefrontal Cortex/diagnostic imagingABSTRACT
Self-referential processing is a complex cognitive function, involving a set of implicit and explicit processes, complicating investigation of its distinct neural signature. The present study explores the functional overlap and dissociability of self-referential and social stimulus processing. We combined an established paradigm for explicit self-referential processing with an implicit social stimulus processing paradigm in one fMRI experiment to determine the neural effects of self-relatedness and social processing within one study. Overlapping activations were found in the orbitofrontal cortex and in the intermediate part of the precuneus. Stimuli judged as self-referential specifically activated the posterior cingulate cortex, the ventral medial prefrontal cortex, extending into anterior cingulate cortex and orbitofrontal cortex, the dorsal medial prefrontal cortex, the ventral and dorsal lateral prefrontal cortex, the left inferior temporal gyrus, and occipital cortex. Social processing specifically involved the posterior precuneus and bilateral temporo-parietal junction. Taken together, our data show, not only, first, common networks for both processes in the medial prefrontal and the medial parietal cortex, but also, second, functional differentiations for self-referential processing versus social processing: an anterior-posterior gradient for social processing and self-referential processing within the medial parietal cortex and specific activations for self-referential processing in the medial and lateral prefrontal cortex and for social processing in the temporo-parietal junction.
Subject(s)
Brain/physiology , Self Concept , Social Perception , Adult , Brain Mapping , Cognition/physiology , Female , Humans , Magnetic Resonance Imaging , Male , Memory, Episodic , Mental Recall/physiology , Middle Aged , Neural Pathways/physiology , Parietal Lobe/physiology , Photic Stimulation , Prefrontal Cortex/physiologyABSTRACT
BACKGROUND: In acute ischemic stroke, diffusion weighted imaging (DWI) shows hyperintensities and is considered to indicate irreversibly damaged tissue. We present the case of a young stroke patient with unusual variability in the development of signal intensities within the same vessel territory. CASE PRESENTATION: A 35-year-old patient presented with symptoms of global aphasia and hypesthesia of the left hand. MRI demonstrated a scattered lesion in the MCA territory. After rtPA therapy the patient received further MRI examination, three times on day 1, and once on day 2, 3, 5 and 43. The posterior part of the lesion showed the usual pattern with increasing DWI hyperintensity and decreased ADC, as well as delayed FLAIR positivity. However, the anterior part of the lesion, which was clearly visible in the first examination completely normalized on the first day and only reappeared on day 2. This was accompanied by a normalization of the ADC as well as an even further delayed FLAIR positivity. CONCLUSION: We showed that interim normalization of DWI and ADC in the acute phase can not only be found in rodent models of stroke, but also in humans. We propose that DWI lesion development might be more variable during the first 24 h after stroke than previously assumed.
Subject(s)
Brain Ischemia/pathology , Diffusion Magnetic Resonance Imaging/methods , Radiographic Image Interpretation, Computer-Assisted/methods , Stroke/pathology , Adult , Female , HumansABSTRACT
Patients with mania show alterations of social behaviour. Neuropsychological studies in euthymic bipolar disorder (BD) have revealed deficits in cognitive, but not emotional aspects of social cognition (SC). Here, we studied the neural signature of social stimulus processing in mania. We expected alterations in regions associated with cognitive SC (dorsal-medial prefrontal cortex, dMPFC). Participants comprised 14 manic patients and 14 matched healthy controls who viewed standardized pictures with social and non-social content during functional magnetic resonance imaging (fMRI). Region-of-interest-analyses focused on areas related to SC (dorsal/ventral medial prefrontal cortex; temporo-parietal junction), determined by a quantitative meta-analysis. Between-group comparisons ('social>non-social') revealed reduced BOLD responses in the right dMPFC in manic patients, but no significant group difference in the ventral MPFC. In addition, manic patients showed elevated BOLD activation in the right temporo-parietal junction during perception of social stimuli, which was correlated with increased delusional ideation. Patients with mania show diminished BOLD responses to social stimuli in the right dMPFC, associated with cognitive SC and this may be related to reported deficits in understanding others' mental states. At the same time, manic patients show hyperactivation of the right temporo-parietal junction, likely related to exaggerated attribution of meaning to social stimuli.