Core Manifestations Research Articles

Wiedemann-Rautenstrauch syndrome: A phenotype analysis.

Wiedemann-Rautenstrauch syndrome (WRS) is a neonatal progeroid disorder characterized by growth retardation, lipodystrophy, a distinctive face, and dental anomalies. Patients reported to date demonstrate a remarkable variability in phenotype, which hampers diagnostics. We performed a literature search, and analyzed 51 reported patients, using the originally reported patients as "gold standard." In 15 patients sufficient information and photographic evidence was available to confirm the clinical diagnosis. In 12 patients the diagnosis was suggestive but lack of data prevented a definite diagnosis, and in 24 patients an alternative diagnosis was likely. Core manifestations of the syndrome are marked pre-natal and severe post-natal growth retardation, an unusual face (triangular shape, sparse hair, small mouth, pointed chin), dental anomalies (natal teeth; hypodontia), generalized lipodystrophy with localized fat masses, and-in some cases-progressive ataxia and tremor. It has been suggested that the syndrome might be caused by biallelic variants in POLR3A, identified by exome sequencing in a single patient only. Therefore, we compared the WRS phenotype with characteristics of conditions known to be caused by autosomal recessively inherited POLR3A mutations. There are major differences but there are also similarities in phenotype, which sustain the suggestion that the syndrome can be caused by disturbed POLR3A functioning.

Influence of event image on destination image: The case of the 2008 Beijing Olympic Games

Abstract Despite the long recognized effects of mega-events on image enhancement, knowledge on the core manifestation of the effects—the influence of event image (EI) on destination image (DI)—remains limited. Accordingly, this study aimed to provide a better understanding of such influence focusing on the 2008 Beijing Olympic Games as the case study. A questionnaire survey was conducted among 702 onsite Chinese tourists during this event. Results showed that (a) generally, EI was positively correlated with DI, and this correlation varied in intensity according to different levels and dimensions of the two image constructs; (b) EI had stronger effects on DI than the established formation agents of DI; and (c) EI and DI mutually predicted each other with similar predicting power. This study disclosed key aspects of the previously unrecognized influences of EI on DI, and offered some general guidelines for managing DI using mega-events as a special and important leverage.

Kraepelin's description of chronic mania: a clinical picture that meets the behavioral variant frontotemporal dementia phenotype.

Chronic mania is an under-investigated condition and few reports have associated this disorder with an organic background. The present work examines Kraepelin's reliable description of chronic mania from a current behavioral neurology viewpoint. Kraepelin had described a cluster of symptoms that are now recognized as core manifestations of the behavioral variant frontotemporal dementia (bvFTD) clinical phenotype. We also carried out additional reviews of original manuscripts from Kraepelin's peers, in order to find any case reports that might fulfill the current diagnostic proposal for bvFTD. Even though we failed to find an ideal case, we found some scholars who seemed to agree that chronic mania should be considered a special form of dementia. The present work highlights, through historical data, the possible overlapping features between primary psychiatric disorders and neuropsychiatric symptoms secondary to neurodegenerative conditions.

Potential Therapeutic Benefits of Maintaining Mitochondrial Health in Peripheral Neuropathies.

Background: Peripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy. Method: The current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity. The article also highlights the therapeutic significance of maintaining a healthy mitochondrial environment in neuronal cells via pharmacological management in context of peripheral neuropathies. Results: Aberrant cellular signaling coupled with changes in neurotransmission, peripheral and central sensitization are found to be responsible for the pathogenesis of variant toxic neuropathies. Current research reports have indicated the possible involvement of mitochondria mediated redox imbalance as one of the principal causes of neuropathy aetiologies. In addition to imbalance in redox homeostasis, mitochondrial dysfunction is also responsible for alterations in physiological bioenergetic metabolism, apoptosis and autophagy pathways. Conclusions: In spite of various etiological factors, mitochondrial dysfunction has been found to be a major pathomechanism underlying the neuronal dysfunction associated with peripheral neuropathies. Pharmacological modulation of mitochondria either directly or indirectly is expected to yield therapeutic relief from various primary and secondary mitochondrial diseases.

Impaired context processing during irony comprehension in schizotypy: An ERPs study

Mentalizing deficits are a core manifestation of schizophrenia spectrum disorders. They contribute to the social handicap associated with the pathology, leading to disruption in autonomy, professional achievement, and interpersonal relationships. However, the underlying mechanisms of these deficits remain poorly understood. The aim of the present study was to test the hypothesis that context processing deficits would be responsible for mentalizing difficulties in schizotypy (personality traits considered as attenuated manifestations of schizophrenic symptoms) by using an irony comprehension task. Irony processing is a mentalizing exercise that requires the ability to take into account the semantic context to understand the literal meaning of the utterance, and to integrate the pragmatic context to infer the speaker's intention. These two steps of processing can be indexed by the N400 and P600 components, respectively, of event-related brain potentials (ERPs). Forty participants were assigned to high or low schizotypy groups according to their Schizotypal Personality Questionnaire (SPQ) score, and ERPs were recorded while they read short stories ending with a literal, ironic, or incompatible statement. In the low-SPQ group, there was a significant N400 semantic context effect (literal targets elicited less negative N400 amplitudes compared to incompatible targets) followed by a P600 pragmatic context effect (ironic targets evoked greater positive P600 amplitudes than literal targets). In contrast, there was neither a N400 nor P600 effect in the high-SPQ group. These abnormalities were associated with high interpersonal SPQ factor scores. These results show a strong association between context processing, mentalizing abilities, and interpersonal functioning in schizophrenia spectrum.

Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates.

Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions. To identify clusters of EPS progression over time and their clinical and neuropathological correlates. 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings. Three clusters of EPS progression were identified: no/low (n = 1,583), medium (n = 1,259), and high (n = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies. Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features.

Non-paraneoplastic Lambert-Eaton myasthenic syndrome presenting dropped head and respiratory failure with normoreflexia

A 57-year-old woman developed insidious dropped head, respiratory failure and autonomic dysfunction with inconspicuous limb weakness, but without diminished deep tendon reflexes. Progressive myopathy affecting truncal muscles was initially suspected, but non-paraneoplastic Lambert–Eaton myasthenic syndrome was finally diagnosed based on the results of electrophysiological studies and positivity for anti-P/Q-type voltage-gated calcium channel antibody without any evidence of malignancy. In general, most patients with Lambert–Eaton myasthenic syndrome have more than one of the core manifestations of Lambert–Eaton myasthenic syndrome including proximal-dominant limb weakness, diminished or absent deep tendon reflexes and autonomic dysfunction. However, this patient presented atypical manifestations, and lacked two core manifestations except for autonomic dysfunction. It is important to take Lambert–Eaton myasthenic syndrome into consideration in the differential diagnosis of patients showing atypical presentation, such as dropped head or respiratory failure, when they have only one core manifestation of Lambert–Eaton myasthenic syndrome.

Maladaptive autonomic regulation in PTSD accelerates physiological aging.

A core manifestation of post-traumatic stress disorder (PTSD) is a disconnection between physiological state and psychological or behavioral processes necessary to adequately respond to environmental demands. Patients with PTSD experience abnormal oscillations in autonomic states supporting either fight and flight behaviors or withdrawal, immobilization, and dissociation without an intervening “calm” state that would provide opportunities for positive social interactions. This defensive autonomic disposition is adaptive in dangerous and life threatening situations, but in the context of every-day life may lead to significant psychosocial distress and deteriorating social relationships. The perpetuation of these maladaptive autonomic responses may contribute to the development of comorbid mental health issues such as depression, loneliness, and hostility that further modify the nature of cardiovascular behavior in the context of internal and external stressors. Over time, changes in autonomic, endocrine, and immune function contribute to deteriorating health, which is potently expressed in brain dysfunction and cardiovascular disease. In this theoretical review paper, we present an overview of the literature on the chronic health effects of PTSD. We discuss the brain networks underlying PTSD in the context of autonomic efferent and afferent contributions and how disruption of these networks leads to poor health outcomes. Finally, we discuss treatment approaches based on our theoretical model of PTSD.

Homeostatic model assessment of insulin resistance as a predictor of metabolic syndrome: Consequences of obesity in children and adolescents

BackgroundObesity and/or insulin resistance have gained increasing attention as the core manifestations of metabolic syndrome. ObjectiveTo evaluate insulin resistance according to homeostasis model assessment of insulin resistance index HOMA-IR in obese children and adolescents with or without metabolic syndrome at risk of type 2 diabetes mellitus. Design and subjects60 obese children and adolescents were recruited, metabolic syndrome was diagnosed according to the modified WHO criteria adapted for children and adolescents. Insulin resistance was calculated using the HOMA-IR. ResultsMetabolic syndrome (MS) was found in 42 subjects (70%), using modified WHO guidelines for diagnosing MS. On comparing MS-related parameters between the groups with (MS+) and without metabolic syndrome (MS−), median body mass index, waist circumference, waist/height ratio, and blood pressure, total cholesterol and triglyceride were significantly higher in the MS+group. Basal insulin level as well as HOMA-IR was also significantly different between MS+ and MS-groups. The presence of insulin resistance according to HOMA-IR was identified in 53% of obese children and adolescents. This HOMA-IR age and sex limit was exceeded by 70% children in the MS+group, but only by 43% children in the MS-group (p<0.001). HOMA-IR was positively correlated with the majority of anthropometric and biochemical parameters. The correlation was strongest with body mass index, waist circumference and diastolic blood pressure. ConclusionsHOMA-IR might be a reliable surrogate measure of insulin resistance and a strong predictor of type 2 diabetes in obese adolescents allowing the development of preventive measures and treatment when needed.

Troubles affectifs et impulsivité

Impulsivity is a complex and important phenomenon in mood disorders. Impulse control disorders, as defined in DSM, are more frequent in mood disorders especially in Bipolar Disorder type I, and are associated with a more severe course of illness. Dimensional studies demonstrate that impulsivity is a core manifestation of bipolar disorder both as state- and trait-dependent markers in patients. Comorbid substance use disorders are often associated with a higher level of impulsivity whereas the relation between suicidal behaviors and higher impulsivity remains uncertain. Moreover, neuropsychological tests were used to study correlation between clinical impulsivity and laboratory measurements of impulsivity. Level of correlation remains weak and several explanations are proposed in the literature.

The Investigation and Differential Diagnosis of Asperger Syndrome in Adults

As a result of the increased public interest in autism spectrum disorders (ASD), certain core manifestations of ASD--impaired social interaction and communication, bizarre interests--are now commonly recognized as being typical of autism, not only in children, but in adults as well. More often than before, general practitioners, neurologists, and psychiatrists find themselves being asked whether a patient is suffering from previously unrecognized Asperger syndrome (AS). The prevalence of ASD is estimated at 1%, and the ratio of diagnosed to undiagnosed cases at about 3:2. Little is known about the diagnostic evaluation of AS in adulthood. We selectively searched the Medline database for pertinent literature, paying special attention to diagnostic manuals and to the guideline of the United Kingdom's National Institute for Health and Care Excellence (NICE). Centrally important aspects of the diagnosis of AS include an assessment of the patient's ability to assume the emotional perspectives of others, non-verbal modes of expression, repetitive behavior patterns, and childhood social behavioral history. The autism quotient (AQ) is now established as a simple but nonspecific screening test. Up to 70% of all affected adults have comorbid disturbances, most often depression and anxiety disorders. The differential diagnosis includes personality disorders, anxiety disorders, obsessive-compulsive disorder, and attention deficit-hyperactivity disorder. The diagnostic assessment should proceed in stepwise fashion, starting from simple screening in primary care and then moving on to evaluation of the suspected diagnosis by a mental health care specialist, followed by extensive further investigation in an outpatient clinic specifically devoted to patients with autism spectrum disorders. The diagnostic assessment of autism in adults requires knowledge of the core and accompanying manifestations of autism and of their differential diagnoses. More research is needed for the development of further screening tests and the precise determination of diagnosis rates, differential diagnoses, nd comorbidities.

Spontaneous parkinsonism is associated with cognitive impairment in antipsychotic-naive patients with first-episode psychosis: a 6-month follow-up study.

There is now growing evidence that parkinsonism and other extrapyramidal signs are highly prevalent in patients with first-episode psychosis who have never been exposed to antipsychotic drugs. However, the neurocognitive correlates of parkinsonism in this population remained to be clarified. A sample comprising 100 consecutive drug-naive patients with first-episode psychosis were enrolled on the study and followed up for 6 months. Seventy-seven completed assessments at 3 time points (baseline, 1 mo, and 6 mo), involving clinical and cognitive examinations and a specific assessment of motor abnormalities. The Simpson-Angus Scale (SAS) was used for the assessment of extrapyramidal signs, and each motor domain was evaluated with a standard assessment scale. Linear mixed models were built to explore the longitudinal relationships between parkinsonism scores and cognitive impairment. Parkinsonism scores showed significant strong longitudinal associations with deficits in memory, executive functioning, and attention. Spontaneous parkinsonism (total SAS score and hypokinesia and rigidity subscores at baseline) showed high 6-month predictive values for cognitive impairment. In addition, they also had high predictive values for neurologic soft-sign abnormalities but not for dyskinesia, akathisia, and pure catatonic abnormalities. No predictive value was found for glabella-salivation or tremor subscores on the SAS scale. These results emphasize the relevance of the assessment of parkinsonism signs prior to starting to administer antipsychotic drugs, as core manifestations of psychotic illness with a high predictive value for cognitive impairment.

The “Aging Males’ Symptoms” (AMS) Scale assesses depression and anxiety

Objective: Emotional distress may be associated with severe aging symptoms. This study aimed to investigate aging symptoms in male psychiatric outpatients and their relationship with anxiety and depression.Method: About 176 male psychiatric outpatients aged 40–80 years were enrolled into this single-center cross-sectional study, and completed self-reported questionnaires including “Aging Males’ Symptoms” (AMS) scale and the Hospital Anxiety and Depression Scale (HADS).Result: Age was correlated with less anxiety (r = −0.23), less psychological (r = −0.16) and more sexual symptoms (r = 0.31). After controlling demographic variables, the partial correlation coefficients of HADS and AMS scores ranged from 0.30 to 0.73. Four groups were defined by HADS: control (C; n = 103), depression (D; n = 18), anxiety (A; n = 26) and mixed anxiety and depression (M; n = 29). The M group had the most severe aging symptoms, and the C group the least. The A group had more psychological and less sexual symptoms than the D group. “Impaired sexual potency” was the only aging symptom in males not significantly different among the four groups.Conclusions: Anxiety and depression was associated with more severe aging symptoms in male psychiatric outpatients. Sexual dysfunction could be regarded as the core manifestation to differentiate aging symptoms from syndromal emotional distress.

Cognitive Impairment in Fibromyalgia

Cognitive and behavioral impairments are core manifestations of fibromyalgia and may be more disabling than pain itself. Involvement of the central nervous system is ascertained by the fact that frontoparietal and limbic cortices are often functionally and structurally affected along the course of this disease. Even though neuroimaging has brought some experimental evidence to support such network disruption, there are currently no clinically effective biomarkers that detect and quantify cognitive and behavioral disturbances in fibromyalgia; thus, traditional scales and tests of neuropsychiatric assessment remain the most important diagnostic tools. This review addresses the most common cognitive and behavioral impairments in people with fibromyalgia, while explaining their pathophysiological basis and currently available therapeutic options.

Singleton–Merten syndrome: An autosomal dominant disorder with variable expression

In 1973, Singleton and Merten described two females with abnormal dentition, unique radiographic changes especially of the hands, and severe calcification and intimal weakening of the aortic arch and valve. Since then three additional cases with similar features have been reported and the diagnosis was suggested in another three individuals. We present an update of one case and the detailed clinical phenotype of six other cases with Singleton-Merten syndrome. The occurrence of the disorder in six members of two families and vertical male-to-male transmission indicate an autosomal dominant pattern of inheritance. Variability in phenotype, also within a single family, is significant. Core manifestations are marked aortic calcification, dental anomalies (delayed eruption and immature root formation of primarily the anterior permanent teeth, and early loss of permanent teeth due to short roots, acute root resorption, high caries, and aggressive alveolar bone loss), osteopenia and acro-osteolysis, and to a lesser extend also glaucoma, psoriasis, muscle weakness, and joint laxity. Additional clinical characteristics described here include particular facial characteristics (high anterior hairline, broad forehead, smooth philtrum, thin upper vermillion) and abnormal joint and muscle ligaments. The cause and pathogenesis of this syndrome remain unknown. © 2013 Wiley Periodicals, Inc.

BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory.

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that has been related not only to neurodevelopment and neuroprotection, but also to synapse regulation, learning, and memory. Research focused on the neurobiology of schizophrenia has emphasized the relevance of neurodevelopmental and neurotoxicity-related elements in the pathogenesis of this disease. Research focused on the clinical features of schizophrenia in the past decades has emphasized the relevance of cognitive deficits of this illness, considered a core manifestation and an important predictor for functional outcome. Variations in neurotrophins such as BDNF may have a role as part of the molecular mechanisms underlying these processes, from the neurodevelopmental alterations to the molecular mechanisms of cognitive dysfunction in schizophrenia patients.

Poster #161 THE CHARACTERISTICS OF REVERSAL RESPONSE INITIATION AND ASSOCIATIVE LEARNING OF REWARD APPROACH AND LOSS AVERSION IN SCHIZOPHRENIA

Mentalizing deficits are a core manifestation of schizophrenia spectrum disorders. They contribute to the social handicap associated with the pathology, leading to disruption in autonomy, professional achievement, and interpersonal relationships. However, the underlying mechanisms of these deficits remain poorly understood. The aim of the present study was to test the hypothesis that context processing deficits would be responsible for mentalizing difficulties in schizotypy (personality traits considered as attenuated manifestations of schizophrenic symptoms) by using an irony comprehension task. Irony processing is a mentalizing exercise that requires the ability to take into account the semantic context to understand the literal meaning of the utterance, and to integrate the pragmatic context to infer the speaker's intention. These two steps of processing can be indexed by the N400 and P600 components, respectively, of event-related brain potentials (ERPs). Forty participants were assigned to high or low schizotypy groups according to their Schizotypal Personality Questionnaire (SPQ) score, and ERPs were recorded while they read short stories ending with a literal, ironic, or incompatible statement. In the low-SPQ group, there was a significant N400 semantic context effect (literal targets elicited less negative N400 amplitudes compared to incompatible targets) followed by a P600 pragmatic context effect (ironic targets evoked greater positive P600 amplitudes than literal targets). In contrast, there was neither a N400 nor P600 effect in the high-SPQ group. These abnormalities were associated with high interpersonal SPQ factor scores. These results show a strong association between context processing, mentalizing abilities, and interpersonal functioning in schizophrenia spectrum.

IFNα causes systemic lupus erythematosus and possibly mediates self-organized criticality theory of autoimmunity (44.47)

Abstract Objectives: The pathogenesis of SLE is unclear. Overstimulation of CD4 T cells by antigen led to the development of autoantibody-inducing CD4 T (aiCD4 T) cell capable of inducing autoantibodies and lupus tissue disease. In this novel ‘Self-organized criticality theory of autoimmunity’, we noted that aiCD4 T cell is induced via de novo TCR revision. We now test IFNα as a mediator for the induction of aiCD4 T cell to cause SLE. Methods: Mouse IFNα gene controlled under TetOp promoter was microinjected into eggs of C57BL/6 to generate TetOp-mIFNα Tg mice. They were mated with EμSR-tTA Tg mice, expressing doxycycline-transactivator (tTA) gene under the control of IgH chain enhancer and SRα promoter, to obtain double Tg mice. Results: By increasing IFNα, anti-dsDNA antibody and immune complex (IC) were generated. Pathological lesions consisted of IC-deposited glomerulonephritis, interstitial lung disease, alopecia, liquefaction and positive skin lupus band test, onion skin splenic lesion, and inflammatory infiltrates to salivary gland and bile duct. There was an increase in IFNγ-producing effector CD4+, full-matured CD8+ CTL, and activated CD3+CD4-CD8- double negative (DN) T cells. The DN T cells not only infiltrated to the glomerular lesions of mice, but also induced de novo glomerulonephritis and alopecia when transferred into naïve recipients. Conclusions: IFNα is responsible for the core manifestation of SLE, and may induce lupus tissue injury via DN T cells.

Mitochondrial DNA deletion mutations in patients with neuropsychiatric symptoms

It has been suggested that mitochondrial dysfunction is important in the pathogenesis of psychiatric disorders such as depression, schizophrenia and dementia. We report herein three adult patients exhibiting such psychiatric symptoms as the core manifestation, accompanied by various degrees of myopathic symptoms. Pathological findings in biopsied skeletal muscle were compatible with mitochondrial myopathy in all cases. Maternal inheritance was not apparent in all three cases; however, two patients were born to consanguineous parents. Mutation analysis on the mitochondrial DNA (mtDNA) and seven nuclear genes, in which pathogenic mutations are known to cause mtDNA deletions, was performed. MtDNA deletion mutations were identified in skeletal muscles of all patients. Neither pathogenic mutations nor copy number variation was identified among the nuclear genes. Although further studies are needed, the molecular pathways inducing mitochondrial abnormalities may be implicated in a variety of psychiatric conditions.

Psoriatic Arthritis: Pharmacotherapy Update

Psoriatic arthritis is a systemic disorder that causes chronic pain, altered physical appearance, and loss of function. The clinical features are diverse, but the core manifestations are psoriasis, peripheral arthritis, axial disease, enthesitis, and dactylitis. Our understanding about the psoriatic arthritis disease state, assessment, and treatment has advanced thanks to significant collaborative efforts by rheumatologists and dermatologists in the development of classification criteria, outcome measures to assess the various clinical domains, and treatment trials with agents also used for diseases such as rheumatoid arthritis and psoriasis. In particular, biologic agents, especially anti-tumor necrosis factor agents, have demonstrated significant efficacy and reasonable safety in all clinical domains of the disease, resulting in amelioration of clinical symptoms, inhibition of structural damage, and improvement in function and quality of life.