Auditory naming is impaired in posterior cortical atrophy and early-onset Alzheimer's disease.

Introduction: Visual naming ability reflects semantic memory retrieval and is a hallmark deficit of Alzheimer's disease (AD). Naming impairment is most prominently observed in the late-onset amnestic and logopenic variant Primary Progressive Aphasia (lvPPA) syndromes. However, little is known about how other patients across the atypical AD syndromic spectrum perform on tests of auditory naming, particularly those with primary visuospatial deficits (Posterior Cortical Atrophy; PCA) and early onset (EOAD) syndromes. Auditory naming tests may be of particular relevance to more accurately measuring anomia in PCA syndrome and in others with visual perceptual deficits. Methods: Forty-six patients with biomarker-confirmed AD (16 PCA, 12 lvPPA, 18 multi-domain EOAD), at the stage of mild cognitive impairment or mild dementia, were administered the Auditory Naming Test (ANT). Performance differences between groups were evaluated using one-way ANOVA and post-hoc t-tests. Correlation analyses were used to examine ANT performance in relation to measures of working memory and word retrieval to elucidate cognitive mechanisms underlying word retrieval deficits. Whole-cortex general linear models were generated to determine the relationship between ANT performance and cortical atrophy. Results: Based on published cutoffs, out of a total possible score of 50 on the ANT, 56% of PCA patients (mean score = 45.3), 83% of EOAD patients (mean = 39.2), and 83% of lvPPA patients (mean = 29.8) were impaired. Total uncued ANT performance differed across groups, with lvPPA performing most poorly, followed by EOAD, and then PCA. ANT performance was still impaired in lvPPA and EOAD after cuing, while performance in PCA patients improved to the normal range with phonemic cues. ANT performance was also directly correlated with measures of verbal fluency and working memory, and was associated with cortical atrophy in a circumscribed semantic language network. Discussion: Auditory confrontation naming is impaired across the syndromic spectrum of AD including in PCA and EOAD, and is likely related to auditory-verbal working memory and verbal fluency which represent the nexus of language and executive functions. The left-lateralized semantic language network was implicated in ANT performance. Auditory naming, in the absence of a visual perceptual demand, may be particularly sensitive to measuring naming deficits in PCA.

Perivascular Innervation in the Nasal Mucosa and Clinical Findings in Patients with Allergic Rhinitis and Idiopathic Rhinitis.

Introduction The nonspecific hyperreactivity of rhinitis has been attributed to neurotrophins activating sensory nerves and inflammatory cells. The relationship between these markers and the intensity of the symptoms is not well established and few studies have evaluated individuals with idiopathic rhinitis. Objective The present study aims to evaluate whether perivascular innervation and nerve growth factor (NGF) are related to the intensity of the clinical conditions in allergic rhinitis (AR) and idiopathic rhinitis (IR). Methods A total of 15 patients with AR and 15 patients with IR with the indication for inferior turbinectomy (associated or not with septoplasty) were selected. The patients received a score according to their signs and symptoms. After the surgery, we quantified eosinophils, mast cells, NGF, and nerve fibers in the nasal turbinate. Results The score of the signs and symptoms was higher in the AR group. Nerve growth factor was found in the cytoplasm of inflammatory cells in the submucosa in greater quantity in the AR group. The nerve fibers were distributed throughout the tissue, mainly in the subepithelial, glandular, and vascular regions, and there was no difference between the groups. Greater perivascular innervation was associated with a higher signs and symptoms score. Conclusions We concluded that these findings suggest that the NGF produced by submucosal inflammatory cells stimulates increased perivascular innervation in rhinitis, thus directly reflecting in more intense clinical conditions, especially in AR.

Atrophy in behavioural variant frontotemporal dementia spans multiple large-scale prefrontal and temporal networks.

The identification of a neurodegenerative disorder's distributed pattern of atrophy-or atrophy 'signature'-can lend insights into the cortical networks that degenerate in individuals with specific constellations of symptoms. In addition, this signature can be used as a biomarker to support early diagnoses and to potentially reveal pathological changes associated with said disorder. Here, we characterized the cortical atrophy signature of behavioural variant frontotemporal dementia (bvFTD). We used a data-driven approach to estimate cortical thickness using surface-based analyses in two independent, sporadic bvFTD samples (n = 30 and n = 71, total n = 101), using age- and gender-matched cognitively and behaviourally normal individuals. We found highly similar patterns of cortical atrophy across the two independent samples, supporting the reliability of our bvFTD signature. Next, we investigated whether our bvFTD signature targets specific large-scale cortical networks, as is the case for other neurodegenerative disorders. We specifically asked whether the bvFTD signature topographically overlaps with the salience network, as previous reports have suggested. We hypothesized that because phenotypic presentations of bvFTD are diverse, this would not be the case, and that the signature would cross canonical network boundaries. Consistent with our hypothesis, the bvFTD signature spanned rostral portions of multiple networks, including the default mode, limbic, frontoparietal control and salience networks. We then tested whether the signature comprised multiple anatomical subtypes, which themselves overlapped with specific networks. To explore this, we performed a hierarchical clustering analysis. This yielded three clusters, only one of which extensively overlapped with a canonical network (the limbic network). Taken together, these findings argue against the hypothesis that the salience network is preferentially affected in bvFTD, but rather suggest that-at least in patients who meet diagnostic criteria for the full-blown syndrome-neurodegeneration in bvFTD encompasses a distributed set of prefrontal, insular and anterior temporal nodes of multiple large-scale brain networks, in keeping with the phenotypic diversity of this disorder.

Perivascular Innervation in the Nasal Mucosa and Clinical Findings in Patients with Allergic Rhinitis and Idiopathic Rhinitis

Abstract Introduction The nonspecific hyperreactivity of rhinitis has been attributed to neurotrophins activating sensory nerves and inflammatory cells. The relationship between these markers and the intensity of the symptoms is not well established and few studies have evaluated individuals with idiopathic rhinitis. Objective The present study aims to evaluate whether perivascular innervation and nerve growth factor (NGF) are related to the intensity of the clinical conditions in allergic rhinitis (AR) and idiopathic rhinitis (IR). Methods A total of 15 patients with AR and 15 patients with IR with the indication for inferior turbinectomy (associated or not with septoplasty) were selected. The patients received a score according to their signs and symptoms. After the surgery, we quantified eosinophils, mast cells, NGF, and nerve fibers in the nasal turbinate. Results The score of the signs and symptoms was higher in the AR group. Nerve growth factor was found in the cytoplasm of inflammatory cells in the submucosa in greater quantity in the AR group. The nerve fibers were distributed throughout the tissue, mainly in the subepithelial, glandular, and vascular regions, and there was no difference between the groups. Greater perivascular innervation was associated with a higher signs and symptoms score. Conclusions We concluded that these findings suggest that the NGF produced by submucosal inflammatory cells stimulates increased perivascular innervation in rhinitis, thus directly reflecting in more intense clinical conditions, especially in AR.

Verbal Encoding Deficits Impact Recognition Memory in Atypical "Non-Amnestic" Alzheimer's Disease.

Memory encoding and retrieval deficits have been identified in atypical Alzheimer's disease (AD), including posterior cortical atrophy (PCA) and logopenic variant primary progressive aphasia (lvPPA), despite these groups being referred to as "non-amnestic". There is a critical need to better understand recognition memory in atypical AD. We investigated performance on the California Verbal Learning Test (CVLT-II-SF) in 23 amyloid-positive, tau-positive, and neurodegeneration-positive participants with atypical "non-amnestic" variants of AD (14 PCA, 9 lvPPA) and 14 amnestic AD participants. Recognition memory performance was poor across AD subgroups but trended toward worse in the amnestic group. Encoding was related to recognition memory in non-amnestic but not in amnestic AD. We also observed cortical atrophy in dissociable subregions of the distributed memory network related to encoding (left middle temporal and angular gyri, posterior cingulate and precuneus) compared to recognition memory (anterior medial temporal cortex). We conclude that recognition memory is not spared in all patients with atypical variants of AD traditionally thought to be "non-amnestic". The non-amnestic AD patients with poor recognition memory were those who struggled to encode the material during the learning trials. In contrast, the amnestic AD group had poor recognition memory regardless of encoding ability.

Structural integrity of the anterior mid-cingulate cortex contributes to resilience to delirium in SuperAging.

Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

Learning to forget: Hippocampal-amygdala connectivity partially mediates the effect of sexual trauma severity on verbal recall in older women undiagnosed with posttraumatic stress disorder.

Verbal learning deficits are common among sexually traumatized women who have not been formally diagnosed with posttraumatic stress disorder (PTSD). Aberrant resting-state functional connectivity (rsFC) of the amygdala and hippocampus are implicated in PTSD and verbal memory impairment. We tested rsFC between bilateral dentate gyrus (DG) and both centromedial (CM) and basolateral (BL) nuclei of the amygdala as statistical mediators for the effect of sexual trauma-related symptom severity on delayed verbal recall performance in 63 older women (age: 60-85 years) undiagnosed with PTSD. Participant data were drawn from the NKI-Rockland Study. Individuals completed a 10-min resting-state scan, Rey Auditory Verbal Learning Test (RAVLT), and the Sexual Abuse Trauma Index (SATI) from the Trauma Symptom Checklist. Z-scores indicating rsFC of DG with BL and CM amygdala seeds were evaluated in two separate mediation models. Higher SATI scores were associated with lower RAVLT after controlling for age, ß = -.23, 95% CI [.48, .03], p = .039. This effect was negated upon adding a negative path from SATI to rsFC of left DG and right CM, ß = -.29, 95% CI [-.52, -.02], p = .022, and a positive path from that seed pair to RAVLT List A recall, ß = .28, 95% CI [.03, 0.48], p = .015. Chi-square fit indices supported partial mediation by this seed pair, p = .762. In the absence of PTSD sexual trauma symptoms partially relate to verbal learning deficits as a function of aberrant rsFC between left hippocampus DG and right amygdala CM nuclei.

Patterns of flow drainage from varicose veins originating in the incompetent great saphenous vein.

Background: Chronic venous insufficiency affects the lives of many people and therefore constitutes a public health problem. Knowledge of the drainage patterns of reflux from varicose veins secondary to incompetent saphenous veins is essential to define the best therapeutic management. Objectives: To determine the reflux drainage patterns from varicose veins originating in incompetent GSV, the prevalence of perforating veins (PV), and their relationships with symptoms. Methods: 55 ultrasound reports were analyzed to determine the drainage patterns of reflux from the GSV, location and diameter of PV drainage, and staging of symptoms. Results: In 64% of the sample, reflux from varicose veins drained to PVs, in 4% reflux drained to the GSV itself, in another 4% drainage was to the small saphenous vein, and in 29% drainage was to varicose trunk veins in which no direct communication with the deep system could be identified. No associations were observed between symptoms and reflux drainage patterns or PV diameters. Conclusions: For this sample, PVs were responsible for draining flow from varicose veins in 64% of cases. Neither PV diameters nor GSV reflux patterns were associated with severity of symptoms.

Introdução: A insuficiência venosa crônica impacta a vida de muitas pessoas, constituindo-se, assim, como um problema de saúde pública. Conhecer o padrão de drenagem do refluxo das varizes associadas à veia safena incompetente é fundamental para definir a melhor programação terapêutica. Objetivos: Determinar os padrões de drenagem do refluxo de varizes originadas da veia safena magna incompetente, a prevalência de veias perfurantes e a relação com os sintomas. Métodos: Foram analisados 55 registros ultrassonográficos de pacientes com refluxo da veia safena magna para determinar padrões de drenagem do refluxo dessa veia, pontos de refluxo das varizes, localização e diâmetro das perfurantes de drenagem e graduação dos sintomas. Resultados: O principal padrão de refluxo encontrado foi originado da junção safenofemoral com comprometimento proximal da veia safena magna. Em 64% dos pacientes, o refluxo das varizes drenou para veias perfurantes - 4% drenavam para a própria veia safena magna; em outros 4%, a drenagem era para a veia safena parva; e, em 29%, a drenavam destinava-se para varizes tronculares em que não se identificou comunicação direta com o sistema venoso profundo. Não foi observada associação dos sintomas com os padrões de drenagem do refluxo ou diâmetro das perfurantes. Conclusão: Para essa amostra, as veias perfurantes foram responsáveis pelo escoamento do fluxo oriundo das varizes em 64% dos casos. O diâmetro das veias perfurantes e o padrão de refluxo da veia safena não estiveram associados à gravidade dos sintomas.

Patterns of flow drainage from varicose veins originating in the incompetent great saphenous vein / Padrões de drenagem do fluxo das varizes oriundas da veia safena magna incompetente

Abstract Background Chronic venous insufficiency affects the lives of many people and therefore constitutes a public health problem. Knowledge of the drainage patterns of reflux from varicose veins secondary to incompetent saphenous veins is essential to define the best therapeutic management. Objectives To determine the reflux drainage patterns from varicose veins originating in incompetent GSV, the prevalence of perforating veins (PV), and their relationships with symptoms. Methods 55 ultrasound reports were analyzed to determine the drainage patterns of reflux from the GSV, location and diameter of PV drainage, and staging of symptoms. Results In 64% of the sample, reflux from varicose veins drained to PVs, in 4% reflux drained to the GSV itself, in another 4% drainage was to the small saphenous vein, and in 29% drainage was to varicose trunk veins in which no direct communication with the deep system could be identified. No associations were observed between symptoms and reflux drainage patterns or PV diameters. Conclusions For this sample, PVs were responsible for draining flow from varicose veins in 64% of cases. Neither PV diameters nor GSV reflux patterns were associated with severity of symptoms.

Resumo Introdução A insuficiência venosa crônica impacta a vida de muitas pessoas, constituindo-se, assim, como um problema de saúde pública. Conhecer o padrão de drenagem do refluxo das varizes associadas à veia safena incompetente é fundamental para definir a melhor programação terapêutica. Objetivos Determinar os padrões de drenagem do refluxo de varizes originadas da veia safena magna incompetente, a prevalência de veias perfurantes e a relação com os sintomas. Métodos Foram analisados 55 registros ultrassonográficos de pacientes com refluxo da veia safena magna para determinar padrões de drenagem do refluxo dessa veia, pontos de refluxo das varizes, localização e diâmetro das perfurantes de drenagem e graduação dos sintomas. Resultados O principal padrão de refluxo encontrado foi originado da junção safenofemoral com comprometimento proximal da veia safena magna. Em 64% dos pacientes, o refluxo das varizes drenou para veias perfurantes - 4% drenavam para a própria veia safena magna; em outros 4%, a drenagem era para a veia safena parva; e, em 29%, a drenavam destinava-se para varizes tronculares em que não se identificou comunicação direta com o sistema venoso profundo. Não foi observada associação dos sintomas com os padrões de drenagem do refluxo ou diâmetro das perfurantes. Conclusão Para essa amostra, as veias perfurantes foram responsáveis pelo escoamento do fluxo oriundo das varizes em 64% dos casos. O diâmetro das veias perfurantes e o padrão de refluxo da veia safena não estiveram associados à gravidade dos sintomas.

The effectiveness of early parental coaching in the autism spectrum disorder

Abstract Objective Analysis of the effectiveness of early Parental Coaching in the Autism Spectrum Disorder. Method Randomized, controlled and blinded clinical trial to analyze parent-child interaction videos. Results The sample consisted of 18 children being followed up at the Autism Outpatient Clinic of a Neuropediatric Center in southern Brazil diagnosed with Autism Spectrum Disorder, between 29 and 42 months of age, randomly allocated to two groups: the Study Group (SG; n = 9), which received Parental Coaching performed by a professional certified by the Early Start Denver Model; and the Control Group (CG; n = 9), which was in a routine follow-up, without treatment and training of parents by a trained professional. The parents of the SG were willing to attend weekly meetings and to apply the instructional techniques at home with their children. It took 12 weeks and an average of 2 h per meeting. Conclusions The learning rate for comprehensive development skills in the Early Start Denver Model checklist, such as receptive communication, expressive communication, social capacity, imitation, cognition, games, fine motor skills, gross motor skills, behavior, and personal independence was significantly higher in the SG, as well as the strategies and the quality of interaction between parents and children. Thus, Parental Coaching presents as a possibility of early intervention in children with Autism Spectrum Disorder.

The effectiveness of early parental coaching in the autism spectrum disorder.

OBJECTIVE: Analysis of the effectiveness of early Parental Coaching in the Autism Spectrum Disorder. METHOD: Randomized, controlled and blinded clinical trial to analyze parent-child interaction videos. RESULTS: The sample consisted of 18 children being followed up at the Autism Outpatient Clinic of a Neuropediatric Center in southern Brazil diagnosed with Autism Spectrum Disorder, between 29 and 42 months of age, randomly allocated to two groups: the Study Group (SG; n=9), which received Parental Coaching performed by a professional certified by the Early Start Denver Model; and the Control Group (CG; n=9), which was in a routine follow-up, without treatment and training of parents by a trained professional. The parents of the SG were willing to attend weekly meetings and to apply the instructional techniques at home with their children. It took 12 weeks and an average of 2h per meeting. CONCLUSIONS: The learning rate for comprehensive development skills in the Early Start Denver Model checklist, such as receptive communication, expressive communication, social capacity, imitation, cognition, games, fine motor skills, gross motor skills, behavior, and personal independence was significantly higher in the SG, as well as the strategies and the quality of interaction between parents and children. Thus, Parental Coaching presents as a possibility of early intervention in children with Autism Spectrum Disorder.

ALK (Anaplastic Lymphoma Kinase) expression in DRG neurons and its involvement in neuron-Schwann cells interaction.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) transiently expressed in specific regions of the central and peripheral nervous systems. In this study, we focused on the rat developing dorsal root ganglion (DRG). This ganglion is composed of heterogeneous sensory neurons characterized by the expression of RTK for neurotrophic factors, such as the nerve growth factor receptor TrkA or the glial-derived neurotrophic factor family receptor Ret, which are specifically detected in nociceptive neurons. In DRG, ALK expression reached a maximum around birth. We showed that ALK is specifically present in a subtype of neurons during DRG development, and that the majority of these neurons co-expressed TrkA and Ret. Interestingly, we identified only one form (220 kDa) of ALK in DRG neurons both in vivo and in vitro. On the opposite, in transfected cells as well as in brain extracts, ALK was identified as two forms (220 and 140 kDa). The DRG is composed of neurons and glial cells, principally satellite Schwann cells. Thus, we hypothesized that the presence of satellite Schwann cells was involved in the absence of truncated ALK. Using two different cell types, HEK293 cells stably expressing ALK, and MSC80 cells, a previously described Schwann cell line, we showed that a factor secreted by the Schwann cells is likely involved in the absence of ALK cleavage. All these data hence open new perspectives concerning the role of ALK in the specification of nociceptive DRG neurons and in the neurons-Schwann cells interaction.

Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase essentially and transiently expressed in specific areas of the developing central and peripheral nervous systems. We previously demonstrated that a membrane-bound and constitutively active form of the ALK protein tyrosine kinase (PTK) domain induced the neuron-like differentiation of PC12 cells through specific activation of the mitogen-activated protein kinase (MAP kinase) pathway. Its PTK domain had been originally identified in a nucleo-cytosolic and constitutively active transforming protein, NPM-ALK. Downstream targets involved in oncogenic proliferation and survival processes have been proposed to include phospholipase Cgamma (PLCgamma), phosphoinositide 3-kinase (PI 3-kinase)/AKT, STAT 3/5 and Src. We therefore postulated that activation of specific signaling pathways leading to differentiation or proliferation can be differently controlled depending on the subcellular localization of ALK PTK domain. To increase knowledge of its physiological role in the nervous system, we focused in the present study on the influence of its subcellular localization on neuronal differentiation. To achieve this goal, we characterized biological responses and transduction pathways in PC12 cells elicited by various constructs encoding membrane-bound (through transmembrane or myristyl sequences) or cytosolic ALK-derived proteins. In order to control the activation of their PTK domain, we used an inducible dimerization system. Here, we demonstrate that membrane attachment of the ALK PTK domain, in PC12 cells, is crucial for initiation of neurite outgrowth and proliferation arrest through a decrease of DNA synthesis. Furthermore, we show that this differentiation process relies on specific and sustained activation of ERK 1/2 proteins. By contrast, activation of the cytosolic form of this domain fails to induce MAP kinase activation and cell differentiation but promotes a PI 3-kinase/AKT-dependent PC12 cell proliferation. These data indicate that subcellular localization of the ALK PTK domain was a determinant for the control and specificity of downstream transduction cascades and was crucial for deciding the fate to which the neuronal cell will be committed.

Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is transiently expressed in specific regions of the central and peripheral nervous systems, suggesting a role in its normal development and function. The nature of the cognate ligands of ALK in vertebrate is still a matter of debate. We produced a panel of monoclonal antibodies (mAbs) directed against the extracellular domain of the human receptor. Two major species of ALK (220 and 140 kDa) were identified in transfected cells, and the use of our mAbs established that the 140-kDa species results from a cleavage of the 220-kDa form. Two mAbs, in the nm range, induced the differentiation of PC12 cells transiently transfected with ALK. In human embryonic kidney 293 cells stably expressing ALK, these two mAbs strongly activated the receptor and subsequently the mitogen-activated protein kinase pathway. We further showed for the first time that activation of ALK also resulted in a specific activation of STAT3. In contrast, other mAbs presented the characteristics of blocking antibodies. Finally, in these cell systems, a mitogenic form of pleiotrophin, a proposed ligand of ALK, failed to activate this receptor. Thus, in the absence of clearly established ligand(s) in vertebrates, the availability of mAbs allowing the activation or the inhibition of the receptor will be essential for a better understanding of the biological roles of ALK.

HB-GAM/Pleiotrophin and Midkine are differently expressed and distributed during retinoic acid-induced neural differentiation of P19 cells.

HB-GAM/Pleiotrophin and Midkine (MK) are developmentally-regulated proteins with putative functions during cell growth and differentiation. Using the P19 cell which is a model to study the events associated with early development, we examined the expression and cellular localization of HB-GAM and MK during neural differentiation of P19 cells induced by retinoic acid (RA). The temporal expressions of HB-GAM and MK transcripts and both the levels and cellular localizations of the corresponding proteins appeared dramatically different. MK mRNA, already expressed in untreated P19 cells, was transiently increased by exposure to RA and then largely down regulated. More interestingly, HB-GAM which was not detected in untreated P19 cells was strongly expressed after 2 days of RA treatment and this expression persists throughout the duration of the culture suggesting that it could be involved in different aspects of this differentiation process.