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Recent evidence suggests a positive impact of bilingualism on cognition, including later onset of dementia. However, monolinguals and bilinguals might have different baseline cognitive ability. We present the first study examining the effect of bilingualism on later-life cognition controlling for childhood intelligence. We studied 853 participants, first tested in 1947 (age = 11 years), and retested in 2008-2010. Bilinguals performed significantly better than predicted from their baseline cognitive abilities, with strongest effects on general intelligence and reading. Our results suggest a positive effect of bilingualism on later-life cognition, including in those who acquired their second language in adulthood., (© 2014 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Recent studies, using predominantly visual tasks, indicate that early bilinguals tend to outperform monolinguals on attention tests. It remains less clear whether such advantages extend to those bilinguals who have acquired their second language later in life. We examined this question in 38 monolingual and 60 bilingual university students. The bilingual group was further subdivided into early childhood (ECB), late childhood (LCB), and early adulthood bilinguals (EAB). The assessment consisted of five subtests from the clinically validated Test of Everyday Attention (TEA). Overall, bilinguals outperformed monolinguals on auditory attention tests, but not on visual search tasks. The latter observation suggests that the differences between bilinguals and monolinguals are specific and not due to a generally higher cognitive performance in bilinguals. Within the bilingual group, ECB showed a larger advantage on attention switching, LCB/EAB on selective attention. We conclude that the effects of bilingualism extend into the auditory domain and are not confined to childhood bilinguals, although their scope might be slightly different in early and late bilinguals.

Evidence suggests that education protects from dementia by enhancing cognitive reserve. However, this may be influenced by several socio-demographic factors. Rising numbers of dementia in India, high levels of illiteracy and heterogeneity in socio-demographic factors provide an opportunity to explore this relationship., Objective: To study the association between education and age at dementia onset, in relation to socio-demographic factors., Methods: Association between age at dementia onset and literacy was studied in relationship to potential confounding factors such as gender, bilingualism, place of dwelling, occupation, vascular risk factors, stroke, family history of dementia and dementia subtypes., Results: Case records of 648 dementia patients diagnosed in a specialist clinic in a University hospital in Hyderabad, India were examined. All patients were prospectively enrolled as part of an ongoing longitudinal project that aims to evaluate dementia subjects with detailed clinical, etiological, imaging, and follow-up studies. Of the 648 patients, 98 (15.1%) were illiterate. More than half of illiterate skilled workers were engaged in crafts and skilled agriculture unlike literates who were in trade or clerical jobs. Mean age at onset in illiterates was 60.1 years and in literates 64.5 years (p=0.0002). Factors independently associated with age at dementia onset were bilingualism, rural dwelling and stroke, but not education., Conclusion: Our study demonstrates that in India, rural dwelling, bilingualism, stroke and occupation modify the relationship between education and dementia., Competing Interests: Disclosure: The authors report no conflicts of interest.

Purpose of Review: Within the last decade, the neurobiology of action processing has moved from an obscure topic of specialist interest to one of the most popular themes in modern neuroscience. However, the wealth of literature and the diversity of approaches and theoretical models can make the field complex and, at times, bewildering. This review presents the main currents of research, examining their theoretical underpinnings in an interdisciplinary context., Recent Findings: The presence of specific deficits in verb and action processing has been documented in a wide range of neurodegenerative diseases, including parkinsonian syndromes and motor neuron disease. Interestingly, most of these disorders affect the motor system, suggesting a systematic relationship between motor functions and their cognitive and linguistic representations. Action processing has been explored with a whole spectrum of methodologies, from neuroimaging to transcranial and intracranial stimulation. The findings have been integrated with other influential concepts and theories, including mirror neurons and embodied cognition., Summary: Converging evidence from patient and imaging studies links the concepts of actions and their processing with the execution of actions through the motor system. The theory of embodied cognition remains influential as well as controversial. However, the points of criticism have changed, reflecting recent paradigm shifts.

Purpose: To investigate brain-wide white matter structural changes associated with amyotrophic lateral sclerosis (ALS) using an automatic single seed point tractography-based segmentation method, probabilistic neighborhood tractography (PNT), which provides quantitative measures of both tract integrity and shape., Materials and Methods: Diffusion MRI data were acquired from 30 patients with ALS (ALS Functional Rating Scale-Revised score > 20) and 30 matched controls. PNT was used to segment 12 major projection, commissural and association fibers, and assess differences in how the shape of an individual subject's tract compares to that of a predefined reference tract, in addition to providing tract-average mean diffusivity (〈D〉) and fractional anisotropy (FA) data., Results: Across all 12 tracts, group-averaged 〈D〉 was larger, while group-averaged FA was equal to or smaller in value for patients than controls. These differences were significant for right cingulum 〈D〉, and left and right corticospinal tract (CST) 〈D〉 and FA (P-values 6 × 10(-5) to 0.03). Tract shape modeling indicated that there were significantly greater topological differences from the reference tract in left and right CST, and right uncinate fasciculus (P-values 0.02 to 0.04) for patients than controls. The rate of disease progression was significantly negatively correlated with bilateral CST FA (P-values 0.01 to 0.02)., Conclusion: ALS, although particularly affecting CST, is associated with subtle changes in white matter tract integrity and shape in several other major fibers within the brain. Correlations between CST integrity and disease progression rate suggest that quantitative tractography may provide useful biomarkers of disease evolution in ALS., (Copyright © 2013 Wiley Periodicals, Inc.)

Among the instruments to evaluate semantic memory, the Pyramids and Palm Trees (PPT) and the Kissing and Dancing (KDT) tests are widely used but none have a performance referential for cognitively normal and impaired Brazilian populations., Objective: [A] To study these two tests in a sample of young healthy Brazilian individuals living in São Paulo; [B] To apply the results to the evaluation of two cases diagnosed with frontotemporal lobar degeneration., Methods: We evaluated 50 normal participants (41 females and 9 males) aged between 20-63 years, with schooling level of 14-20 years. In addition, two individuals diagnosed with frontotemporal lobar degeneration were examined, one with behavioral-variant frontotemporal dementia and the other with semantic dementia., Results: On the two tests, no effects of age, gender and schooling on the performance of normal individuals were observed. According to the performance of the sample of controls, scores below 46 points on the PPT and below 47 on the KDT are suggestive of deficits in semantic memory. The analyses of both cases indicated double dissociation in establishing associations between nouns and action verbs. Although the two patients had low scores on both tests, the patient with behavioral-variant frontotemporal dementia performed better on the PPT compared to the KDT, while the patient with semantic dementia showed the reverse, performing better on the KDT., Conclusion: The PPT and KDT are suitable tests for use in the Brazilian population, with minimal need for adjustments. They are applicable tools both for cognitive assessment and research in semantic memory. In the present study, we obtained representative values of performance for cognitively unimpaired individuals and demonstrated the utility of these instruments for cognitive assessment of patients with FTLD., Competing Interests: Disclosure: The authors report no conflicts of interest.

Postmortem studies of synapses in human brain are problematic because of the axial resolution limit of light microscopy and the difficulty in preserving and analyzing ultrastructure with electron microscopy (EM). Array tomography (AT) overcomes these problems by embedding autopsy tissue in resin and cutting ribbons of ultrathin serial sections. Ribbons are imaged with immunofluorescence, allowing high-throughput imaging of tens of thousands of synapses to assess synapse density and protein composition. The protocol takes ~3 d per case, excluding image analysis, which is done at the end of the study. Parallel processing for transmission electron microscopy (TEM) using a protocol modified to preserve the structure in human samples allows complementary ultrastructural studies. Incorporation of AT and TEM into brain banking is a potent way of phenotyping synapses in well-characterized clinical cohorts in order to develop clinicopathological correlations at the synapse level. This will be important for research in neurodegenerative disease, developmental disease and psychiatric illness.

For more than a century the research on Motor Neuron Disease (MND) has been dominated by a tension between the concept of a selective, purely motor degeneration and a growing realisation of the high frequency and importance of cognitive symptoms that can culminate in dementia. The present paper aims at integrating these two, seemingly mutually exclusive interpretations of the disease. It is proposed that the cognitive and motor symptoms in MND are due to the same selective neurodegenerative process, spreading along the lines of functional connections in the nervous system. Accordingly, the most impaired aspects of cognitive function are those with the closest functional links to the motor system, a pattern explaining a disproportionate impairment of verb and action processing in this disease. The dementia associated with MND can be interpreted as the fifth major clinical presentation of MND, alongside bulbar, thoracic, upper and lower limb presentation. It follows the same rules of disease progression as other presentations, spreading contiguously from region to region, with a predominantly caudal direction. Accordingly, dementia tends to precede other presentations and is often followed by bulbar symptoms. We believe that the presented model contributes to a more accurate concept of MND, integrating cognitive and motor features within the same disease mechanism. At the same time it highlights the importance of MND for cognitive neuroscience and, in particular, for theories of embodied cognition., (Copyright © 2011 Elsevier Srl. All rights reserved.)

Introduction: The motor features of corticobasal syndrome (CBS) are well recognized but the fact that many, if not all, affected patients develop cognitive impairment is still underrecognized. The dementia of CBS overlaps most with a language variant of frontotemporal dementia: progressive nonfluent aphasia (PNFA). The aim of this study was to determine the usefulness of Addenbrooke's Cognitive Examination-Revised (ACE-R) in the evaluation of CBS and to document similarities and differences between CBS and PNFA., Materials and Methods: Patients with well-defined CBS or PNFA from two tertiary referral centers were selected along with matched controls., Results: Twenty-one patients with CBS, 23 patients with PNFA and 47 age- and education- matched controls were included. Both CBS and PNFA groups showed substantial impairment on the ACE-R (f = 17.3-80.2, p < 0.001) and were significantly impaired in all domains (p < 0.001). The only significant difference between CBS and PNFA was in the visuospatial domain (p < 0.009), being worse in CBS. Using a cutoff of 88/89 out of 100, 90% of CBS and 82.6% of PNFA patients were impaired. At this cutoff of 88/89, ACE-R in CBS had sensitivity and specificity values of 91 and 98%, respectively., (Copyright © 2011 S. Karger AG, Basel.)

This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n=372) or progressive supranuclear palsy (n=311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort. The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively. On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy. Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale. The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy). Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole. These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinson's disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.

Objective: To compare the clinical features at presentation in patients with frontotemporal dementia (FTD) who develop amyotrophic lateral sclerosis (ALS) with those of patients with behavioral variant FTD (bvFTD) who do not develop ALS., Design: Archival data analysis on 61 deceased patients with FTD. We reviewed the clinical features at presentation (behavioral changes, psychotic symptoms, language, and executive and memory problems) and survival., Setting: Early Onset Dementia Clinic, Cambridge, England. Patients From a total of 156 patients with a clinical diagnosis of behavioral FTD, we selected 61 deceased patients with comprehensive medical records, including 43 with bvFTD and 18 with FTD/ALS., Main Outcome Measures: Clinical features and survival., Results: There was a significant association between the presence of delusions (50%; odds ratio, 4.4; 95% confidence interval, 1.3-14.5) and diagnosis of FTD/ALS (n = 18), whereas the behavioral features were identical in both groups. The interval between the onset of behavioral changes and diagnosis of ALS was less than 2 years in 12 (67%) of the patients with FTD/ALS. The median survival from symptom onset was significantly shorter for the FTD/ALS group (2.4 years; 95% confidence interval, 1.8-3.0 years) than for the bvFTD group (6.6 years; 5.6-7.6 years)., Conclusions: Delusions are particularly common in patients who develop FTD/ALS. The occurrence of delusions in the context of behavioral FTD should lead to an early search for ALS features.

Selective verb and noun deficits have been observed in a number of neurological conditions and their occurrence has been interpreted as evidence for different neural networks underlying the processing of specific word categories. We describe the first case of a familial occurrence of a selective deficit of verb processing. Father (Individual I) and son (Individual II) developed a movement disorder resembling progressive supranuclear palsy (PSP) and associated with dementia. A second child of Individual II remained symptom-free on consecutive examinations. The dissociation between the processing of nouns and verbs in Individuals I and II was confirmed with different methods, including a longitudinal assessment of naming, comprehension, picture and word association, as well as a lexical decision task. The difference remained stable on follow-up testing despite overall deterioration. It was associated with left-sided frontal hypometabolism on FDG-PET imaging (Individual II) and with ubiquitin-positive inclusions on post-mortem examination (Individual I). The association of a selective verb deficit with a familial movement disorder raises the question whether related genetic factors might influence both movements and their abstract conceptual representations in the form of action verbs. By demonstrating a link between pathology, genetics, imaging and abstract cognitive impairments this study advances our understanding of degenerative brain disease with implications for both neuroscience and clinical practice.

We recently reported on a series of patients who experienced acute cellular rejection (ACR) during the treatment of hepatitis C virus (HCV) infection in our posttransplantation cohort. Our hypothesis is that HCV clearance improves hepatic microsomal function, which in turn results in lower trough cyclosporine (CyA) and tacrolimus (TAC) levels, predisposing the patient to ACR. Records of all patients receiving transplants for HCV infection at our center from 1993 to June 2002 were reviewed. Two hundred three patients were identified. Thirty-seven patients (18%) were treated with interferon-based therapies in combination with ribavirin. Twelve patients were selected for analysis because they became HCV RNA negative during therapy, and 18 patients with no antiviral response were selected as controls (7 other patients had incomplete data or had switched from one immunosuppression [IS] therapy to the other). Baseline IS levels were compared with the first available level after documented negative HCV RNA results in the study group and the last on-treatment IS level in the control group. We also compared frequency and percentage of change in IS levels during therapy. Mean decline in CyA trough levels in the study group was from 187.28 ng/mL at baseline to 118.14 ng/mL immediately after becoming HCV RNA negative (-36.92%; P =.018). Mean decline in TAC levels was from 7.34 ng/mL at baseline to 5.02 ng/mL immediately after becoming HCV RNA negative (-29.17%; P =.044). Overall, 6 of 12 patients who cleared HCV RNA during therapy experienced ACR; 1 patient died as a result of ACR. Using percentage of decrease from baseline IS level, we combined results for patients administered CyA and TAC and found a significant decrease from baseline IS levels in responders (-31.8% after HCV RNA clearance on treatment; P =.0001). Nonresponders experienced a 0.98% decline in IS levels while on treatment, and the difference was significant compared with the change in the responder group (P =.006). A greater proportion of antiviral therapy responders also experienced trough IS levels 20% less than baseline than nonresponder controls during therapy (P =.0006). In conclusion, IS levels decreased significantly in patients responding favorably to anti-HCV therapy. This decrease in IS levels may have a key role in predisposing these patients to ACR.

Although living donor liver transplantation (LDLT) is a successful procedure for most recipients, outcomes in patients who undergo transplantation as United Network for Organ Sharing status 2A are marginal. There are no published data on living donor liver transplant recipient outcomes relative to Model for End-Stage Liver Disease (MELD) scores. Such information could be useful in living donor liver transplant recipient selection. We retrospectively analyzed all non-fulminant hepatic failure, right hepatic lobe, adult-to-adult living donor liver transplant recipients at our center between August 1997 and March 2002. We calculated MELD scores at the time of LDLT and correlated scores with 1-year patient and graft survival and hospital days during the 90-day post-LDLT period. There were 62 recipients with greater than 6 months of follow-up: 38 men, 24 women; mean age, 47.9 years; 42 white, 1 black, 17 Hispanic, and 2 Asian patients. Twenty-nine patients had hepatitis C virus infection; 4 patients, hepatitis C virus infection and alcoholic liver disease; 4 patients, alcoholic liver disease; 4 patients, cryptogenic cirrhosis; 13 patients, primary sclerosing cholangitis; 5 patients, autoimmune hepatitis; and 3 patients, primary biliary cirrhosis. Mean and median MELD scores were 15.2 and 13, respectively (range, 6 to 40). One-year patient and graft survival were 59 of 62 patients (95%) and 52 of 62 patients (84%), respectively. There was no statistically significant difference between median MELD scores of dead versus living patients (15 v 13; P =.15) or patients who underwent retransplantation versus those who did not (16.5 v 13; P =.30). Mean and median hospital days in the 90-day post-LDLT period were 23.7 and 16.0 days, respectively. Living donor liver transplant recipients with a MELD score of 18 or greater had significantly more hospital days compared with recipients with a MELD score less than 18 (35.2 v 19.8 days; P =.01). In conclusion, MELD scores did not predict post-LDLT patient or graft survival at 1 year. However, higher MELD scores (> or =18) were associated with more hospital days during the 3-month post-LDLT period.

Primary sclerosing cholangitis (PSC) is the fourth leading diagnosis in liver transplant recipients in the United States. The disease is known to recur in 15% to 30% of liver transplant recipients. We set out to investigate how different immunosuppression regimens affected natural history of PSC after liver transplantation at our center. We reviewed records of all patients who underwent a liver transplantation at our institution in between 1988 and 2000 and had a diagnosis of PSC at the time of liver transplantation. Primary sclerosing cholangitis recurred in 15 of 71 patients (21.1%) who had complete records and survived more than 30 days after liver transplantation. Although recurrence of primary sclerosing cholangitis was most often seen (but not statistically significantly so) in patients who received maintenance corticosteroids, the time to recurrence was not significantly different between those who were treated with maintenance, those who were not successfully weaned, and those who successfully weaned off corticosteroids within 3 months after liver transplantation. Orthoclone (OKT3) therapy (Ortho-Biotech, Inc., Raritan, NJ) was associated with a higher risk of primary sclerosing cholangitis recurrence (29% versus 10%, P <.05). Recurrence was not influenced by immunosuppression with either cyclosporine or tacrolimus. Coexistent inflammatory bowel disease was a cause of failure to wean off corticosteroids, was associated with a shorter time to recurrence of sclerosing cholangitis, and was responsible for significant comorbidity (colon cancer in 7.3%). Primary sclerosing cholangitis recurrence is commonly seen after liver transplantation. More immunosuppression seems to be detrimental to the outcome of our patients with sclerosing cholangitis: use of OKT3 was associated with a greater incidence of recurrence. Length of corticosteroid use did not affect timing or risk of recurrence, and because it has been proven that early corticosteroid withdrawal after liver transplantation is beneficial, we continue to recommend this practice.

Sirolimus is a new immunosuppressive agent increasingly being used in liver transplant recipients. There is concern that sirolimus may be associated with wound complications and hepatic artery thrombosis (HAT). We have used sirolimus as primary immunosuppression in 170 liver transplant recipients and therefore reviewed our experience with wound complications and HAT in our cohort of patients. Records of all 170 patients administered sirolimus as primary immunosuppression and 180 historic controls were reviewed. Numbers of wound and hepatic artery complications were recorded, as well as the prevalence of obesity, reoperation, diabetes, and OKT3 use, all of which are risk factors for wound complications. The prevalence of wound complications was 12.4% in sirolimus-treated patients compared with 13.9% in historic controls (P = not significant [NS]). The prevalence of hepatic artery complications was 5.3% in sirolimus-treated patients compared with 8.3% in historic controls (P = NS). The prevalence of obesity and OKT3 administration was significantly lower in sirolimus-treated patients. Multivariate analysis failed to show an association between sirolimus therapy and hepatic artery or wound complications. The prevalence of wound and hepatic artery complications is not different in liver transplant recipients administered sirolimus as part of a primary immunosuppressive regimen compared with historic controls.

We sought to determine the pattern of cognitive deficits in patients with Wilson's disease (WD) with different type and degree of neurological involvement, and to interpret the findings in relation to the underlying pathology. A total of 67 WD patients were examined with a neuropsychological test battery assessing different aspects of cognitive processing. The patients were subdivided into three groups: neurologically asymptomatic, neurological with pure basal ganglia lesions, and neurological with more extensive pathology. The results were compared with 50 matched healthy controls. Patients with a neurological form of WD showed a mild but definitive impairment in all cognitive functions. In contrast, the neurologically asymptomatic patients showed no deficits when compared with normal controls. Multifocal pathology was associated with more severe cognitive deficits than selective basal ganglia lesions but did not contribute significantly to memory impairment. A range of cognitive functions, including frontal-executive ability, aspects of memory and visuospatial processing, are affected in the neurologically symptomatic WD patients. In contrast, no subliminal deficits were observed in the asymptomatic patients. The lesions of the basal ganglia seem to be of central importance in explaining the symptomatology., (Copyright 2002 Movement Disorder Society)

Two recent brief reports suggest that recipients of living donor liver transplants achieve higher levels of immunosuppressive agents than cadaveric (CAD) liver transplant recipients administered the same dose. These results could have important implications regarding the dosing of immunosuppressives in living donor liver transplant recipients. We report our findings relative to immunosuppressive doses and levels in a cohort of 46 living donor liver transplant recipients. Immunosuppressive blood levels and doses were recorded weeks 1, 2, 3, and 4 and months 2, 3, 4, 5, and 6 for 46 living donor liver transplant recipients and 66 matched CAD liver transplant recipients who underwent transplantation between August 1997 and May 2001. The ratio of level to dose also was recorded at each interval. The mean overall cyclosporine A dose was similar in living donor liver transplant recipients (323 mg/d) compared with CAD recipients (344 mg/d; P = not significant [NS]). The mean overall tacrolimus dose was 15% lower in patients who underwent living donor liver transplantation (LDLT; 5.7 mg/d) than CAD transplantation (6.7 mg/d), although statistical significance was not achieved (P =.08). The mean overall cyclosporine A level was 18% higher in those undergoing LDLT (275 ng/mL) than CAD transplantation (234 ng/mL; P =.015). The mean overall tacrolimus level was the same in living donor liver transplant recipients (10.8 ng/mL) and CAD recipients (10.2 ng/mL; P = NS). The overall cyclosporine A level-dose ratio was 26% higher for those undergoing LDLT (0.83) than CAD transplantation (0.66; P =.01). The overall tacrolimus level-dose ratio was 26% higher for those undergoing LDLT (1.82) than CAD transplantation (1.44; P =.01). In conclusion, (1) living donor liver transplant recipients achieve higher blood levels of tacrolimus and cyclosporine A for a given dose compared with CAD recipients, and (2) this difference is observed up to 6 months after transplantation, when hepatic regeneration is completed.