A. W. Campbells Australian career: 1905-1937

The Australian Alfred Walter Campbell (1868-1937) is remembered as one of the two chief pioneers of the study of the cytoarchitectonics of the primate cerebral cortex. He had worked in Britain carrying out neuroanatomical and neuropathological research for almost two decades before his famous monograph on Histological Studies on the Localisation of Cerebral Function appeared in 1905. In that year he returned to his native Australia and practiced for over 30 years in Sydney as a neurologist rather than a neuropathologist, publishing mainly clinical material though he was involved in the investigation of the epidemic of Australian X disease, a viral encephalitis. His abrupt change in both the nature and the location of his career at a time when he was well established in Britain appears to have been a consequence of his marriage and the need to provide for a family. His simultaneous apparent abandonment of research seems not to have really been the case. As judged from the contents of a paper presented to a local medical congress in Sydney in 1911, it appears that, in Australia, Campbell did carry out a major comparative anatomical and histological investigation of the possibility of localization of function in the cerebellar cortex. He never published this work in detail. His investigation let him to conclude that no such localization of function existed, a view contrary to the then topical interpretation of Bolk (1906), but one in accordance with Gordon Holmes' views a decade later. Campbell's circumstances in Sydney, his extremely reticent nature and the essentially negative outcome of his investigation probably explain his failure to make his study more widely known.

Corticosteroid-induced glaucoma in a child after a scleral reinforcement procedure

Corticoteroid-induced glaucoma can result from either topical or systemic corticosteroid use. Compared with adults, the corticosteroid response in children is less well known. The case is reported of a child who developed glaucoma after receiving topical corticosteroids following a scleral re-inforcement procedure. The raised intraocular pressure was controlled after cessation of the corticosteroids and with the use of antiglaucoma therapy. As many forms of cortico-steroids are widely used, children on corticosteroids should have regular intraocular pressure measurements as part of their management.

A role for the dominant thalamus in language? A linguistic comparison of two cases subsequent to unilateral thalamotomy procedures in the dominant and non-dominant hemispheres

Background: Thalamotomy has been reported to be successful in ameliorating the motor symptoms of tremor and/or rigidity in people with Parkinson's disease (PD), emphasising the bona fide contribution of this subcortical nucleus to the neural circuitry subserving motor function. Despite evidence of parallel yet segregated associative and motor cortico-subcortical-cortical circuits, comparatively few studies have investigated the effects of this procedure on cognitive functions. In particular, research pertaining to the impact of thalamotomy on linguistic processes is fundamentally lacking. Aims: The purpose of this research was to investigate the effects of thalamotomy in the language dominant and non-dominant hemispheres on linguistic functioning, relative to operative theoretical models of subcortical participation in language. This paper compares the linguistic profiles of two males with PD, aged 75 years (10 years of formal education) and 62 years (22 years of formal education), subsequent to unilateral thalamotomy procedures within the language dominant and non-dominant hemispheres, respectively. Methods & Procedures: Comprehensive linguistic profiles comprising general and high-level linguistic abilities in addition to on-line semantic processing skills were compiled up to 1 month prior to surgery and 3 months post-operatively, within perceived on'' periods (i.e., when optimally medicated). Pre- and post-operative language performances were compared within-subjects to a group of 16 non-surgical Parkinson's controls (NSPD) and a group of 16 non-neurologically impaired adults (NC). Outcomes & Results: The findings of this research suggest a laterality effect with regard to the contribution of the thalamus to high-level linguistic abilities and, potentially, the temporal processing of semantic information. This outcome supports the application of high-level linguistic assessments and measures of semantic processing proficiency to the clinical management of individuals with dominant thalamic lesions. Conclusions: The results reported lend support to contemporary theories of dominant thalamic participation in language, serving to further elucidate our current understanding of the role of subcortical structures in mediating linguistic processes, relevant to cortical hemispheric dominance.

Effects of intravenous injection of Clostridium perfringens type D epsilon toxin in calves

In cattle, a neurological lesion similar to that produced in sheep and goats by Clostridium perfringens type D enterotoxaemia has been reported. However, no causal relationship has been established between this disease and the lesion in cattle. The effects of single and multiple intravenous injections of epsilon toxin in three calves aged 6 months were studied. A further calf was inoculated intravenously with saline solution and used as a control. Epsilon toxin invariably produced neurological signs within 2-60 min of the end of the injection process. Clinical signs consisted of loss of consciousness, recumbency, convulsions, paddling, opisthotonus, hyperaesthesia and dyspnoea. Gross changes consisted of severe acute pulmonary oedema, which was particularly marked in the interlobular septa. The histological lesions consisted of intra-alveolar and interstitial oedema of the lung and variable degrees of perivascular proteinaceous oedema in the internal capsule, thalamus and cerebellar white matter. No clinical or post-mortem changes were observed in the control calf. These results show that calves are susceptible to the intravenous injection of epsilon toxin, and that they can show at least some of the histological lesions produced in sheep and goats by this toxin. (C) 2002 Harcourt Publishers Ltd.

Granulomatous meningoencephalomyelitis in dogs

Granulomatous meningoencephalomyelitis (GME) is a morphological description of an inflammatory disorder of the canine central nervous system (CNS). It has been reported in many areas of the world. including Australia, and is one of the more common nervous disorders of dogs. Most breeds of dogs of both sexes and all ages can be affected but young to middle-aged small and terrier breeds have been stated as being more susceptible. There are variable anatomical forms and distribution of the lesions in the CNS; the presenting clinical signs can reflect singly or collectively cerebellar, cerebral, and brain stem dysfunction. Meningeal and spinal cord involvement are also common. There is no specific diagnostic test but a combination of clinical signs, history and cerebro-spinal fluid cytology are useful indicators. However differential diagnosis from other inflammatory disorders of the brain is difficult. No infectious agent aetiology has been established for GME and therefore no satisfactory therapeutic approach is available. The role of the immune system in terms of either initiating or potentiating the lesions in the CNS appears to be the most likely direction for further investigation into the nature of this disorder.

Distribution of two splice variants of the glutamate transporter GLT-1 in rat brain and pituitary

We have performed immunocytochemistry on rat brains using a highly specific antiserum directed against the originally described form of the glutamate transporter GLT-1 (referred to hereafter as GLT-1alpha), and another against a C-terminal splice variant of this protein, GLT-1B. Both forms of GLT-1 were abundant in rat brain, especially in regions such as the hippocampus and cerebral cortex, and macroscopic examination of sections suggested that both forms were generally regionally coexistent. However, disparities were evident; GLT-1alpha was present in the intermediate lobe of the pituitary gland, whereas GLT-1B was absent. Similar marked disparities were also noted in the external capsule, where GLT1A labeling was abundant but GLT-1B was only occasionally encountered. Conversely, GLT-1B was more extensively distributed, relative to GLT-1alpha, in areas such as the deep cerebellar nuclei. In most regions, such as the olfactory bulbs, both splice variants were present but differences were evident in their distribution. In cerebral cortex, patches were evident where GLT-1B was absent, whereas no such patches were evident for GLT-1alpha. At high resolution, other discrepancies were evident; double-labeling of areas such as hippocampus indicated that the. two splice variants may either be differentially expressed by closely apposed glial elements or that the two splice variants may be differentially targeted to distinct membrane domains of individual glial cells. (C) 2002 Wiley-Liss, Inc.

Localization of taurine transporters, taurine, and H-3 taurine accumulation in the rat retina, pituitary, and brain

The nervous system contains an abundance of taurine, a neuroactive sulfonic acid. Antibodies were generated against two cloned high-affinity taurine transporters, referred to in this study as TAUT-1 and TAUT-2. The distribution of such was compared with the distribution of taurine in the rat brain, pituitary, and retina. The cellular pattern of [H-3] taurine uptake in brain slices, pituitary slices, and retinas was examined by autoradiography. TAUT-2 was predominantly associated with glial cells, including the Bergmann glial cells of the cerebellum and astrocytes in brain areas such as hippocampus. Low-level labeling for TAUT-2 was also observed in some neurones such as CA1 pyramidal cells. TAUT-1 distribution was more limited; in the posterior pituitary TAUT-1 was associated with the pituicytes but was absent from glial cells in the intermediate and anterior lobes. Conversely, in the brain TAUT-1 was associated with cerebellar Purkinje cells and, in the retina, with photoreceptors and bipolar cells. Our data suggest that intracellular taurine levels in glial cells and neurons may be regulated in part by specific high-affinity taurine transporters. The heterogeneous distribution of taurine and its transporters in the brain does not reconcile well with the possibility that taurine acts solely as a ubiquitous osmolyte in nervous tissues. (C) 2002 Wiley-Liss, Inc.

Oxidative stress is responsible for deficient survival and dendritogenesis in Purkinje neurons from ataxia-telangiectasia mutated mutant mice

Atm gene-disrupted mice recapitulate the majority of characteristics observed in patients with the genetic disorder ataxia-telangiectasia (A-T). However, although they exhibit defects in neuromotor function and a distinct neurological phenotype, they do not show the progressive neurodegeneration seen in human patients, but there is evidence that ataxia-telangiectasia mutated ( Atm)-deficient animals have elevated levels of oxidized macromolecules and some neuropathology. We report here that in vitro survival of cerebellar Purkinje cells from both Atm knock-out and Atm knock-in mice was significantly reduced compared with their wild-type littermates. Although most of the Purkinje neurons from wild-type mice exhibited extensive dendritic elongation and branching under these conditions, most neurons from Atm-deficient mice had dramatically reduced dendritic branching. An antioxidant ( isoindoline nitroxide) prevented Purkinje cell death in Atm-deficient mice and enhanced dendritogenesis to wild-type levels. Furthermore, administration of the antioxidant throughout pregnancy had a small enhancing effect on Purkinje neuron survival in Atm gene-disrupted animals and protected against oxidative stress in older animals. These data provide strong evidence for a defect in the cerebellum of Atm-deficient mice and suggest that oxidative stress contributes to this phenotype.

Nutritional effects on neuron numbers

Undemutrition during early life is known to cause deficits and distortions of brain structure although it has remained uncertain whether or not this includes a diminution of the total numbers of neurons. Estimates of numerical density (e.g. number of cells per microscopic field, or number of cells per unit area of section, or number of cells per unit volume of tissue) are extremely difficult to interpret and do not provide estimates of total numbers of cells. However, advances in stereological techniques have made it possible to obtain unbiased estimates of total numbers of cells in well defined biological structures. These methods have been utilised in studies to determine the effects of varying periods of undernutrition during early life on the numbers of neurons in various regions of the rat brain. The regions examined so far have included the cerebellum, the dentate gyrus, the olfactory bulbs and the cerebral cortex. The only region to show, unequivocally, that a period of undernutrition during early life causes a deficit in the number of neurons was the dentate gyrus. These findings are discussed in the context of other morphological and functional deficits present in undernourished animals.

Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats

Pesticide exposure during brain development could represent an important risk factor for the onset of neurodegenerative diseases. Previous studies investigated the effect of permethrin (PERM) administered at 34 mg/kg, a dose close to the no observable adverse effect level (NOAEL) from post natal day (PND) 6 to PND 21 in rats. Despite the PERM dose did not elicited overt signs of toxicity (i.e. normal body weight gain curve), it was able to induce striatal neurodegeneration (dopamine and Nurr1 reduction, and lipid peroxidation increase). The present study was designed to characterize the cognitive deficits in the current animal model. When during late adulthood PERM treated rats were tested for spatial working memory performances in a T-maze-rewarded alternation task they took longer to choose for the correct arm in comparison to age matched controls. No differences between groups were found in anxiety-like state, locomotor activity, feeding behavior and spatial orientation task. Our findings showing a selective effect of PERM treatment on the T-maze task point to an involvement of frontal cortico-striatal circuitry rather than to a role for the hippocampus. The predominant disturbances concern the dopamine (DA) depletion in the striatum and, the serotonin (5-HT) and noradrenaline (NE) unbalance together with a hypometabolic state in the medial prefrontal cortex area. In the hippocampus, an increase of NE and a decrease of DA were observed in PERM treated rats as compared to controls. The concentration of the most representative marker for pyrethroid exposure (3-phenoxybenzoic acid) measured in the urine of rodents 12 h after the last treatment was 41.50 µ/L and it was completely eliminated after 96 h.

Alterações da substância branca cerebral relacionadas com o envelhecimento

INTRODUÇÃO: Estudos prévios, com técnicas de imagem, documentam de forma consistente a existência de alterações da substância branca cerebral relacionadas com o envelhecimento (ASBRE). Tais alterações poderão ter um papel importante no declínio funcional do idoso, reflectindo‐se sobretudo no desempenho motor e cognitivo, com repercussão evidente na prática clínica. Apesar disso, a caracterização em definitivo dos fenótipos clínicos e da evolução das ASBRE continua por esclarecer, possivelmente pelas dificuldades metodológicas de que se reveste o seu estudo, incluindo: a adequação das baterias neuropsicológicas, a utilização de amostras de doentes com diferentes graus de severidade e de envolvimento regional, as limitações das diferentes escalas e a sensibilidade dos diferentes métodos de imagem. A Ressonância Magnética (RM) de difusão tem revelado grande sensibilidade para as alterações isquémicas, admitindo‐se que poderá permitir uma melhor caracterização das ASBRE e deste modo possibilitar uma correlação mais precisa com as variáveis cognitivas e motoras, permitindo avaliar ainda a substância branca aparentemente normal (SBAN). OBJECTIVOS: Descrever a evolução imagiológica das ASBRE no intervalo de um ano e analisar a sua expressão clínica e impacto funcional; identificar factores preditivos de progressão das ASBRE e de declínio funcional associado. Descrever a expressão clínica e perfil evolutivo dos doentes com ASBRE com envolvimento preferencial da região parieto‐occipital; comparar este grupo de doentes com os doentes com ASBRE, sem envolvimento preferencial desta região. Medir os coeficientes de difusão aparente (CDA), utilizando regiões de interesse (RDI), em diferentes localizações da substância branca, incluindo substância branca lesada e SBAN, descrever sua evolução temporal no intervalo de um ano e determinar suas correlações clínicas e imagiológicas. MÉTODOS: Utilizando uma amostra de conveniência, foram estudados 30 doentes, com mais de 65 anos, sem incapacidade funcional ou com incapacidade mínima, avaliada pela escala de actividades instrumentais da vida diária (IADL), apresentando ASBRE em TC. Foi utilizado um protocolo exaustivo de avaliação clínica (com particular destaque para as funções motoras e cognitivas) e imagiológica, em dois momentos de avaliação separados por um ano de intervalo (t0 e t1). As ASBRE foram avaliadas com escalas visuais, escala ARWMC e escala de Fazekas, e os doentes foram estudados em função do grau de severidade (ligeiro versus moderado a grave na escala de Fazekas) e de um envolvimento preferencial posterior (definido como 2 ou mais pontos na escala ARWMC na região parieto‐occipital por comparação com a região frontal). Os CDA foram avaliados mediante estudo de RDI, na substância branca frontal lesada (SBFL) e SBAN frontal, parieto‐occipital e dos pedúnculos cerebelosos. Para verificar diferenças na ordem de distribuição das variáveis foi usado o teste de Mann‐Whitney e para comparação de proporções, o teste exacto de Fisher. Na comparação entre a avaliação em t0 e t1 foi usado o teste Wilcoxon Signed Ranks na comparação da distribuição da ordem das variáveis e o teste McNemar na análise de frequências. Na análise correlacional foram utilizados os testes de T para variáveis emparelhadas e as correlações entre estas foram efectuadas com o coeficiente de correlação de Spearman ou de Pearson. O trabalho foi aprovado pela Comissão de Ética do hospital onde foi realizado e todos os doentes incluídos assinaram um consentimento informado. RESULTADOS: A idade média da população estudada foi 72,5 anos (17 doentes eram do sexo masculino). No final de um ano, 1 doente tinha falecido e 3 doentes não completaram a avaliação imagiológica. Registou‐se uma progressão significativa das ASBRE segundo a escala ARWMC (t0: 8,37 / t1: 9,65 ; p<0,001). Na análise funcional, motora e cognitiva, não houve um agravamento significativo. Avaliando os doentes em t0 e t1 segundo o grau de severidade das ASBRE, o grupo com atingimento moderado a grave (ASBRE2) comparado com o grupo com atingimento ligeiro (ASBRE1) apresentava: maior extensão de lesão da substância branca (ARWMC t0: 11,9 / 4,8 ; p<0.001 ; t1: 14,0 / 5,9 ; p<0,001); tendência a pior desempenho funcional (IADL t0: 90,7 / 99,2 ; p=0,023; t1: 86,4 / 96,7 ; p=n.s.) e motor (SPPB t0: 9,8 / 10,3 ; p=n.s. ; t1: 9,5 / 10,5 ; p=0,058); tendência a maior compromisso do humor (Escala Cornell t0: 6,7 / 3,5 ; p=0,037; t1: 6,2 / 4,5 ; p=n.s.). Analisando a evolução, de t0 para t1, de cada um dos grupos (ASBRE2 e ASBRE1) registou‐se: aumento da extensão da lesão da substância branca em ambos (ASBRE2: 12,0 / 14,0;z=‐2,687 ; p=0,007; ASBR1: 4,8 / 5,9 ; z=‐2,724 ; p=0,006); variação não significativa funcional e motora; tendência ao agravamento em ambos na prova de Cancelamento de dígitos (ASBRE2: 17,5 / 17,4 ; p=n.s. ; ASBRE1: 19,9 / 16,9 ; z=‐2,096 ; p=0,036);tendência à melhoria em ambos no MMS (ASBRE2: 25,7 / 27,5 ; z=‐2,155 ; p=0,031; ASBRE1: 27,5 / 28,2 ; p=n.s). Avaliando os doentes em t0 e t1 em função do padrão de distribuição das ASBRE, os doentes com um envolvimento preferencial posterior (ASBREP) comparados com os restantes (ASBREnP), apresentavam: maior extensão da lesão (ARWMC t0: 10,8 / 6,9 ; p=0,025; t1: 12,9 / 7,6 ; p=0,011); diferenças não significativas no desempenho motor; tendência a melhor desempenho na prova dos Labirintos (t0: 8,1 / 11,8 ; p=0,06; t1: 8,7 / 9,5 ; p=n.s.) e Cancelamento de dígitos (t0: 20,9 / 17,4 ; p=0,045; t1: 18,5 / 16,3 ; p=n.s.); tendência a maior compromisso depressivo na GDS (t0: 5,0 / 3,68 ; p=n.s. ; t1: 5,7 / 3,3 p=0,033). Analisando o perfil evolutivo de t0 para t1, registou‐se: aumento da extensão da lesão nos dois grupos (ASBREP: 10,8 / 12,9 ; z=‐2,555 ; P=0,011; ASBREnP: 6,4 / 7,6 ; z=‐2,877 ; p=0,04); variação em sentidos diferentes com melhoria funcional no grupo ASBREP (91,0 / 95,5 ; z=‐0,926 ; p=0,036) e agravamento no grupo ASBREnP (96,7 / 89,8 ; z=‐2,032 ; p=0,042); variação sem sentidos diferentes, com agravamento significativo no grupo ASBREnP no item estação de pé do SPPB (ASBREP 3,8/3,9 p=n.s.; ASBREnP 3,9/3,6; z=‐2,236 ; p=0,025); tendência à melhoria nos dois grupos no MMS (ASBREP: 27,2 / 28,2 ; p=n.s.; ASBREnP: 26,3 / 27,7 ; z=‐2,413 ; p=0,016) e tendência em sentidos diferentes no Trail Making, com eventual melhoria no grupo ASBREP (113,9 / 91,6 ; p=n.s.) e agravamento no grupo ASBREnP (113,7 / 152,0 ; z=‐2,155 ; p=0,031). Na análise da imagem, utilizando a escala ARWMC e o estudo dos CDA, na avaliação transversal na inclusão, a comparação entre as pontuações médias da escala ARWML nas diferentes regiões mostrava diferenças significativas (F=39,54 , p<0,0001). A análise comparativa post‐hoc de Bonferroni mostrou valores significativamente mais altos para as regiões frontais e parieto‐occipitais (p<0,0001). Os valores médios dos CDA eram significativamente diferentes entre regiões (F=44,56; p<0,0001), sendo mais altos na SBFL (p<0,0001). Não existia diferença significativa entre os valores registados na SBAN nas regiões frontais e parieto‐occipitais. As pontuações regionais da escala ARWMC e os valores médios dos CDA correlacionavam‐se todos de forma positiva. A pontuação da escala ARWMC na região frontal correlacionava‐se significativamente com os valores do CDA da SBFL (r=0,467 ; p=0,012). Existia tendência para uma correlação positiva entre as pontuações da escala ARWMC na região frontal e os valores médios dos CDA na SBAN frontal (r=0,276 ; p=0,155). As pontuações da escala ARWMC e os CDA correlacionavam‐se de forma positiva com a idade e com a tensão arterial (TA). Foram encontradas correlações significativas entre: idade e SBAN frontal (r=0,440 ; p=0,019); TA diastólica e SBFL (r=0,386 ; p=0,034); TA sistólica e SBAN Parieto‐occipital (r=0,407 ; P=0,032). Na avaliação motora e cognitiva, dado elevado número de variáveis, foi efectuada uma análise de factor principal. Registou‐se uma tendência global negativa na correlação entre as pontuações da escala visual na região frontal, os valores dos CDA, e o desempenho motor e cognitivo. Na análise evolutiva, (n=19), registou‐se variação significativa dos CDA, com aumento na SBFL (Direita: z=‐2,875 ; p=0,004 ; Esquerda: z=‐2,113 ; p=0,035) e diminuição na SBAN dos pedúnculos cerebelosos (Direita: z=‐2,094 ; p=0,036 ; Esquerda: z=‐1,989 ; p=0,047). Foi observada uma correlação negativa entre a variação do CDA na SBAN dos pedúnculos cerebelosos e na SBFL contralateral (SBAN pedúnculo cerebeloso Esquerdo / SBFL Direita: r=‐0,133 ; p=n.s.; SBAN pedúnculo cerebeloso Direito / SBFL Esquerda: r=‐0,561 ; p=0,012). Os valores dos CDA à direita correlacionavam‐se de forma positiva com a velocidade da marcha (r=0,562 ; p=0,012). CONCLUSÕES: A progressão das ASBRE pode ser observada com uma escala visual detalhada no intervalo de um ano. Contudo, o eventual agravamento da incapacidade funcional, motora e cognitiva, não parece ser apreciável em igual intervalo de tempo. A maior severidade das ASBRE associa‐se a uma tendência para um maior compromisso funcional, motor e possivelmente do humor. A questão da progressão em escalas simplificadas, de um estádio ligeiro para um estádio moderado a grave, não é elucidada pelos resultados do presente trabalho. Os doentes com um envolvimento preferencial da região parieto‐occipital poderão constituir um subgrupo distinto que, apesar de ter maior extensão de lesão, parece ter um melhor desempenho motor e cognitivo. O perfil evolutivo destes doentes parece igualmente ser distinto, não se observando a tendência ao agravamento funcional, motor e cognitivo (sobretudo em provas de função executiva) que se encontra nos restantes doentes. A análise transversal na inclusão, utilizando uma escala visual e o estudo dos CDA, sugere que a severidade das ASBRE se correlaciona com o compromisso motor e cognitivo, bem como com a idade e com a TA. Uma maior vulnerabilidade da substância branca frontal à lesão vascular parece ter um papel importante no compromisso motor e na disfunção executiva, (essencialmente à custa do compromisso da atenção), possivelmente associada à desconexão dos circuitos fronto‐subcorticais. A análise dos CDA sugere que isso é válido igualmente para a SBAN e sublinha que, as imagens de RM convencional poderão não traduzir a verdadeira extensão da lesão e consequentemente do compromisso motor e cognitivo. A relação entre a progressão da doença vascular em lesões frontais constituídas e a redução do CDA no pedúnculo cerebeloso contralateral poderá estar associada a um pior desempenho motor. A disrupção dos circuitos fronto‐cerebelosos, determinando hipometabolismo e diminuição da perfusão no cerebelo, poderá ser responsável pela diminuição do CDA no cerebelo. ABSTRACT INTRODUCTION: Previous studies, with new imaging techniques, have consistently documented the presence of age‐related white matter lesions (ARWML), emphasizing their role in agerelated functional decline, mainly related to motor and cognitive impairment, and inherent consequences in clinical practice. However clinical significance of ARWML remains to be elucidated, probably on account of methodological difficulties such as: specific neuropsychological batteries, utilization of samples with different degrees of severity and regional involvement, utilization of different imaging scales and different sensitivity of imaging techniques. Recently, Diffusion Weighted Magnetic Ressonance imaging (DWI) has shown a higher sensitivity to ischemic lesions, suggesting it might be superior for characterization of ARWML, allowing more precise correlation with motor and cognitive variables, and evaluating also normal appearing white matter (NAWM). OBJECTIVES: To describe imagiologic evolution of ARWML within one year interval and to analyse its clinical and functional significance. To identify predictors of ARWML progression and associated functional impairment. To describe clinical characteristics and evolution profile of patients with predominantly posterior lesions; to compare this group of patients with patients without predominantly posterior lesions. To study average Apparent Diffusion Coeficcients (ADC) in different white matter regions using regions of interest (ROI); to analyse their evolution profile and to determine their clinical and imagiologic correlations. METHODS: A sample of 30 patients older than 65 years, without functional impairment or with minimal impairment, according to the Instrumental Activities of Daily Lliving scale, with ARWML on CT scan, were studied in a cross‐sectional design. An extensive clinical(with detailed motor and cognitive evaluation) and imagiologic protocol was applied in two one‐year interval separate moments (t0 and t1). ARWML were studied using visual scales, ARWMC and Fazekas’s scale, and patients were studied according to degree of severity (Fazekas scale mild versus moderate / severe) and preferential involvement of the posterior region (defined as 2 or more points in the ARWMC scale in the parietooccipital region compared with frontal region). Evaluation of ADC was performed using ROI in frontal lesioned white matter (FLWM) and NAWM (frontal, parieto‐occipital and cerebellar regions). To study differences in the distribution of variables the Mann‐Whitney test was used and to compare proportions the exact Fisher Test was used. To compare temporal evolution profile between t0 and t1, the Wilcoxon Signed ranks Test was used to analyse the distribution of variables and the Mc Nemar Test to analyse frequencies. Correlation analysis was performed using Spearman or Pearson tests. The study was approved by the local Ethics Committee and all patients signed an informed consent. RESULTS: Mean age was 72.5 years (17 patients were male). By the end of the study, one patient was dead and 3 patients did not undergo brain imaging. There was a higher extent of ARWML evaluated with the ARWMC scale (t0: 8.37 / t1: 9.65 ; p<0.001). Functional, motor and cognitive performance did not progress significantly. Evaluating patients in t0 and t1 according to the degree of severity (Fazekas scale), the moderate / severe group of patients (WML2), compared with the mild group (WML1), showed: higher extent of lesion (ARWMC scale t0: 11.9 / 4.8 ; p<0.001 ; t1: 14.0 / 5.9 ; p<0.001); tendency to worse functional (IADL t0: 90.7 / 99.2 ; p=0.023; t1: 86.4 / 96.7 ; p=n.s.) and motor (SPPB t0: 9.8 / 10.3 ; p=n.s. ; t1: 9.5 / 10.5 ; p=0.058) performance; tendency to higher depressive scores (Cornell Scale t0: 6.7 / 3.5 ; p=0.037; t1: 6.2 / 4.5; p=n.s.). Analysing the evolution profile from t0 to t1 of each group (WML2 and WML1), there was a higher extent of lesion (ARWMC scale) in both (WML2: 12.0 / 14.0; z=‐2.687 ; p=0.007; WML1: 4.8 / 5.9 ; z=‐2.724 ; p=0.006); non‐significant variation in functional and motor performances; tendency to worse performance on the Digit Cancelling (WML2: 17.5 / 17.4 ; p=n.s. ; WML1: 19.9 / 16.9 ; z=‐2.096 ; p=0,036) and to better performance on the MMS (WML2: 25.7 / 27.5 ; z=‐2.155 ; p=0.031; WML1: 27.5/ 28.2 ; p=n.s). Evaluating patients in t0 and t1 according to the regional distribution of ARWML, patients with predominantly posterior lesions (WMLP) compared with the rest of the group (WMLnP), showed: higher extent of lesion (ARWMC scale t0: 10.8 / 6.9 ; p=0.025; t1:12.9 / 7.6 ; p=0.011); non significant differences on motor evaluation; tendency to a better performance on Maze (t0: 8.1 / 11.8 ; p=0.06; t1: 8.7 / 9.5 ; p=n.s.) and Digit cancelling (t0: 20.9 / 17.4 ; p=0.045; t1: 18.5 / 16.3 ; p=n.s.) tests;tendency to higher scores on GDS (t0: 5.0 / 3.68 ; p=n.s. ; t1: 5.7 / 3.3 p=0.033). Analysing the evolution profile from t0 to t1 of each group (WMLP and WMLnP), there was: higher extent of lesion (ARWMC scale) in both groups (WMLP: 10.8 / 12.9 ;z=‐2,555 ; P=0,011; WMLnP: 6.4 / 7.6 ; z=‐2.877; p=0.04); variation in different directions with better functional performance in the group WMLP (91.0 / 95.5 ;z=‐0.926 ; p=0.036) and worse in WMLnP (96.7 / 89.8 ; z=‐2.032 ; p=0.042); variation in different directions with worse motor performance in one SPPB item (total stands) in the group WMLnP (WMLP 3.8/3.9 p=n.s.; ASBREnP 3.9/3.6; z=‐2.236 ; p=0.025);tendency to improvement in both groups in MMS (WMLP: 27.2 / 28.2 ; p=n.s.; WMLnP:26.3 / 27.7 ; z=‐2.413 ; p=0.016); tendency to a variation in different directions in the Trail Making Test, with possible improvement in the group WMLP (113.9 / 91.6 ;p=n.s.) and worsening in the group WMLnP (113.7 / 152.0 ; z=‐2.155 ; p=0.031). Imaging analysis in the inclusion, using the ARWMC scale and ADC evaluation, showed significant differences in different regions (F=39.54, p<0.0001). Comparative post‐hoc Bonferroni analysis showed significantly higher scores in the frontal and parieto‐occipital regions (p<0.0001. ADC values were significantly different between regions (F=44.56; p<0.0001), being higher in FLWM (p<0‐0001). There was no significant difference between ADC in NAWM in frontal and parieto‐occipital regions. ARWMC scores and ADC values correlated positively. Significant correlations were found between frontal ARWMC score and FLWM ADC values (r=0.467 ; p=0.012). ARWMC scores and ADC values correlated positively with age and blood pressure. Significant correlations were: age and frontal NAWM (r=0.440 ; p=0.019); Diastolic blood pressure and FLWM (r=0.386 ; p=0.034); sistolic blood pressure and parietooccipital NAWM (r=0.407 ; P=0.032). Due to the higher number of motor and cognitive variables a preliminary study was done, using principal component analysis. A global tendency to a negative correlation was found between ARWMC scores, ADC values and motor and cognitive performances. Evolutive analysis of ADC (n=19), showed a significant variation, with higher values in t1 in FLWM (Right: z=‐2.875 ; p=0.004 ; Left: z=‐2.113 ; p=0.035) and lower values in t1 in cerebellar NAWM (Right: z=‐2.094 ; p=0.036 ; Left: z=‐1.989 ; p=0.047). A negative correlation was found between ADC variation in cerebellar NAWM and contralateral FLWM (Left cerebellar NAWM / Right FLWM: r=‐0.133 ; p=n.s.; Right cerebellar NAWM/ Left FLWM: r=‐0.561 ; p=0.012). ADC values on the right correlated positively with walking speed (r=0,562 ; p=0,012). CONCLUSIONS: Progression of ARWML can be documented with a detailed visual scale in a one year interval. However, functional, motor and cognitive impairment, do not seem to progress significantly within the same period. A higher severity of ARWML is associated with a tendency to a worse functional and motor performance (and possibly to higher scores in depression scales). The issue of progression in a simplified visual scale from a mild to a moderate / severe degree of ARWML is not further elucidated. Patients with predominantly posterior lesions may be a subset of ARWML patients, with a different profile, that despite higher extent of lesion, seem to fair better than the rest of the group, namely with better performance on motor and cognitive tests. Evolution profile of this subset of patients also seems to be different, without a clearcut tendency to worsening functional, motor and cognitive (particularly for executive function tests) performance that is observed in the rest of the group. Imaging analysis, with a visual scale and ADC evaluation, suggests that severity of ARWML correlates negatively with cognitive and motor performance and positively with age and blood pressure. A higher vulnerability of frontal white matter to vascular disease seems to play an important role in motor and cognitive dysfunction, mainly determined by impairment of attention skills associated with frontal‐subcortical disconnection. DWI results, suggest that this may also be true for NAWM, underlining that conventional MR images may not represent the true extent of cognitive decline. The relation between vascular disease progression inside frontal lesions and ADC reduction in contralateral cerebellar peduncles, may be associated with a worse motor performance. Disruption of fronto‐cerebellar cicuits, with associated regional hypometabolism, may be responsible for the reduction of cerebellar ADC.

Neural mechanisms of stimulus generalization in auditory fear conditioning

Dissertation presented to obtain the Ph.D degree in Neuroscience Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa

Neuroschistosomiasis due to Schistosoma mansoni: a review of pathogenesis, clinical syndromes and diagnostic approaches

Neuroschistosomiasis (NS) is the second most common form of presentation of infection by the trematode, Schistosoma mansoni. Granulomatous inflammatory reaction occurs as a result of schistosome eggs being transmitted to spinal cord or brain via the vascular system, or by inadvertent adult worm migration to these organs. The two main clinical syndromes are spinal cord neuroschistosomiasis (acute or subacute myelopathy) and localized cerebral or cerebellar neuroschistosomiasis (focal CNS impairment, seizures, increased intracranial pressure). Presumptive diagnosis of NS requires confirming the presence of S. mansoni infection by stool microscopy or rectal biopsy for trematode eggs, and serologic testing of blood and spinal fluid. The localized lesions are identified by signs and symptoms, and confirmed by imaging techniques (contrast myelography, CT and MRI). Algorithms are presented to allow a stepwise approach to diagnosis.

Partial Rhombencephalosynapsis.

Clinical history - A 4-year-old boy, born prematurely at 29 weeks (twin pregnancy), with periventricular leukomalacia and epilepsy underwent brain MRI. Neurological examination showed severe developmental retardation with axial hypotonia, spastic tetraparesis and convergent strabismus. Imaging findings - Cranial MRI revealed typical aspects of partial rhombencephalosynapsis with vermian hypoplasia, midline fusion of the cerebellar hemispheres and transversely oriented folia and fissures. There was also mild dilatation and dysmorphism of the ventricular system, the septum pellucidum was absent, the hippocampi were malrotated and had vertical orientation and additional finding of associated periventricular cystic leukomalacia. Discussion - Rhombencephalosynapsis (RS) is a rare congenital defect of the cerebellum classically characterised by vermian agenesis or hypogenesis, fusion of the hemispheres, and closely apposed or fused dentate nuclei. It is now considered to result from an absence of division of the cerebellar hemispheres, following an insult between the 28th and 44th day of gestation (i.e., before the formation of the vermis). Other features have also been described such as fusion of the thalami and cerebral peduncles, malrotated hippocampi, corpus callosum agenesis, hypoplastic chiasm, absence of the septum pellucidum, ventriculomegaly, agenesis of the posterior lobe of the pituitary and cortical malformations. Musculoskeletal, cardiovascular, urinary tract, and respiratory abnormalities have been reported. Typical symptoms consist of swallowing difficulties, delayed motor acquisitions, muscular hypotonia, spastic quadriparesis, cerebellar signs including dysarthria, gait ataxia, abnormal eye movements, and seizures and hydrocephalus. The major MRI signs consist of fused cerebellar hemispheres, with absent or hypoplastic vermis, narrow diamond-shaped fourth ventricle and fused dentate nuclei. In a minority of cases, partial RS has been identified by MRI, demonstrating the presence of the nodulus and the anterior vermis and absence of part of the posterior vermis with only partial fusion of the hemispheres in the inferior part. Other cerebellar malformations involving vermian agenesis or hypoplasia include the Dandy–Walker continuum, Joubert syndrome, tectocerebellar dysraphy or pontocerebellar hypoplasias, and are now easily distinguished from RS by both brain MRI and morphology.