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Reports on a patient who developed a dysexecutive syndrome and a moderate learning deficit following a head trauma. Definition of anosognosia; Main groups of theories that attempted to account for anosognosia; Evaluation of the patient's anosognosia.

Background The FOXO longevity pathway and β-catenin pathway are major signalling systems that may regulate cell survival. Whether GSK3/β-catenin may interact with longevity signalling to regulate diseased neuron survival and whether this may translate into the modification of human neurodegenerative disease remain unknown. Aims We aimed to test the role of FOXO neighbours such as β-catenin on the effects of expanded polyQs/mutant huntingtin. Methods We used complementary approaches based on a model of neuronal dysfunction induced by expanded polyQ expression, a cellular model of HD pathogenesis based on full length huntingtin expression and genotype analysis using DNA samples from HD patients. Results In , we observed that neuroprotection by the sirtuin sir-2.1 requires the DAF-16/FOXO partner BAR-1/β-catenin and the DAF-16 target ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. In mutant htt striatal cells from HdhQ111 knock-in mice, β-catenin, FOXO3a, SIRT1 and UCP2 promote cell survival, with a cooperation of β-catenin and SIRT1. In Huntington's disease (HD) patients, a single nucleotide polymorphism in GSK-3β, a major repressor of β-catenin activity, modulates the age at onset of motor symptoms as observed in the French and European cohorts. In these cohorts, GSK-3β may also act in synergy with TCERG1 (also named CA150). TCERG1 is an evolutionary conserved gene known as a neuroprotective factor in models of HD and daf-16/FOXO interactor in nematodes, and is confirmed to modify HD onset age. Conclusion These data reveal a role for β-catenin on HD neuron survival and they identify GSK-3β as a modifier of age at onset of motor symptoms in HD. [ABSTRACT FROM PUBLISHER]

This is the second part of a review summarizing progress and prospects in gene therapy clinical research. Twenty key diseases/strategies are succinctly described and commented on by leaders in the field. This part includes clinical trials for skin diseases, neurological disorders, HIV/AIDS, ornithine transcarbamylase deficiency, alpha(1)-antitrypsin deficiency, haemophilia and cancer.

Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.

Background: Huntington's disease is a neurodegenerative disease of genetic origin that mainly affects the striatum. It has severe motor and cognitive consequences and, up to now, no treatment. Motor and cognitive functions can be restored in experimental animal models by means of intrastriatal transplantation of fetal striatal neuroblasts. We explored whether grafts of human fetal striatal tissue could survive and have detectable effects in five patients with mild to moderate Huntington's disease., Methods: After 2 years of preoperative assessment, patients were grafted with human fetal neuroblasts into the right striatum then, after a year, the left striatum. Final results were assessed 1 year later on the basis of neurological, neuropsychological, neurophysiological, and psychiatric tests. The results obtained were compared with those of a cohort of 22 untreated patients at similar stages of the disease who were followed up in parallel. Repeated magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning with fluorine-18-labelled fluorodeoxyglucose was also done to assess metabolic activity., Findings: The final PET-scan assessment showed increased metabolic activity in various subnuclei of the striatum in three of five patients, contrasting with the progressive decline recorded in the two other patients in the series, as seen in patients with untreated Huntington's disease. Small areas of even higher metabolic activity, coregistering with spherical hyposignals on MRI were also present in the same three patients, suggesting that grafts were functional. Accordingly, motor and cognitive functions were improved or maintained within the normal range, and functional benefits were seen in daily-life activities in these three patients, but not in the other two., Interpretation: Fetal neural allografts could be associated with functional, motor, and cognitive improvements in patients with Huntington's disease.

We present a single case study of a brain-damaged patient, AD, suffering from visual face and object agnosia, with impaired visual perception and preserved mental imagery. She is severely impaired in all aspects of overt recognition of faces as well as in covert recognition of familiar faces. She shows a complete loss of processing facial expressions in recognition as well as in matching tasks. Nevertheless, when presented with a task where face and voice expressions were presented concurrently, there was a clear impact of face expressions on her ratings of the voice. The cross-modal paradigm used here and validated previously with normal subjects (de Gelder & Vroomen, 1995, 2000), appears as a useful tool in investigating spared covert face processing in a neuropsychological perspective, especially with prosopagnosic patients. These findings are discussed against the background of different models of the covert recognition of face expressions., (Copyright 2000 Academic Press.)

Neurodegenerative diseases are a major public health problem since they affect as a mean 1% of the people in industrialized countries, and will progress along with the ageing of the population. For ten years, a major research endeavor aims at developing new therapeutics against these diseases. These new approaches are based either on the substitution of affected neurons by homogous neuroblasts that are able to replace them anatomically and functionally (fetal neural grafts), or on the use of neuroprotective proteins (by gene therapy) that are able to promote natural defenses of neural cells. Clinical results have been obtained with fetal neural transplants over the past decade, in patients with Parkinson's and, more recently, Huntington's disease. The neuroprotective approach is under evaluation.