What did we learn from neural grafts in Huntington disease?

Huntington's disease is a rare, severe, and inherited neurodegenerative disorder that affects young adults. To date, there is no treatment to stop its progression. The primary atrophy of the striatum in HD, is limited in space and centrally focalised in the brain and thus constitutes a good candidate for graft. Therefore, transplantation of foetal cells from the ganglionic eminence, the germinal zone of the striatum, has the potential to restore disrupted fronto-cortical circuits and corresponding clinical functions. The international Multicentric intracerebral Grafting in Huntington's disease trial was not as successful as two pilot trials (Créteil and London) which showed promising results in the 2000s, displaying stabilisation/recovery of symptoms in some patients. A point-by-point comparison of the differences between MIG-HD and the pilot trial from Créteil in which similar data are available provides lessons on the grafting procedure and allows for strategic thinking before embarking on future trials. MIG-HD demonstrated the existence of intracerebral alloimmunisation leading to acute or chronic graft rejection into the brain and showed the limitations of surgical standardisation and immunosuppression. It has also improved the safety of the procedure and provided guidance for the follow-up of future patients. Indeed, even if disease modifiers treatments are currently the focus of intense research, they may not stop or slow the progression of the disease sufficiently, or even be administered in all patients, to prevent brain atrophy in all cases. Although disease-modifying therapies are currently the subject of intense research, they may not stop or slow disease progression sufficiently, or may not be given to all patients to prevent brain atrophy. A combination with intracerebral transplantation to repair the damaged structures may thus prove beneficial. Altogether, pursuing research in intracerebral transplantation remains necessary.

Clinical description of the broad range of neurological presentations of COVID-19: A retrospective case series.

BACKGROUND: Neurological disorders associated with SARS-CoV-2 infection represent a clinical challenge because they encompass a broad neurological spectrum and may occur before the diagnosis of COVID-19. METHODS: In this monocentric retrospective case series, medical records from patients with acute neurological disorders associated with SARS-CoV-2 infection from medicine departments of an academic center in Paris area were collected between March 15th and May 15th 2020. Diagnosis of SARS-CoV-2 was ascertained through specific RT-PCR in nasopharyngeal swabs or based on circulating serum IgG antibodies. RESULTS: Twenty-six patients diagnosed with SARS-CoV-2 infection presented with neurological disorders: encephalitis (N=8), encephalopathy (N=6), cerebrovascular events (ischemic strokes N=4 and vein thromboses N=2), other central nervous system (CNS) disorders (N=4), and Guillain-Barré syndrome (N=2). The diagnosis of SARS-CoV-2 was delayed on average 1.6 days after the onset of neurological disorder, especially in case of encephalitis 3.9 days, encephalopathy 1.0 day, and cerebrovascular event 2.7 days. CONCLUSIONS: Our study confirms that COVID-19 can yield a broad spectrum of neurological disorders. Because neurological presentations of COVID-19 often occur a few days before the diagnosis of SARS-COV-2 infection, clinicians should take preventive measures such as patient isolation and masks for any new admission to avoid nosocomial infections. Anti-SARS-CoV2 antibody detection in RT-PCR SARS CoV-2 negative suspected cases is useful to confirm a posteriori the diagnosis of atypical COVID-19 presentations.

Striatal connectivity in pre-manifest Huntington's disease is differentially affected by disease burden.

BACKGROUND AND PURPOSE: Different amounts of cumulative exposure to the toxic mutant form of the huntingtin protein might underlie the distinctive pattern of striatal connectivity in pre-manifest Huntington's disease (pre-HD). The aim of this study was to investigate disease-burden-dependent cortical-striatal and subcortical-striatal loops at different pre-HD stages. METHODS: A total of 16 participants with pre-HD and 25 controls underwent magnetic resonance imaging to investigate striatal structural and functional connectivity (FC). Individuals with pre-HD were stratified into far-from-onset and close-to-onset disease groups according to the disease-burden score. Cortical-striatal and subcortical-striatal FC was investigated through seed-region of interest (ROI) and ROI-to-ROI approaches, respectively. The integrity of white-matter pathways originating from striatal seeds was investigated through probabilistic tractography. RESULTS: In far-from-onset pre-HD, the left caudate nucleus showed cortical increased FC in brain regions overlapping with the default mode network and increased coupling connectivity with the bilateral thalamus. By contrast, close-to-onset individuals showed increased fractional anisotropy (and mean diffusivity) in the right caudate nucleus and widespread striatal atrophy. Finally, we reported an association between cortical-caudate FC and caudate structural connectivity, although this did not survive multiple comparison correction. CONCLUSIONS: Functional reorganization of the caudate nucleus might underlie plasticity compensatory mechanisms that recede as individuals with pre-HD approach clinical symptom onset and neurodegeneration.

Guidelines for clinical pharmacological practices in Huntington's disease.

OBJECTIVE: Evidence-based medicine is a difficult goal to achieve in rare diseases where randomized controlled trials are lacking. This report provides guidelines that capitalize on both the literature and expertise of the French National Huntington Disease Reference Centre to optimalize pharmacological therapeutic interventions for Huntington's disease (HD). MATERIAL AND METHODS: HD experts conducted a systematic analysis of the literature from 1965 to 2013, using a scoring procedure established by the French National Authority for Health. These experts offered their views when evidence was missing to set up provisional guidelines for care in HD. These guidelines were then scored and amended through two subsequent online questionnaires (using SurveyMonkey® scoring), and one face-to-face meeting with an external multidisciplinary working group as a step towards validation. RESULTS: Except for the beneficial effects of tetrabenazine in chorea, none of the published recommendations were grounded on established scientific evidence. Second-generation antipsychotics are nevertheless the first choice for patients with psychiatric manifestations (low level of evidence). All other guidelines are based on low-level evidence and little professional agreement. CONCLUSION: Patients' care has greatly improved over the last few years despite the lack of high-level evidence standards. Guidelines are based on the expertise of trained specialists from the French National Plan for Rare Diseases. This strategy should now be extended internationally to promote future studies and to harmonize worldwide care of HD.

Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis.

PURPOSE: Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders. METHODS: We searched MEDLINE and EMBASE for randomized controlled trials in which oral formulations of second-generation antipsychotic drugs were compared head-to-head or against placebo or against haloperidol. Trials had to be of at least 6 months duration to be included. We used a network meta-analysis to combine direct and indirect comparisons of the cognitive effects between antipsychotics. RESULTS: Nine studies were eligible. The median trial duration was 52 weeks. Quetiapine, olanzapine and risperidone had better effects on global cognitive score than amisulpride (p < 0.05) and haloperidol (p < 0.05). When memory tasks were considered, ziprasidone had better effect than amisulpride (0.28 [0.02-0.54]) and haloperidol (0.32 [0.09-0.55]). Quetiapine was better than other drugs (p < 0.001) on attention and processing speed tasks, followed by ziprasidone (p < 0.05) and olanzapine (p < 0.05). The effects of quetiapine, risperidone and olanzapine were better than those of amisulpride (p < 0.05) on executive functions. CONCLUSIONS: Our results suggest differences between antipsychotics in their effect on the overall cognitive score in schizophrenia. Quetiapine and olanzapine had the most positive effects, followed by risperidone, ziprasidone, amisulpride and haloperidol in that order. Significant differences were also observed according to specific cognitive tasks.

Regenerative medicine in Huntington's disease: current status on fetal grafts and prospects for the use of pluripotent stem cell.

Huntington's disease is currently incurable, but cell therapy is seen as a promising alternative treatment. We analyze the safety and efficacy of the intrastriatal transplantation of human fetal neuroblasts from ganglionic eminences in patients with Huntington's disease. A few rare surgical incidents were reported, but the main difficulty associated with this therapeutic approach is the occurrence of recipient alloimmunization against the graft and the lack of availability, standardization and quality control for the fetus-derived products required for cell therapy. Some patients showed sustained cognitive improvement over periods of more than six years, and motor improvements for more than four years. Grafting outcomes are variable even within individual transplantation centers. The reasons for this variability are poorly understood, highlighting the need for further research in this specific area. With the perspective of additional trials in the future, we review here the development of human pluripotent stem cell-derived cell therapy products for HD, and their advantages and disadvantages with respect to fetal cells.

Striatal degeneration impairs language learning: evidence from Huntington's disease.

Although the role of the striatum in language processing is still largely unclear, a number of recent proposals have outlined its specific contribution. Different studies report evidence converging to a picture where the striatum may be involved in those aspects of rule-application requiring non-automatized behaviour. This is the main characteristic of the earliest phases of language acquisition that require the online detection of distant dependencies and the creation of syntactic categories by means of rule learning. Learning of sequences and categorization processes in non-language domains has been known to require striatal recruitment. Thus, we hypothesized that the striatum should play a prominent role in the extraction of rules in learning a language. We studied 13 pre-symptomatic gene-carriers and 22 early stage patients of Huntington's disease (pre-HD), both characterized by a progressive degeneration of the striatum and 21 late stage patients Huntington's disease (18 stage II, two stage III and one stage IV) where cortical degeneration accompanies striatal degeneration. When presented with a simplified artificial language where words and rules could be extracted, early stage Huntington's disease patients (stage I) were impaired in the learning test, demonstrating a greater impairment in rule than word learning compared to the 20 age- and education-matched controls. Huntington's disease patients at later stages were impaired both on word and rule learning. While spared in their overall performance, gene-carriers having learned a set of abstract artificial language rules were then impaired in the transfer of those rules to similar artificial language structures. The correlation analyses among several neuropsychological tests assessing executive function showed that rule learning correlated with tests requiring working memory and attentional control, while word learning correlated with a test involving episodic memory. These learning impairments significantly correlated with the bicaudate ratio. The overall results support striatal involvement in rule extraction from speech and suggest that language acquisition requires several aspects of memory and executive functions for word and rule learning.

[Presentation of an assessment battery for visual mental imagery and visual perception]. / Normalisation d'une batterie d'évaluation de l'imagerie mentale visuelle et de la perception visuelle.

INTRODUCTION: The relationship between visual perception and visual mental imagery are at the center of a lively theoretical debate between those postulating common neurocognitive processes between perception and imagery and those who emphasize the differences between these two entities. Neuropsychology can make an important contribution to this debate, by assessing associations and dissociations between perceptual and imaginal deficits in patients with brain damage. However, currently there is no standardized test battery available for such assessments. MATERIAL AND METHODS: Here we present a battery of paper-and-pencil tests assessing different domains of visual mental imagery and visual perception abilities: object form and color, animals, orthographic material, numbers, faces, and space. We also explored the effects of age, educational level and gender on performance on a group of 103 participants free of neurological damage. RESULTS: The battery includes two parts: one composed of 14 tests assessing mental imagery and the second part composed of eight tests assessing the abilities of visual perception. We calculated the correlations between the tests, and found that, with the exception of orthographic material, there were generally poor correlations between imagery and perceptual tests. CONCLUSION: This result seems inconsistent with hypotheses postulating a strict correspondence between perceptual and imagery abilities.

[French adaptation of the Hopkins Verbal Learning Test]. / Adaptation française du <>.

INTRODUCTION: A number of tests are currently used in clinical and research settings for the assessment of patients with memory deficits. Among them, the Hopkins Verbal Learning Test (HVLT) is particularly appropriate for the longitudinal follow-up of patients with memory disorders because it exists in six parallel forms, and therefore avoids the risk of learning effect at retest. Since a test with these characteristics is not available in French, we decided to adapt a French version of the HVLT. METHODS: 180 normal subjects participated in the study. Their mean age was 41 years (SD=11), and they had had on average 12 years of schooling (SD=3). The subjects were randomly divided into 6 groups of 30 subjects. One of the six forms of the French version of the HVLT was administered orally to each group of subjects. Each form consisted of a list of 12 words belonging to 3 different semantic categories. For the construction of the French version of the HVLT, we adopted the same procedure as used in the original version of the test taking into account the French lexical and semantic characteristics of the items. In the first part of the test, the list was administered three times to the subjects. Following each administration, subjects were asked for an immediate free recall. Twenty minutes later, used for intercurrent tasks, subjects were asked for a delayed free recall, which was immediately followed by a recognition memory task. In this task, subjects listened to a list of 24 words, 12 belonging to the studied list and 12 were distractors; the subjects were asked to recognize the 12 studied words. RESULTS: The subjects' performance was equivalent in the six forms of the test, except for the immediate recall of Form 3 (which was excluded from the test). No significant difference emerged in free recall, delayed free recall, and recognition across the five remaining forms of the test. CONCLUSION: Our study provides a useful tool for the longitudinal evaluation of patients with memory impairment and may become the test of reference in European longitudinal clinical trials. The French adaptation of the HVLT represents only a first step, because it needs to be standardized, in order to provide norms, and validated, in order to provide values of sensitivity and specificity.

Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF.

Huntington's disease (HD) is an autosomal dominant genetic disease with devastating clinical effects on cognitive, psychological, and motor functions. These clinical symptoms primarily relate to the progressive loss of medium-spiny GABA-ergic neurons of the striatum. There is no known treatment to date. Several neurotrophic factors have, however, demonstrated the capacity to protect striatal neurons in various experimental models of HD. This includes the ciliary neurotrophic factor (CNTF), the substance examined in this protocol. An ex vivo gene therapy approach based on encapsulated genetically modified BHK cells will be used for the continuous and long-term intracerebral delivery of CNTF. A device, containing up to 106 human CNTF-producing BHK cells surrounded by a semipermeable membrane, will be implanted into the right lateral ventricle of 6 patients. Capsules releasing 0.15-0.5 microg CNTF/day will be used. In this phase I study, the principal goal will be the evaluation of the safety and tolerability of the procedure. As a secondary goal, HD symptoms will be analyzed using a large battery of neuropsychological, motor, neurological, and neurophysiological tests and the striatal pathology monitored using MRI and PET-scan imaging. It is expected that the gene therapy approach described in this protocol will mitigate the side effects associated with the peripheral administration of recombinant hCNTF and allow a well-tolerated, continuous intracerebroventricular delivery of the neuroprotective factor.

Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study.

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.

Disruption of residual reading capacity in a pure alexic patient after a mirror-image right-hemispheric lesion.

A 74-year-old woman became a letter-by-letter reader after the occurrence of a left occipito-temporal hematoma. Seven months later, she suffered a second, mirror-image hematoma in the right hemisphere. After this second lesion, her residual reading capacity deteriorated dramatically in terms of both accuracy and reading latencies for words and isolated letters. Our findings support the hypothesis that the right hemisphere contributes to the residual reading capacities of pure alexic patients.

Somatosensory cortical activations are suppressed in patients with tactile extinction: a PET study.

OBJECTIVE: To investigate whether tactile extinction alters the cortical somatosensory activations induced by hand vibration. BACKGROUND: Tactile extinction occurs mainly after right-brain lesions and consists of the inability to perceive a contralesional cutaneous stimulation when a similar stimulus is applied to the mirror region of the ipsilesional hemibody. The pathophysiology of tactile extinction is poorly understood, but it is considered to be a deficit of selective attention of somatosensory stimuli. Although other theories have been proposed, our understanding of the pathophysiology of tactile extinction may benefit from functional imaging studies. METHODS: We selected three patients with pure tactile extinction and a mainly subcortical right-brain lesion that spared the primary sensorimotor cortex (SM1). We used PET to investigate the responses to unilateral and bilateral hand vibration in SM1 and the secondary somatosensory cortical area (SII). RESULTS: During bilateral hand vibration, activation was normal in the left SM1, suppressed in the right SM1, and markedly decreased in both SII, which was consistent with the extinction of the left-hand stimulus. During unilateral left-hand vibration, the activation of the right SM1 was still markedly impaired, but the activation of both SII was normal. CONCLUSIONS: We found marked changes in the activation of cortical somatosensory areas induced by hand vibration in patients with tactile extinction. The role of selective attention in cortical activation is also examined.

Right-side neglect in Alzheimer's disease.

Unilateral neglect--the inability to pay attention to events occurring on one side of space--usually occurs for left-side events after focal right-hemisphere damage. We report a 73-year-old woman with probable AD and no evidence of focal brain lesions who showed signs of right-side neglect and extinction. Neglect was more severe after 1 year. Neuroimaging techniques demonstrated an asymmetry of cortical involvement, with cortical atrophy and hypoperfusion predominant in the left posterior regions. Unilateral neglect should be assessed systematically in AD.

Retest effects and cognitive decline in longitudinal follow-up of patients with early HD.

OBJECTIVE: To assess the natural progression of cognitive impairment in Huntington's disease (HD) and to reveal factors that may mask this progression. BACKGROUND: Although numerous cross-sectional studies reported cognitive deterioration at different stages of the disease, progressive cognitive deterioration has been, up to now, difficult to demonstrate in neuropsychological longitudinal studies. METHODS: The authors assessed 22 patients in early stages of HD at yearly intervals for 2 to 4 years (average, 31.2 +/- 10 months), using a comprehensive neuropsychological battery based on the Core Assessment Program for Intracerebral Transplantation in Huntington's Disease (CAPIT-HD). RESULTS: The authors observed a significant decline in different cognitive functions over time: these involved primarily attention and executive functions but also involved language comprehension, and visuospatial immediate memory. Episodic memory impairment that was already present at the time of enrollment did not show significant decline. The authors found a significant retest effect at the second assessment in many tasks. CONCLUSION: Many attention and executive tasks adequately assess the progression of the disease at an early stage. For other functions, the overlapping of retest effects and disease progression may confuse the results. High interindividual and intraindividual variability seem to be hallmarks of the disease.

Multiple-domain dissociation between impaired visual perception and preserved mental imagery in a patient with bilateral extrastriate lesions.

A brain-damaged patient is described whose pattern of performance provides insight into both the functional mechanisms and the neural structures involved in visual mental imagery. The patient became severely agnosic, alexic, achromatopsic and prosopagnosic following bilateral brain lesions in the temporo-occipital cortex. However, her mental imagery for the same visual entities that she could not perceive was perfectly preserved. This clear-cut dissociation held across all the major domains of high-level vision: object recognition, reading, colour and face processing. Our findings, together with other reports on domain-specific dissociations and functional brain imaging studies, provide evidence to support the view that visual perception and visual mental imagery are subserved by independent functional mechanisms, which do not share the same cortical implementation. In particular, our results suggest that mental imagery abilities need not be mediated by early visual cortices.

Decision-making capacity and surrogate designation in French ICU patients.

OBJECTIVE: To evaluate the capacity and willingness of French-speaking patients to designate a surrogate within 24 h of their ICU admission. French laws fail to indicate what should be done when an otherwise legally competent patient transiently loses his decision-making capacity. DESIGN: Surrogate designation was prospectively evaluated during two study periods. Only conscious patients were assessed using the Glasgow Come Score in the first study period, and all admitted patients were assessed in the second period. Decision-making capacity was evaluated using the Mini Mental Status Examination (MMSE) in the second study period. SETTING: Twenty six-bed intensive care unit (ICU) in a French teaching hospital. PATIENTS AND PARTICIPANTS: Over a 8-month period 495 patients were included in the study, 415 in the first study period and 80 in the second. MEASUREMENTS AND RESULTS: Of the 495 patients 185 (37.3%) were interviewed, and 62.7% designated a surrogate. The surrogate was the spouse in 50% of cases and a child in 28.4%. Only 25.8% were considered to have decision-making capacity; 78.1% of competent patients and 28% of the patients without decision-making capacity agreed to designate a surrogate. CONCLUSIONS: Surrogate designation by a patient should be evaluated in the light of the decision-making capacity of the patient. The traditional French paternalism still practiced by many French physicians appears out of tune with the wishes of their patients. We suggest that there is a need for developing a simple and effective tool for assessing decision-making capacity in ICU patients.

The role of the output phonological buffer in the control of speech timing: a single case study.

A patient with a selective impairment of speech output, associating phonemic paraphasias and pervasive preverbal pauses, it is described. Experimental data are discussed in relation to current models of speech production. On clinical evaluation, the pattern of paraphasias was strongly suggestive of a functional lesion affecting the output phonological buffer. This hypothesis received substantial support from a study of word and non-word repetition, as well as from a study of picture naming latencies, with various imposed delays between stimulus presentation and vocal response. In order to determine the origin of the preverbal pauses, the patient was also submitted to other timed motor tasks implicity probing higher levels of word production (gender decision and phonemic matching). We suggest that the pauses probably resulted from the conjunction of several mechanisms, including a general slowing apparent in all timed motor tasks, as well as a more specific time lag in speech initiation originating from the output buffer or from the articulator itself.

Preserved imagery for colours in a patient with cerebral achromatopsia.

We report the case of a patient who, after sequential bilateral strokes in the occipital regions sparing the primary visual cortex, developed a severe deficit of colour perception. At variance with other reports of acquired achromatopsic patients, she showed a perfectly vivid visual imagery for colours. These findings, together with similar data in domains other than colour processing, challenge the theories which posit that the same cognitive processes are involved in both the perception and the retrieval from memory of a given stimulus.

Dissociation between distal and proximal left limb agraphia and agraphesthesia in a patient with a callosal disconnection syndrome.

A few neuropsychological studies have suggested the existence of bilateral hemispheric representations for the proximal parts of the limbs in humans. We report the case of a patient who presented with a callosal disconnection syndrome, which at a later stage of disease became restricted to left agraphia, left agraphesthesia and left auditory extinction. The anomic character of the agraphesthesia was demonstrated. Tactile naming was normal, which allows us to conclude that separate callosal pathways related to the left language areas transmit information for graphesthesia and tactile naming. Agraphia and agraphesthesia were not observed when the proximal part of the left upper limb was utilized. These observations support the conclusion that writing and graphesthesia with the proximal part of the limb can be mediated by the ipsilateral cortex.