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Biomedical subjects

Lucette Lacomblez

Publications and source records attributed to Lucette Lacomblez.

At least 19 recordsLinked to original sources
PubMed2007

Deletion of the parkin and PACRG gene promoter in early-onset parkinsonism.

Autosomal recessive mutations in the parkin gene (PARK2) have been identified as a common cause of familial and also sporadic, early-onset parkinsonism (EOPD): point mutations, exonic deletions, and duplications or triplications have been described. Here we report a novel mutation, consisting of a deletion of the promoter and exon 1 of parkin (c.1-?_7+?del), in a family compatible with autosomal recessive EOPD and an isolated case. The former was compound heterozygous for the parkin c.1-?_7+?del mutation and an exon 3 deletion (c.172-?_412+?del). The latter was homozygous for the parkin c.1-?_7+?del mutation. The promoter region is shared by parkin and the neighboring parkin coregulated gene (PACRG), which are oriented head-to-head and are transcribed on opposite DNA strands. There were no parkin transcripts in lymphoblasts from the patients carrying the parkin c.1-?_7+?del mutation. The phenotypes of patients with promoter deletions and consequently absence of parkin and possibly PACRG expression, were similar to and no more severe than those of other EOPD patients with parkin mutations.

Adolescent↗
PubMed2006

Utility of the Mattis dementia rating scale to assess the efficacy of rivastigmine in dementia associated with Parkinson's disease.

INTRODUCTION: The severe, cortical, cholinergic depletion accompanying Parkinson's disease (PD) is considered as a highly probable correlate of cognitive and behavioural dysfunction. Recent studies have demonstrated that cholinesterase inhibitors (notably rivastigmine) are beneficial in patients suffering from dementia associated with PD (PDD). However, the primary efficacy variables used in such work came from scales designed for Alzheimer's disease (AD), even though the cognitive symptoms in PD and AD dementia do not overlap completely. The aim of the present study (a double-blind, placebo-controlled clinical trial) was to determine the utility of the Mattis dementia rating scale - the most commonly used scale in PD patients - to assess the efficacy of a 24-week rivastigmine treatment. METHODS: Twenty-eight patients with PD, who constituted a subgroup of patients enrolled to the EXPRESS study (Emre et al, N Engl J Med 2004) participated in this study. They suffered from mild to moderately severe dementia (MMSE scores above 10 and below 24), with an onset of cognitive symptoms occurring at least two years after the diagnosis of PD. Patients were randomly assigned to treatment with rivastigmine (3 to 12 mg per day) or placebo. The Mattis dementia rating scale was administered to patients from six centres in France at the baseline and end-point visits. RESULTS: Compared with placebo, a 24-week rivastigmine treatment led to a significant improvement in the overall score on the Mattis dementia rating scale (p = 0.031), with a trend towards a significant improvement in the "Attention" subscale score (p = 0.061). Correlation analysis showed that in the rivastigmine group, performance on the Mattis "Attention" and "Initiation" subscales appeared to contribute heavily to the improvement in the overall score. Moreover, the latter was also related to an improvement in activities of daily living and a reduction in behavioural disturbances. DISCUSSION: By using the Mattis dementia rating scale (which comprises items that are sensitive to executive dysfunction), the present study confirmed that rivastigmine has a beneficial effect on cognitive function in PDD. Despite our study's small sample size, the Mattis scale was able to detect this improvement and could thus be considered as an interesting outcome measure in further work.

Aged↗
PubMed2006

Neuropsychological changes in patients with primary lateral sclerosis.

Primary lateral sclerosis (PLS) has been defined as rare, and the neuropsychological changes remain poorly defined. We studied 20 patients with a diagnosis of PLS. We carried out an extensive psychometric testing including a general assessment (memory, language, attention, visual-constructional ability and praxis) and a more specific assessment of prefrontal and premotor cortex functions in order to characterize the neuropsychological profile of the patients compared to matched controls, and explore executive functions and premotor cortex functions. None of the PLS patients was demented but they all presented memory deficits reflecting an executive dysfunction. All patients but three had signs of premotor and/or prefrontal cortex deficits. The cognitive impairment in PLS, specifically related to a frontal lobe dysfunction, seems qualitatively similar to ALS. Our results suggest a patchy distribution of cortical involvement in PLS but it remains difficult to draw any definite conclusion as to the spatio-temporal progression of the disease into the different regions of the frontal lobe.

Adult↗
PubMed2006

Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia.

We conducted a French multicentric cross-sectional study to describe in detail the demographic, neurological and behavioural characteristics of the frontal variant of frontotemporal dementia (fvFTD) and to characterize the pattern of brain perfusion SPECT in comparison to a healthy control group. A total of 68 fvFTD patients had technetium-99m-ECD brain perfusion SPECT at inclusion, 61 of which also underwent an in-depth evaluation including 70 items assessing behaviour, language and affect/emotion at onset and at inclusion. The mean age-at-onset was 60.4 +/- 7.8 years (35-75). Twenty-six per cent of the patients were older than 65 at onset. A positive familial history consistent with an autosomal dominant inheritance was found in 18% of the patients. At onset, the behavioural profile was predominantly inert in 25% of the patients, disinhibited in 18% and mixed in others. The behavioural features progressed to predominantly mixed or inert forms. Although, inertia was associated with predominant medial frontal and cingulate hypoperfusion, and patients with disinhibition exhibited predominant ventromedial prefrontal and temporal hypoperfusion, there were no major clinical differences between disinhibited and inert patients. Forty-five per cent of the deceased patients survived <6 years (short survival), and 34% of the patients survived >8 years (long survival). This shows that the final outcome of fvFTD is highly variable. No clinical factors predictive of short or long survival were identified. Unexpected, however, was the finding that brainstem hypoperfusion distinguished patients with a short survival from patients with long survival. In conclusion, this study shows that fvFTD is clinically a rather homogeneous entity. It also provides evidence that different behavioural presentations at onset are related to different anatomical localizations of degenerative damage. Finally, it demonstrates the prognostic value of brainstem hypoperfusion in a subgroup of patients with a short survival.

Adult↗
PubMed2006

Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma.

Oligodeoxynucleotides containing CpG motifs (CpG ODNs) display a strong immunostimulating activity and drive the immune response toward the Th1 (T helper type 1) phenotype. These ODNs have shown promising efficacy in preclinical studies when injected locally in several cancer models. We conducted a phase 1 trial to define the safety profile of CpG-28, a phosphorothioate CpG ODN, administered intratumorally by convection-enhanced delivery in patients with recurrent glioblastoma. Cohorts of three to six patients were treated with escalating doses of CpG-28 (0.5-20 mg), and patients were observed for at least four months. Twenty-four patients entered the trial. All patients had previously been treated with radiotherapy, and most patients had received one or several types of chemotherapy. Median age was 58 years (range, 25-73) and median KPS was 80% (range, 60%-100%). Adverse effects possibly or probably related to the studied drug were moderate and consisted mainly in worsening of neurological conditions (four patients), fever above 38 degrees C that disappeared within a few days (five patients), and reversible grade 3 lymphopenia (seven patients). Only one patient experienced a dose-limiting toxicity. Preliminary evidence of activity was suggested by a minor response observed in two patients and an overall median survival of 7.2 months. In conclusion, CpG-28 was well tolerated at doses up to 20 mg per injection in patients with recurrent glioblastoma. Main side effects were limited to transient worsening of neurological condition and fever.

Adjuvants, Immunologic↗
PubMed2005

Interactions between the dopamine agonist, bromocriptine and the efflux protein, P-glycoprotein at the blood-brain barrier in the mouse.

Bromocriptin (BCT) is a dopaminergic receptor agonist, poorly transported through the blood-brain barrier (BBB) and responsible for central side effects. Interactions between BCT and the efflux protein, P-glycoprotein (Pgp), have been described in vitro but nothing is known in vivo nor at the BBB level. At the BBB, in vivo, we investigated BCT as (i) a Pgp substrate by comparing the brain uptake in CF1 mdr1a(-/-) and mdr1a(+/+) mice with or without inhibitors of Pgp (valspodar, elacridar); (ii) a Pgp inducer by looking at the effect of repeated doses of BCT on cerebral uptake of digoxin and comparing it to the effect of dexamethasone and rifampicin; (iii) a Pgp inhibitor by determining the effect of a single dose of BCT on cerebral uptake of digoxin and comparing it to the effect of valspodar. CF1 mdr1a(-/-) mice showed much higher brain uptake of BCT than CF1 mdr1a(+/+) mice and brain uptake of BCT was higher in CF1 mdr1a(+/+) mice pre-treated with valspodar or elacridar indicating that BCT is a Pgp substrate at the BBB level. Brain uptake of digoxin was not modified in CF1 mdr1a(+/+) mice pre-treated with a single dose or repeated doses of BCT, indicating that BCT is neither a Pgp inductor nor a Pgp inhibitor at the BBB in the chosen experimental setting. In vivo, at the mouse BBB level and in our experimental conditions, bromocriptin is a Pgp substrate but is not a Pgp modulator.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Quantitative simultaneous (99m)Tc-ECD/123I-FP-CIT SPECT in Parkinson's disease and multiple system atrophy.

PURPOSE: The purpose of this study was to investigate the feasibility and utility of dual-isotope SPECT for differential diagnosis of idiopathic Parkinson's disease (IPD) and multiple system atrophy (MSA). METHODS: Simultaneous (99m)Tc-ECD/123I-FP-CIT studies were performed in nine normal controls, five IPD patients, and five MSA patients. Projections were corrected for scatter, cross-talk, and high-energy penetration, and iteratively reconstructed while correcting for patient-specific attenuation and variable collimator response. Perfusion and dopamine transporter (DAT) function were assessed using voxel-based statistical parametric mapping (SPM2) and volume of interest quantitation. DAT binding potential (BP) and asymmetry index (AI) were estimated in the putamen and caudate nucleus. RESULTS: Striatal BP was lower in IPD (55%) and MSA (23%) compared to normal controls (p<0.01) , and in IPD compared to MSA (p<0.05). AI was greater for IPD than for MSA and controls in both the caudate nucleus and the putamen (p<0.05). There was significantly decreased perfusion in the left and right nucleus lentiformis in MSA compared to IPD and controls (p<0.05). CONCLUSION: Dual-isotope studies are both feasible in and promising for the diagnosis of parkinsonian syndromes.

Cysteine↗
PubMed2005

Pharmacology of Alzheimer's disease: appraisal and prospects.

Ten years after the introduction of the first drug, tacrine, in the treatment of Alzheimer's disease, it seems appropriate to re-appraise the pharmacological processes of innovation in the research field of dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, regarding experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets to consider in priority. This review deals with this objective in three parts: (1) assessment of current therapeutics, (2) discussion of the experimental models and clinical practices and (3) prospective drugs of the future. The implementation of considered strategies will require the involvement and close cooperation between political decisions, pharmaceutical companies and the scientific community.

Alzheimer Disease↗
PubMed2005

Psychopathology in amyotrophic lateral sclerosis: a preliminary study with 27 ALS patients.

Considering the few studies published on the psychopathology of ALS patients, we carried out a preliminary study evaluating depression, anxiety, emotional reactions and coping strategies in such patients. Twenty-seven ALS patients were included and evaluated using a semi-structured interview, after which they were asked to complete a questionnaire. The rater asessed the DSM-IV criteria for a major depressive episode, dysthymia and generalized anxiety, using the MADRS scale for depression, the Covi anxiety scale and the Depressive Mood scale. Subsequently, patients completed the Ways of Coping checklist. Patients were neither anxious nor depressed. Patients whose diagnosis was recent (less than six months) presented greater emotional deficit. Patients younger than 50 years of age used problem focused strategies more frequently. Those having received the diagnosis in the preceeding six months used emotion focused strategies significantly more often.The absence of characterized depression and anxiety confirmed results of the literature. The significance of this study is found in the observation of specific emotional reactions present in the first six months following diagnosis disclosure. The results show that it is useful to continue the affective evaluation of these patients and to undertake longitudinal studies starting at the time of diagnosis disclosure.

Adult↗
PubMed2004

Deficit of preparatory attention in frontotemporal dementia.

We studied preparatory attention in patients suffering from frontotemporal dementia in the beginning stages of the disease, using an experimental test developed by LaBerge, Auclair, and Siéroff (2000). In this experimental test, a distracter can appear while subjects have to prepare to respond to a simple target. The probability that a distracter can appear in a trial is varied across three blocks. Normal controls show an increase of response times to targets (slope) as a function of the distracter probability, preparatory attention to the target is reduced by the increase of the distracter probability. Patients suffering from frontotemporal dementia show a slope of response times which is more than twice as large as the slope obtained by their matched controls. Such an abnormal increase of response times to targets is interpreted as a deficit in preparatory attention. Patients also show more omissions than controls. We suggest that this deficit in preparatory attention is related to the frontal lesion presented by the patients and can result in higher distractibility, a symptom frequently encountered in these patients.

Aged↗
PubMed2004

Xaliproden in amyotrophic lateral sclerosis: early clinical trials.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. We report the safety and functional efficacy results of a double-blind, placebo-controlled phase II study of xaliproden, a non-peptidic compound with growth factor activities, in 54 ALS patients treated for up to 32 weeks. In order to overcome the interference of mortality with functional assessment in exploratory studies, we identified from our ALS database prognostic factors to establish a staging process for selection pf patients: age, disease duration, slopes of deterioration of the functional scores calculated during the two months prior to the inclusion, and the value at entry of the forced vital capacity (FVC). The six months intent-to-treat analysis showed no statistically significant effect but a trend in favour of 2 mg xaliproden compared to placebo for reduction in the rate of deterioration of FVC, limbs functional score, and manual muscle testing score (MMT). The results in the completer analysis showed a significant 43% slower rate of deterioration in FVC (P=0.046) in xaliproden-treated patients but not in functional and MMT scores. These results support the use of a staging process to select suitable patients for phase II studies, and suggest that xaliproden may have potential effects in ALS and deserve further study.

Adult↗
PubMed2004

Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

Adult↗
PubMed2004

[Memory complaints in 200 subjects meeting the diagnostic criteria for age-associated memory impairment: psychoaffective and cognitive correlates].

We studied 200 subjects recruited by general practioners and meeting the seminal criteria for the age-associated memory impairment construct (AAMI). These criteria did not allow to select an homogeneous population. Three groups could be distinguished. First, 18 subjects had apparent psychoaffective disturbances, mainly related to anxiety. Second, 41 subjects had lower memory performance than the other subjects and could be classified as severe AAMI or late-life forgetfulness, former constructs similar to the present construct of mild cognitive impairment (MCI). A large majority of subjects (n -/+ 141) had no apparent psychoaffective disturbances and normal memory performance. They could correspond to the proper AAMI construct. Actually, two subgroups could be distinguished in these subjects. Half of them had low cognitive complaints, assessed by the cognitive difficulties scale, compared to those formerly found in a population of 1349 subjects aged over 50, studied by GP, but not specifically recruited on the presence of memory complaints. These subjects could be considered as quite normal subjects. The other half of AAMI subjects had higher scores of memory complaints and more psychoafective disturbances than the subjects of the first group. No relationship was found between subjective complaints and memory performance in the total population as well as in any subgroup. The main correlate of memory complaints was the score on the Zung anxiety scale in the total population, the LLF and the AAMI groups. This study do not support the existence of a specific category of aged subjects intermediate between normal subjects without subjective memory decline and patients with MCI or incipient Alzheimer's disease. Memory complaints appear to be related to psychoaffective disturbances even in subjects with low memory performance.

Aged↗
PubMed2004

[Planning and activities of daily living in Alzheimer's disease and frontotemporal dementia].

OBJECTIVE: To study the relationship between the disturbances in activities of daily living and the scores on tests assessing planning activities in frontotemporal dementia (FTD) and Alzheimer's disease (AD). METHODS: Eleven patients with FTD were compared to 11 patients with AD and 29 healthy controls. Cognitive status, evaluated by the Dementia Rating Scale (DRS) and the Mini Mental State Examination (MMSE) was identical in the two groups of patients. Activities of daily living were assessed by three questionnaires completed by the main caregiver: (1) the Cognitive Difficulties Scale (CDS); (2) the NADL, a composite scale including the Physical self-maintenance scale (ADL) the Instrumental activities of daily living (IADL) the social activities scale, (SADL); (3) the Dysexecutive Questionnaire (DEX) from the Behavioural Assessment of the Dysexecutive Syndrome. Planning abilities were assessed by the tower of London and three tests from the BADS: the key search, the zoo map and the six elements. RESULTS: No quantitative differences were found between FTD and AD patients in daily living activities disturbances or scores on planning tests. Both were closely related to the global cognitive performance assessed by the DRS or the MMSE but no clear relationship was found between them. The scores on the tower of London were not correlated to those on the tests from the BADS. CONCLUSION: Neither assessment of activities of daily living or scores on the planning tests could differentiate FTD from AD. Planning appears as a multidimensional construct poorly assessed by the usual assessment tools.

Activities of Daily Living↗
PubMed2004

[Biology of motivation].

Motivation is a concept largely studied by modern psychology and mainly applied in the fields of learning at school, performance at work, competition in sport. Recently neuropsychiatry put forward the syndrome of apathy, a major disorder of the motivation which appears as frequently observed in several neurodegenerative disorders and in particular in Alzheimer's disease. The question raised in the present review is to detect and gather the data which would prove the existence of a physiology and a neurobiology of the motivation, a real prerequisite for any pharmacological project. Precisely, frontal lobe and cingular cortex appear as critical in the activation of motivational process. Acetylcholine and dopamine, at the present time, are considered as the main neurotransmitters involved in such anatomical circuits explaining that pharmacology focuses its interest on acetylcholinesterase inhibitors and dopamine agonists. Studies specifically devoted to motivation and apathy are anxiously expected and should be based on the most recent acquisitions of the neurophilosophy.

Animals↗