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Frontotemporal dementia and amyotrophic lateral sclerosis are rare neurodegenerative diseases with no effective treatment. The development of biomarkers allowing an accurate assessment of disease progression is crucial for evaluating new therapies. Concretely, neuroimaging and transcriptomic (microRNA) data have been shown useful in tracking their progression. However, no single biomarker can accurately measure progression in these complex diseases. Additionally, large samples are not available for such rare disorders. It is thus essential to develop methods that can model disease progression by combining multiple biomarkers from small samples. In this paper, we propose a new framework for computing a disease progression score (DPS) from cross-sectional multimodal data. Specifically, we introduce a supervised multimodal variational autoencoder that can infer a meaningful latent space, where latent representations are placed along a disease trajectory. A score is computed by orthogonal projections onto this path. We evaluate our framework with multiple synthetic datasets and with a real dataset containing 14 patients, 40 presymptomatic genetic mutation carriers and 37 controls from the PREV-DEMALS study. There is no ground truth for the DPS in real-world scenarios, therefore we use the area under the ROC curve (AUC) as a proxy metric. Results with the synthetic datasets support this choice, since the higher the AUC, the more accurate the predicted simulated DPS. Experiments with the real dataset demonstrate better performance in comparison with state-of-the-art approaches. The proposed framework thus leverages cross-sectional multimodal datasets with small sample sizes to objectively measure disease progression, with potential application in clinical trials.

Reduced empathy is a common symptom in frontotemporal dementia (FTD). Although empathy deficits have been extensively researched in sporadic cases, few studies have explored the differences in familial forms of FTD.

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72and GRNcohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72and GRNpatients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRNpatients had higher levels than C9orf72(86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276and NCT04014673.

ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72patients, 45 presymptomatic C9orf72mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.

ObjectiveTo investigate cognitive inhibition in presymptomatic C9orf72mutation carriers (C9+) and its associated neuroanatomical correlates.MethodsThirty-eight presymptomatic C9orf72mutation carriers (C9+, mean age 38.2±8.0 years) and 22 C9− controls from the PREV-DEMALS cohort were included in this study. They underwent a cognitive inhibition assessment with the Hayling Sentence Completion Test (HSCT; time to completion (part B−part A); error score in part B) as well as a 3D MRI.ResultsC9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B−part A) compared to C9− individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum.ConclusionThe HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.

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IMPORTANCE: Presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. OBJECTIVES: To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers. DESIGN, SETTING, AND PARTICIPANTS: The PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Eighty-four participants entered the study between October 2015 and April 2017; 80 (95%) were included in cross-sectional analyses of baseline data. All participants underwent neuropsychological testing and magnetic resonance imaging; 63 (79%) underwent diffusion tensor magnetic resonance imaging. Gray matter volumes and diffusion tensor imaging metrics were calculated within regions of interest. Anatomical and microstructural differences between individuals who carried the C9orf72 mutation (C9+) and those who did not carry the C9orf72 mutation (C9−) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017. MAIN OUTCOMES AND MEASURES: Differences in neuropsychological scores, gray matter volume, and white matter integrity between C9+ and C9− individuals. RESULTS: Of the 80 included participants, there were 41 C9+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39 C9− individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with C9− individuals, C9+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; P = .01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5]; P = .004), atrophy in 8 cortical regions of interest and in the right thalamus, and white matter alterations in 8 tracts. When restricting the analyses to participants younger than 40 years, compared with C9− individuals, C9+ individuals had lower praxis scores and intransitive gesture scores, atrophy in 4 cortical regions of interest and in the right thalamus, and white matter alterations in 2 tracts. CONCLUSIONS AND RELEVANCE: Cognitive, structural, and microstructural alterations are detectable in young C9+ individuals. Early and subtle praxis alterations, underpinned by focal atrophy of the left supramarginal gyrus, may represent an early and nonevolving phenotype related to neurodevelopmental effects of C9orf72 mutation. White matter alterations reflect the future phenotype of frontotemporal lobar degeneration/amyotrophic lateral sclerosis, while atrophy appears more diffuse. Our results contribute to a better understanding of the preclinical phase of C9orf72 disease and of the respective contribution of magnetic resonance biomarkers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02590276

Scaling up and replication of successful innovative integrated care models for chronic diseases is one of the targets of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). MACVIA-LR®(MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon) is a Reference Site of the EIP on AHA. The main objective of MACVIA-LR®is to develop innovative solutions in order to (1) improve the care of patients affected by chronic diseases, (2) reduce avoidable hospitalization and (3) scale up the innovation to regions of Europe. The MACVIA-LR®project also aims to assess all possible aspects of medicine—including non-pharmacologic approaches—in order to maintain health and prevent chronic diseases. These approaches include hydrotherapy and balneotherapy which can be of great importance if health promotion strategies are considered. Balneotherapy at Balaruc-les-Bains focusses on musculoskeletal diseases and chronic venous insufficiency of the lower limbs. Each year, over 46,000 people attend an 18-day course related to a new falls prevention initiative combining balneotherapy and education. On arrival, each person receives a flyer providing information on the risk of fall and, depending on this risk, a course is proposed combining education and physical activity. A pilot study assesses the impact of the course 6 and 12 months later. This health promotion strategy for active and healthy ageing follows the FEMTEC (World Federation of Hydrotherapy and Climatotherapy) concept.

IMPORTANCE: Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described. OBSERVATIONS: We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA. A heterozygous p.Arg110* (c.328C>T) GRN mutation was identified in this patient. CONCLUSIONS AND RELEVANCE: This study extends the clinical spectrum of GRN mutations that may be responsible for a PCA phenotype. The GRN phenotypes overlap other degenerative dementias and highlight the limits of actual nosologic boundaries in dementias. The GRN gene should be analyzed in patients with PCA, particularly when the damage progresses to anterior cerebral regions and a family history of dementia is present.

IMPORTANCE: Mutations in the progranulin (GRN) gene are responsible for 20% of familial cases of frontotemporal dementias. All cause haploinsufficiency of progranulin, a protein involved in inflammation, tissue repair, and cancer. Carriers of the GRN mutation are characterized by a variable degree of asymmetric brain atrophy, predominantly in the frontal, temporal, and parietal lobes. We describe 4 GRN mutation carriers with remarkable widespread white matter lesions (WML) associated with lobar atrophy shown on magnetic resonance imaging. OBSERVATIONS: Four GRN mutation carriers (age at onset, 56-65 years) presenting with severe WML were selected from 31 GRN mutation carriers who were followed up in our dementia centers. The WML were predominantly in the frontal and parietal lobes and were mostly confluent, affecting the periventricular subcortical white matter and U-fibers. In all patients, common vascular, metabolic, inflammatory, dysimmune, and mitochondrial disorders were excluded and none had severe vascular risk factors. CONCLUSIONS AND RELEVANCE: Our data suggest that white matter involvement may be linked to progranulin pathological processes in a subset of GRN mutation carriers. The plasma progranulin measurement, which is predictive of GRN mutations, and GRN sequencing should thus be included in investigations of patients with frontotemporal lobar degenerations who show unusual white matter hyperintensities and atrophy on magnetic resonance imaging.

Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).

The aim of this study was to establish the frequency of ATXN2polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2could act as a modifier gene in patients carrying the C9orf72expansion.

IMPORTANCE Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified. OBJECTIVE To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype). DESIGN, SETTING, AND PARTICIPANTS Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated. MAIN OUTCOMES AND MEASURES Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers. RESULTS We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia. CONCLUSIONS AND RELEVANCE Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.

IMPORTANCE Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. OBJECTIVE To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. DESIGN A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. SETTING Primary care or referral center. PARTICIPANTS An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. MAIN OUTCOMES AND MEASURES Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. RESULTS We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. CONCLUSIONS AND RELEVANCE Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

IMPORTANCE The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS. OBJECTIVE To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases. DESIGN Whole-exome sequencing and follow up-screening by Sanger sequencing. SETTING Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France. PARTICIPANTS A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype. INTERVENTIONS Whole-exome sequencing in a family and Sanger sequencing of CSF1R. MAIN OUTCOMES AND MEASURES Mutations in CSF1R. RESULTS We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS. CONCLUSIONS AND RELEVANCE These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.

Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3).

Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.

Familial encephalopathy with neuroserpin inclusion bodies is a recently described neurodegenerative disease that is responsible for progressive myoclonic epilepsy or presenile dementia. In a French family with the S52R mutation of the neuroserpin gene, progressive myoclonic epilepsy was associated with a frontal syndrome. The typical cerebral inclusions (Collins bodies) were abundant in the frontal cortex and in the head of the caudate nucleus but spared the cerebellum.

Dystonia syndromes constitute a heterogeneous group of phenotypes that may be caused by different heredodegenerative, metabolic, or genetic diseases.

In dominant spinocerebellar ataxias (SCAs), the issue of whether non‐CAG dependent factors contribute to onset age remains unsettled. Data on SCA genotype, onset age, normal/expanded CAG repeat length, sex of the patient and transmitting parent, and family details were available from 802 patients. Based on the model [log10(age at onset) = k− bCAGexp+ ϵ], we examined changes in adjusted R2and residual standard error following incorporation of the other factors in this model. The expanded repeat explained 44.3 to 74.9% of onset age variance, although this was less than 50% in SCA3 and SCA6, implicating a large effect of non‐CAG factors. The relation between onset age and CAG repeat was similar for SCA1, 3, 6, and 7, but different for SCA2, pointing to different polyglutamine effects in SCA2. For SCA2 and SCA3, 17.1 and 45.5% of onset age variance, respectively, were explained by currently (unidentified) familial factors. We found a significant contribution of the nonexpanded allele in SCA1 and SCA6. Besides polyglutamine motif (determined by the expanded CAG repeat length), we identified the following age at onset modifiers: protein context in SCA2; familial factors in SCA2 and SCA3; and the nonexpanded CAG repeat in SCA1 and SCA6. Ann Neurol 2005

We report a group of 252 patients with a Huntington's disease-like (HDL) phenotype, including 60 with typical Huntington's disease, who had tested negative for pathological expansions in the IT15 gene, the major mutation in Huntington's disease. They were screened for repeat expansions in two other genes involved in HDL phenotypes: those encoding the junctophilin-3 (JPH3/HDL2) and prion (PRNP/HDL1) proteins. In addition, because of the clinical overlap between patients with HDL disease and autosomal dominant cerebellar ataxia or dentatorubral and pallidoluysian atrophy (DRPLA), we investigated trinucleotide repeat expansions in genes encoding the TATA-binding protein (TBP/SCA17) and atrophin-1 (DRPLA). Two patients carried 43 and 50 uninterrupted CTG repeats in the JPH3 gene. Two other patients had 44 and 46 CAA/CAG repeats in the TBP gene. Patients with expansions in the TBP or JPH3 genes had HDL phenotypes indistinguishable from Huntington's disease. Taking into account patients with typical Huntington's disease, their frequencies were evaluated as 3% each in our series of typical HDL patients. Interestingly, incomplete penetrance of the 46 CAA/CAG repeat in the TBP gene was observed in a 59-year-old transmitting, but healthy, parent. Furthermore, we report a new configuration of the expanded TBP allele, with 11 repeats on the first polymorphic stretch of CAGs. Expansions in the DRPLA gene and insertions in the PRNP gene were not found in our group of patients. Further genetic heterogeneity of the HDL phenotype therefore exists.

Desymmetrisation of silylcyclopenta-2,4-diene was carried out by an asymmetric copper(I)-mediated cyclopropanation. An in-depth investigation with various ligands led to the discovery that the PyBox ligands 10a−c were the most efficient ligands for this transformation and led to the cyclopropane 7a with an ee of up to 72%. Further studies aimed at providing insights into the origin of this enantiocontrol are also provided. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Recently, a single nucleotide polymorphism that results in an amino acid change (Q7R) was identified in a previously undescribed gene, named saitohin, nested within the taugene. We analyzed the distribution of this polymorphism in 499 patients with Alzheimer's disease, 91 patients with frontotemporal dementia, and 402 controls. This polymorphism was in complete disequilibrium with the well‐defined extended tauhaplotype. We failed to replicate the association between the RR genotype and late‐onset Alzheimer's disease, but we found a trend toward an association between the QQ genotype and frontotemporal dementia. Thus, the saitohinQ allele, which is a novel determinant of the tau H1haplotypes, might represent a causative factor involved in the determinism of several tauopathies.

An unusually high frequency of atypical Parkinson syndrome has been delineated over the last 5 years in the French West Indies. Postural instability with early falls, prominent frontal lobe dysfunction and pseudo-bulbar palsy were common and three-quarters of the patients were L-dopa unresponsive. One-third of all patients seen had probable progressive supranuclear palsy (PSP). This new focus of atypical parkinsonism is reminiscent of the one described in Guam and may be linked to exposure to tropical plants containing mitochondrial complex I inhibitors (quinolines, acetogenins, rotenoids). Two hundred and twenty consecutive patients with Parkinson's syndrome seen by the neurology service at Pointe à Pitre, Guadeloupe University Hospital were studied. Currently accepted operational clinical criteria for Parkinson's syndromes were applied. The pathological findings of three patients who came to autopsy are reported. Fifty-eight patients had probable PSP, 96 had undetermined parkinsonism and 50 had Parkinson's disease, 15 had amyotrophic lateral sclerosis with parkinsonism and one had probable multiple system atrophy. All three PSP patients in whom post-mortem study was performed had early postural instability, gaze palsy and parkinsonian symptoms, followed by a frontolimbic dementia and corticobulbar signs. Neuropathological examination showed an accumulation of tau proteins, predominating in the midbrain. There was an exceptionally large accumulation of neuropil threads in Case 1. Biochemical studies detected a major doublet of pathological tau at 64 and 69 kDa in brain tissue homogenates. All cases were homozygous for the H1 tau haplotype, but no mutation of the tau gene was observed. Clinical, neuropathological and biochemical features were compatible with the diagnosis of PSP, although some unusual pathological features were noted in Case 1. A cluster of cases presenting with atypical parkinsonism is reported. Guadeloupean parkinsonism may prove to be a tauopathy identical or closely related to PSP.

An unusually high frequency of atypical Parkinson syndrome has been delineated over the last 5 years in the French West Indies. Postural instability with early falls, prominent frontal lobe dysfunction and pseudo‐bulbar palsy were common and three‐quarters of the patients were l‐dopa unresponsive. One‐third of all patients seen had probable progressive supranuclear palsy (PSP). This new focus of atypical parkinsonism is reminiscent of the one described in Guam and may be linked to exposure to tropical plants containing mitochondrial complex I inhibitors (quinolines, acetogenins, rotenoids). Two hundred and twenty consecutive patients with Parkinson’s syndrome seen by the neurology service at Pointe à Pitre, Guadeloupe University Hospital were studied. Currently accepted operational clinical criteria for Parkinson’s syndromes were applied. The pathological findings of three patients who came to autopsy are reported. Fifty‐eight patients had probable PSP, 96 had undetermined parkinsonism and 50 had Parkinson’s disease, 15 had amyotrophic lateral sclerosis with parkinsonism and one had probable multiple system atrophy. All three PSP patients in whom post‐mortem study was performed had early postural instability, gaze palsy and parkinsonian symptoms, followed by a frontolimbic dementia and corticobulbar signs. Neuropathological examination showed an accumulation of tau proteins, predominating in the midbrain. There was an exceptionally large accumulation of neuropil threads in Case 1. Biochemical studies detected a major doublet of pathological tau at 64 and 69 kDa in brain tissue homogenates. All cases were homozygous for the H1 tau haplotype, but no mutation of the tau gene was observed. Clinical, neuropathological and biochemical features were compatible with the diagnosis of PSP, although some unusual pathological features were noted in Case 1. A cluster of cases presenting with atypical parkinsonism is reported. Guadeloupean parkinsonism may prove to be a tauopathy identical or closely related to PSP.

At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain a CAG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases with ADCA. An expanded repeat with 46 repeat units was detected in a single index case from Belgium. In this family, two affected members and six unaffected, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbances with onset in their fourth to sixth decade. The main neuropathological finding was severe neuronal loss and gliosis in the Purkinje cell layer. Immunohistochemical analysis showed neuronal intranuclear inclusions containing expanded polyglutamine, indicating that this disease shares several features with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiatric manifestations.

At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain a CAG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases with ADCA. An expanded repeat with 46 repeat units was detected in a single index case from Belgium. In this family, two affected members and six unaffected, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbances with onset in their fourth to sixth decade. The main neuropathological finding was severe neuronal loss and gliosis in the Purkinje cell layer. Immunohistochemical analysis showed neuronal intranuclear inclusions containing expanded polyglutamine, indicating that this disease shares several features with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiatric manifestations.

Two series of three trioxanes and 18 disubstituted peroxides were synthesised and evaluated for their in vitro trichomonacidal activity against Trichomonas vaginalis . The most active compound, 2-methylprop-2-yl 2-methoxyeth-1-yl peroxide exhibited an IC 50 value of 1.0±0.2 μM whereas other dialkyl peroxides had various IC 50 values which could not be correlated to their molecule structure. The best compound was about five times more active than metronidazole. The amount of generated oxygen or free radicals cannot explain completely the activity suggesting another way of action for these compounds on T. vaginalis .

Spinocerebellar ataxia 12 (SCA12) is an autosomal dominant cerebellar ataxia (ADCA) described in a single family with a CAG repeat expansion in the PPP2R2B gene. We screened 247 index cases, including 145 families with ADCA, for this expansion. An expanded repeat ranging from 55 to 61 triplets was detected in 6 affected and 3 unaffected individuals at risk in a single family from India. The association of the PPP2R2B CAG repeat expansion with disease in this new family provides additional evidence that the mutation is causative. Ann Neurol 2001;49:117–121

A clear-cut correlation between antimalarial potency and the alkylative property of synthetic tricyclic trioxanes 5–10 is reported. Thus, trioxanes 5 and 7, substituted at the C-5a angular position by a methyl or a cyano group, proved to be completely devoid of antimalarial activity, and did not alkylate the heme model Mn^IITPP. In contrast, both the anti-Plasmodium activity and the alkylative property were restored in the C-5a-unsubstituted analog 8, bearing a methoxymethyl group at C-3. Reaction of 8 with Mn^IITPP furnished the covalent adduct 18, resulting from trapping of the methoxymethyl radical by the heme model. All these results reinforce the hypothesis that the metalloporphyrin closely interacts with the peroxide bond of the drug to bring about activation of these trioxane antimalarial agents.

SPOCK, previously identified as testican, is a modular proteoglycan that carries both chondroitin and heparan sulfate glycosaminoglycan side chains. The overall genomic organization has been established. The SPOCK gene spans at least 70 kb and is composed of 11 exons: the first half of the gene is dramatically expanded, but the second half is more compact.In situhybridization and YAC mapping independently linked the SPOCK gene to 5q31, a region containing an impressive number of genes encoding growth factors, cytokines, and neurotransmitter and hormone receptors. The gene is located between the IL9 and the EGR1 genes, bordering the smallest commonly deleted region of chromosome 5.

Leber's congenital amaurosis (LCA, MIM 2040001), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies2,3. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG4). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digitoocular sign of Franceschetti5). Hypermetropia and keratoconus frequently develop in the course of the disease6,7. The observation by Waardenburg8of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photore-ceptors or extremely early degeneration of cells that have developed normally9. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series10,11. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.

Background and Purpose:Echolucent carotid plaques compared with echogenic plaques could carry a significant risk of transient ischemic attacks and strokes, but the reproducibility of new ultrasonic methods has not yet been proved. The objective was to evaluate interobserver and intraobserver agreement in characterizing the carotid plaques studied by both B mode imaging and color Doppler imaging, which is the only ultrasonic method available for recognizing anechoic lesions. Methods:Fifty-three carotid plaques greater than 40% in diameter were selected from four centers and simultaneously analyzed by 9 observers. Five types of plaques were defined by their echo structure: class I = uniformly anechogenic, class II = predominantly hypoechogenic with >50% hypoechogenic area, class III = predominantly echogenic with >50% echogenic area, class IV = uniformly echogenic, class V = unclassified plaques. The luminal surface was characterized as either 1 = regular, 2 = recess of more than 2 mm in depth and width, or 3 = unclassified. Agreement of these variables was calculated by using the kappa index, agreement proportion and an intraclass correlation coefficient. Results:Interobserver reproducibility was only fair for type I (kappa = 0.47) and for the luminal surface (class 1, kappa = 0.52 and class 2, kappa = 0.41). Agreement proportion was 0.51 in hypoechoic plaques and 0.64 in the determination of the regular surface. Mean intraobserver agreement was fair (kappa = 0.47 ± 0.1) for plaque echogenicity to good (kappa = 0.63 ± 0.19) for surface. Conclusion:This study shows that the semiquantitative classification, first developed by Gray-Weale, then by Nicolaides, could be improved, thus giving rise to a new outlook in the debated field of ulcerations.

Abstract: Leber's congenital amaurosis (LCA) is an autosomal recessive disease responsible for congenital blindness. It is the earliest and most severe inherited retinal dystrophy in human and its genetic heterogeneity has long been recognised. We have recently reported on the first localisation of a disease gene (LCAI) to the short arm of chromosome 17 by homozygosity mapping in five families of North African origin. Here, we refine the genetic mapping of LCAI to chromosome 17p13 between loci D17S938 and D17S1353 and provide strong support for the genetic heterogeneity of this condition (maximum likelihood for heterogeneity, 17.20 in 1nL; heterogeneity versus homogeneity,P = 0.0002, heterogeneity versus no linkage,P < 0.0001)

The complete deduced primary structure of mouse brain testican has been established from cDNA cloning. The cDNA encodes a polypeptide of 442 amino acids belonging to the proteoglycan family. The mouse brain testican core protein is 95% identical to its human testicular counterpart. In situ hybridization investigations revealed that mouse testican mRNA is mainly present in a subpopulation of pyramidal neurons localized in the CA3 area of the hippocampus. An immunocytochemical approach, with antibodies directed against an overexpressed chimeric antigen, produced in bacterial systems, showed that testican is associated with the postsynaptic region of these pyramidal neurons. Testican includes several putative functional domains related to extracellular or pericellular proteins associated with binding and/or regulatory functions. On the basis of its structural organization and its occurrence in postsynaptic areas, this proteoglycan might contribute to various neuronal mechanisms in the central nervous system.

The complete deduced primary structure of mouse brain testican has been established from cDNA cloning. The cDNA encodes a polypeptide of 442 amino acids belonging to the proteoglycan family. The mouse brain testican core protein is 95% identical to its human testicular counterpart. In situhybridization investigations revealed that mouse testican mRNA is mainly present in a subpopulation of pyramidal neurons localized in the CA3 area of the hippocampus. An immunocytochemical approach, with antibodies directed against an overexpressed chimeric antigen, produced in bacterial systems, showed that testican is associated with the postsynaptic region of these pyramidal neurons. Testican includes several putative functional domains related to extracellular or pericellular proteins associated with binding and/or regulatory functions. On the basis of its structural organization and its occurrence in postsynaptic areas, this proteoglycan might contribute to various neuronal mechanisms in the central nervous system.

À l’approche de thérapies ciblées dans les formes génétiques de démence frontotemporale (DFT) et sclérose latérale amyotrophique (SLA), l’identification des biomarqueurs d’évolution présymptomatique et conversion clinique représente un enjeu majeur.