Daisy Rinaldi
University of Paris
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Featured researches published by Daisy Rinaldi.
Neurology | 2015
Isaac M. Adanyeguh; Daisy Rinaldi; Pierre Gilles Henry; Samantha Caillet; Romain Valabregue; Alexandra Durr; Fanny Mochel
Objective: Based on our previous work in Huntington disease (HD) showing improved energy metabolism in muscle by providing substrates to the Krebs cycle, we wished to obtain a proof-of-concept of the therapeutic benefit of triheptanoin using a functional biomarker of brain energy metabolism validated in HD. Methods: We performed an open-label study using 31P brain magnetic resonance spectroscopy (MRS) to measure the levels of phosphocreatine (PCr) and inorganic phosphate (Pi) before (rest), during (activation), and after (recovery) a visual stimulus. We performed 31P brain MRS in 10 patients at an early stage of HD and 13 controls. Patients with HD were then treated for 1 month with triheptanoin after which they returned for follow-up including 31P brain MRS scan. Results: At baseline, we confirmed an increase in Pi/PCr ratio during brain activation in controls—reflecting increased adenosine triphosphate synthesis—followed by a return to baseline levels during recovery (p = 0.013). In patients with HD, we validated the existence of an abnormal brain energy profile as previously reported. After 1 month, this profile remained abnormal in patients with HD who did not receive treatment. Conversely, the MRS profile was improved in patients with HD treated with triheptanoin for 1 month with the restoration of an increased Pi/PCr ratio during visual stimulation (p = 0.005). Conclusion: This study suggests that triheptanoin is able to correct the bioenergetic profile in the brain of patients with HD at an early stage of the disease. Classification of evidence: This study provides Class III evidence that, for patients with HD, treatment with triheptanoin for 1 month restores an increased MRS Pi/PCr ratio during visual stimulation.
Movement Disorders | 2012
Fanny Mochel; Tra My Nguyen; Dinesh K. Deelchand; Daisy Rinaldi; Romain Valabregue; Claire Wary; Pierre G. Carlier; Alexandra Durr; Pierre Gilles Henry
We wished to identify noninvasive in vivo biomarkers of brain energy deficit in Huntington disease.
Journal of Neurology, Neurosurgery, and Psychiatry | 2016
Fanny Mochel; Elodie Hainque; Domitille Gras; Isaac M. Adanyeguh; Samantha Caillet; Bénédicte Héron; Agathe Roubertie; Elsa Kaphan; Romain Valabregue; Daisy Rinaldi; Sandrine Vuillaumier; Raphael Schiffmann; Chris Ottolenghi; Jean-Yves Hogrel; Laurent Servais; Emmanuel Roze
Objective On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7–47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional 31P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results Patients with GLUT1-DS experienced a mean of 30.8 (±27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (±2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (±21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. Conclusions Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. Trial registration number NCT02014883.
Movement Disorders | 2015
Isaac M. Adanyeguh; Pierre Gilles Henry; Tra My Nguyen; Daisy Rinaldi; Céline Jauffret; Romain Valabregue; Uzay E. Emir; Dinesh K. Deelchand; Alexis Brice; Lynn E. Eberly; Gülin Öz; Alexandra Durr; Fanny Mochel
Spinocerebellar ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Proton magnetic resonance spectroscopy (1H MRS) using an optimized semiadiabatic localization by adiabatic selective refocusing (semi‐LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n = 16), SCA2 (n = 12), SCA3 (n = 21), and SCA7 (n = 12) and healthy controls (n = 33). Compared with controls, patients displayed lower total N‐acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, whereas the glial marker, myoinositol (myo‐Ins), was elevated. Patients also showed higher total creatine as reported in Huntingtons disease, another polyglutamine repeat disorder. A strong correlation was found between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N‐acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo‐Ins) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. The neurometabolic profiles detected in patients underlie cell‐specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof‐of‐concept therapeutic trials.
Brain Research | 2013
S. Gigout; Jacques Louvel; Daisy Rinaldi; Benoît Martin; R. Pumain
Electroencephalographic generalized spike and wave discharges (SWD), the hallmark of human absence seizures, are generated in thalamocortical networks. However, the potential alterations in these networks in terms of the efficacy of the reciprocal synaptic activities between the cortex and the thalamus are not known in this pathology. Here, the efficacy of these reciprocal connections is assessed in vitro in thalamocortical slices obtained from BS/Orl mice, which is a new genetic model of absence epilepsy. These mice show spontaneous SWD, and their features can be compared to that of BR/Orl mice, which are free of SWD. In addition, since gap junctions may modulate the efficacy of these connections, their implications in pharmacologically-induced epileptiform discharges were studied in the same slices. The thalamus and neocortex were independently stimulated and the electrically-evoked responses in both structures were recorded from the same slice. The synaptic efficacy of thalamocortical and corticothalamic connections were assessed by measuring the dynamic range of synaptic field potential changes in response to increasing stimulation strengths. The connection efficacy was weaker in epileptic mice however, this decrease in efficacy was more pronounced in thalamocortical afferents, thus introducing an imbalance in the reciprocal connections between the cortex and thalamus. However, short-term facilitation of the thalamocortical responses were increased in epileptic mice compared to non-epileptic animals. These features may favor occurrence of rhythmical activities in thalamocortical networks. In addition, carbenoxolone (a gap junction blocker) decreased the cumulative duration of 4-aminopyridine-induced ictal-like activities, with a slower time course in epileptic mice. However, the 4-aminopyridine-induced GABA-dependent negative potentials, which appeared to trigger the ictal-like activities, remained. Our results show that the balance of the reciprocal connections between the thalamus and cortex is altered in favor of the corticothalamic connections in epileptic mice, and suggest that gap junctions mediate a stronger cortical synchronization in this strain.
Neurology | 2017
Giulia Coarelli; Alhassane Diallo; Morgane Sonia Thion; Daisy Rinaldi; Fabienne Calvas; Ouahid Lagha Boukbiza; Alina Tataru; Perrine Charles; Christine Tranchant; Cecilia Marelli; Claire Ewenczyk; Maya Tchikviladzé; Marie-Lorraine Monin; Bertrand Carlander; Mathieu Anheim; Alexis Brice; Fanny Mochel; Sophie Tezenas du Montcel; Sandrine Humbert; Alexandra Durr
Objective: Polyglutamine (PolyQ) diseases are dominantly transmitted neurologic disorders, caused by coding and expanded CAG trinucleotide repeats. Cancer was reported retrospectively to be rare in patients with PolyQ diseases and we aimed to investigate its prevalence in France. Methods: Consecutive patients with Huntington disease (HD) and spinocerebellar ataxia (SCA) were questioned about cancer, cardiovascular diseases, and related risk factors in 4 university hospitals in Paris, Toulouse, Strasbourg, and Montpellier. Standardized incidence ratios (SIR), based on age- and sex-adjusted rate of the French population, were assessed for different types of cancer. Results: We questioned 372 patients with HD and 134 patients with SCA. SIR showed significantly reduced risk of cancer in HD: 23 observed cases vs 111.05 expected ones (SIR 0.21, 95% confidence interval [CI] 0.13–0.31), as well as in SCA: 7 observed cases vs 34.73 expected (SIR 0.23, 95% CI 0.08–0.42). This was surprising since risk behavior for cancer was increased in these patients, with significantly greater tobacco and alcohol consumption in patients with HD vs patients with SCA (p < 0.0056). There was no association between CAG repeat size and cancer or cardiovascular disease. However, in patients with HD, skin cancers were more frequent than expected (5 vs 0.98, SIR 5.11, 95% CI 1.65–11.95). Conclusions: There was a decreased cancer rate in PolyQ diseases despite high incidence of risk factors. Intriguingly, skin cancer incidence was higher, suggesting a crosstalk between neurodegeneration and skin tumorigenesis.
JAMA Neurology | 2018
Anne Bertrand; Junhao Wen; Daisy Rinaldi; Marion Houot; Sabrina Sayah; Agnès Camuzat; Clémence Fournier; Sabrina Fontanella; Alexandre Routier; Philippe Couratier; Florence Pasquier; Marie-Odile Habert; Didier Hannequin; Olivier Martinaud; Paola Caroppo; Richard Levy; Bruno Dubois; Alexis Brice; Stanley Durrleman; Olivier Colliot; Isabelle Le Ber; Prevdemals Study
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
Neurobiology of Aging | 2018
Dario Saracino; Fabienne Clot; Agnès Camuzat; Vincent Anquetil; Didier Hannequin; Lucie Guyant-Maréchal; Mira Didic; Léna Guillot-Noël; Daisy Rinaldi; Morwena Latouche; Sylvie Forlani; Yassaman Ghassab; Cinzia Coppola; Giuseppe Di Iorio; Isabelle David; Ftd-Als; Eric Le Guern; Alexis Brice; Isabelle Le Ber
Valosin-containing protein (VCP) mutations are rare causes of autosomal dominant frontotemporal dementias associated with Pagets disease of bone, inclusion body myopathy, and amyotrophic lateral sclerosis. We analyzed the VCP gene in a cohort of 199 patients with frontotemporal dementia and identified 7 heterozygous mutations in unrelated families, including 3 novel mutations segregating with dementia. This expands the VCP mutation spectrum and suggests that although VCP mutations are rare (3.5% in this study), the gene should be analyzed even in absence of the full syndromic complex. Reporting genetic variants with convincing arguments for pathogenicity is important considering the large amount of data generated by next-generation sequencing and the growing difficulties to interpret rare genetic variants identified in isolated cases.
NeuroImage: Clinical | 2018
Isaac M. Adanyeguh; Vincent Perlbarg; Pierre Gilles Henry; Daisy Rinaldi; Elodie Petit; Romain Valabregue; Alexis Brice; Alexandra Durr; Fanny Mochel
Objective As gene-based therapies may soon arise for patients with spinocerebellar ataxia (SCA), there is a critical need to identify biomarkers of disease progression with effect sizes greater than clinical scores, enabling trials with smaller sample sizes. Methods We enrolled a unique cohort of patients with SCA1 (n = 15), SCA2 (n = 12), SCA3 (n = 20) and SCA7 (n = 10) and 24 healthy controls of similar age, sex and body mass index. We collected longitudinal clinical and imaging data at baseline and follow-up (mean interval of 24 months). We performed both manual and automated volumetric analyses. Diffusion tensor imaging (DTI) and a novel tractography method, called fixel-based analysis (FBA), were assessed at follow-up. Effect sizes were calculated for clinical scores and imaging parameters. Results Clinical scores worsened as atrophy increased over time (p < 0.05). However, atrophy of cerebellum and pons showed very large effect sizes (>1.2) compared to clinical scores (<0.8). FBA, applied for the first time to SCA, was sensitive to microstructural cross-sectional differences that were not captured by conventional DTI metrics, especially in the less studied SCA7 group. FBA also showed larger effect sizes than DTI metrics. Conclusion This study showed that volumetry outperformed clinical scores to measure disease progression in SCA1, SCA2, SCA3 and SCA7. Therefore, we advocate the use of volumetric biomarkers in therapeutic trials of autosomal dominant ataxias. In addition, FBA showed larger effect size than DTI to detect cross-sectional microstructural alterations in patients relative to controls.
NMR in Biomedicine | 2018
Isaac M. Adanyeguh; Marie Lorraine Monin; Daisy Rinaldi; Leorah Freeman; Alexandra Durr; Stéphane Lehéricy; Pierre Gilles Henry; Fanny Mochel
The striatum is a well‐known region affected in Huntington disease (HD). However, other regions, including the visual cortex, are implicated. We have identified previously an abnormal energy response in the visual cortex of patients at an early stage of HD using 31P magnetic resonance spectroscopy (31P MRS). We therefore sought to further characterize these metabolic alterations with 1H MRS using a well‐validated semi‐localized by adiabatic selective refocusing (semi‐LASER) sequence that allows the measurement of an expanded number of neurometabolites. Ten early affected patients [Unified Huntington Disease Rating Scale (UHDRS), total motor score = 13.6 ± 10.8] and 10 healthy volunteers of similar age and body mass index (BMI) were recruited for the study. We performed 1H MRS in the striatum – the region that is primarily affected in HD – and the visual cortex. The protocol allowed a reliable quantification of 10 metabolites in the visual cortex and eight in the striatum, compared with three to five metabolites in previous 1H MRS studies performed in HD. We identified higher total creatine (p < 0.05) in the visual cortex and lower glutamate (p < 0.001) and total creatine (p < 0.05) in the striatum of patients with HD compared with controls. Less abundant neurometabolites [glutamine, γ‐aminobutyric acid (GABA), glutathione, aspartate] showed similar concentrations in both groups. The protocol allowed the measurement of several additional metabolites compared with standard vendor protocols. Our study points to early changes in metabolites involved in energy metabolism in the visual cortex and striatum of patients with HD. Decreased striatal glutamate could reflect early neuronal dysfunction or impaired glutamatergic neurotransmission.