Publications by authors named "Diane Dufour-Rainfray"

18 Publications

  • Page 1 of 1

The contributions of metabolomics in the discovery of new therapeutic targets in Alzheimer's disease.

Fundam Clin Pharmacol 2021 Jan 23. Epub 2021 Jan 23.

UMR 1253, Université de Tours, Inserm, 37000, France.

Alzheimer's disease (AD) leads to the progressive loss of memory and other cognitive functions. It is the most common form of dementia in the elderly and has become a major public health problem due to the increase in life expectancy. Although the detection of AD is based on several neuropsychological tests, imaging and biological analyses, none of these biomarkers allows a clear understanding of the pathophysiological mechanisms involved in the disease, and no efficient treatment is currently available. Metabolomics, which allows the study of biochemical alterations underlying pathological processes, could help to identify these mechanisms, to discover new therapeutic targets and to monitor the therapeutic response and disease progression. In this review, we have summarized and analyzed the results from a number of studies on metabolomics analyses performed in biological samples originated from the central nervous system, in AD subjects and in animal models of this disease. This synthesis revealed modified expression of specific metabolites in pathological conditions which allowed the identification of significantly impacted metabolic pathways both in animals and humans, such as the arginine biosynthesis and the alanine, aspartate and glutamate metabolism. We discuss the potential biochemical mechanisms involved, the extent to which they could impact the specific hallmarks of AD, and the therapeutic approaches which could be proposed as a result.
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http://dx.doi.org/10.1111/fcp.12654DOI Listing
January 2021

Analytical validation of eight methods of thyroglobulin measurement in fine-needle aspiration washouts.

Ann Clin Biochem 2021 01 3;58(1):54-65. Epub 2020 Nov 3.

Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire, Angers, France.

Background: Thyroglobulin (Tg) assay in washout fluids of fine needles, after cervical lymph nodes aspiration, is used for detecting metastases from differentiated thyroid carcinomas. Assay methods are the same as for Tg in serum. However, with non-serum samples, methods require extensive validation to notably check for the absence of matrix effect. This study fits this context. Our objectives were to assess analytic performances, in washout fluid, of eight different Tg assay methods and to compare them to validated data in serum.

Methods: Eleven medical laboratories participated in this study. The matrix tested was phosphate-buffer saline containing 1% bovine serum albumin (PBS-1% BSA). Samples used were dilutions, in this buffer, of Certified Reference Material (CRM 457). We verified, for all methods, the limit of detection, precision, linearity, trueness and accuracy.

Results: In PBS-1% BSA, the functional sensitivities (FS) were comparable to those expected for serum. All the methods were linear. The relative biases of trueness were between -24.5 and 10.2% around 1 g/L. Total analytical error was ≤40% near the functional sensitivity values.

Conclusion: No quantitatively important matrix effect was observed. All the methods showed their ability to measure Tg in PBS-1% BSA, over the concentration range of interest, with acceptable total analytical error. We validated the functional sensitivity value as a decision threshold in thyroidectomized patients after treatment and with low concentrations of serum Tg.
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http://dx.doi.org/10.1177/0004563220968369DOI Listing
January 2021

[Mutltifaceted biological roles of adiponectin].

Ann Biol Clin (Paris) 2020 06;78(3):243-252

Sorbonne Université, Inserm UMR_S 938, Centre de recherche Saint-Antoine, Institut hospitalo-universitaire de cardio-métabolisme et nutrition (ICAN), Paris, France, Hôpital Tenon, AP-HP, Service de biochimie et hormonologie, UF Bio-marqueurs inflammatoires et métaboliques, Paris, France, Hôpitaux universitaires Henri Mondor, AP-HP, Département de biochimie-pharmacologie-biologie moléculaire-génétique médicale, Créteil, France.

Adiponectin is a major adipokine involved in energy homeostasis that exerts insulin-sensitizing properties. The level of adiponectin is reduced in situations of insulin resistance and is negatively associated with several pathophysiological situations including abdominal obesity, metabolic syndrome, steatosis and non-alcoholic steatohepatitis, type 2 diabetes, some cancers and cognitive diseases. These aspects are discussed in this review.
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http://dx.doi.org/10.1684/abc.2020.1562DOI Listing
June 2020

[Mutltifaceted biological roles of leptin].

Ann Biol Clin (Paris) 2020 06;78(3):231-242

Hôpitaux universitaires Henri Mondor, AP-HP, Département de biochimie-pharmacologie-biologie moléculaire-génétique médicale, Créteil, France, Sorbonne Université, Inserm UMR_S 938, Centre de recherche Saint-Antoine, Institut hospitalo-universitaire de cardio-métabolisme et nutrition (ICAN), Paris, France, Hôpital Tenon, AP-HP, Service de biochimie et hormonologie, UF Bio-marqueurs inflammatoires et métaboliques, Paris, France.

The identification of leptin allowed the discovery of a new endocrine system. This major adipokine controlling energy homeostasis is also involved in the regulation of neuroendocrine function and fertility. Unfortunately, leptin is not able to treat common obesity, which associates hyperleptinemia and resistance to the hormone. Conversely, treatment with recombinant leptin is effective in situations of leptin deficiency. Several pathophysiological situations associated with adipose tissue dysfunctions and abnormal regulation of leptin secretion are discussed in this review. The advantage of the potential use of the leptin assay in some pathophysiological conditions is proposed.
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http://dx.doi.org/10.1684/abc.2020.1560DOI Listing
June 2020

An automated alert system based on the p-Tau/Tau ratio to quickly inform health professionals upon a suspected case of sporadic Creutzfeldt-Jakob disease.

J Neurol Sci 2020 08 1;415:116971. Epub 2020 Jun 1.

CHU Tours, Service de de médecine nucléaire in vitro, F-37044 Tours, France; UMR 1253, iBrain, Université de Tours, Inserm, Tours, France; Groupe de Biologie Spécialisée de la Société Française de Médecine Nucléaire, France.

Introduction: Knowing the risk of potential sporadic Creutzfeldt-Jakob disease (sCJD) instrument-contamination is essential in hospitals. We examined the relevance of the p-Tau/Tau ratio to exclude a probable case of sCJD in clinical practice, and we established an alert system to quickly inform health professionals in case of positivity.

Methods: This retrospective study was conducted on 143 cerebrospinal fluid samples from patients suspected for sCJD. The distinction between probable cases of sCJD and other patients was based on clinical, paraclinical and biological (14-3-3, Tau, p-Tau, Aβ ) data. From this experience, the health professionals developed an alert system to be implemented upon a suspected case of sCJD.

Results: A significant decrease in p-Tau/Tau ratio between sCJD and the other diseases was observed (p < 0 .001). The combined Tau test presented a sensitivity higher than 14-3-3 (100% versus 92.3%, p =0 .006) and an equivalent specificity (90% versus 96.1%). The time required for obtaining results was higher for 14-3-3 due to the centralization of investigations in some laboratories (3 weeks versus 2 h). In the presence of these elements, the triggering of the alert system was based on the p-Tau/Tau ratio. This system involves sending an automatic mail to the hospital department involved in the patient's care and the hospital hygiene team, which oversees the application of the procedures.

Conclusion: The p-Tau/Tau concentrations present the desired criteria for use in current medical practice to fight against iatrogenic transmission. The alert system confirms a probable case of sCJD instantly to health professionals. Hygiene and sterilization measures can be applied immediately.
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http://dx.doi.org/10.1016/j.jns.2020.116971DOI Listing
August 2020

Aβ1-42 and Tau as Potential Biomarkers for Diagnosis and Prognosis of Amyotrophic Lateral Sclerosis.

Int J Mol Sci 2020 Apr 21;21(8). Epub 2020 Apr 21.

UMR 1253, iBrain, University of Tours, Inserm, 37000 Tours, France.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, but its definitive diagnosis delays around 12 months. Although the research is highly active in the biomarker field, the absence of specific biomarkers for diagnosis contributes to this long delay. Another strategy of biomarker identification based on less specific but sensitive molecules may be of interest in clinical practice. For example, markers related to other neurodegenerative diseases such as Alzheimer's disease (AD) could be fully explored. Here, we compared baseline levels of amyloidβ1-42 (Aβ1-42), total Tau, and phosphorylated-Tau (phospho-Tau) protein in the cerebrospinal fluid (CSF) of ALS patients to controls and correlated it with clinical parameters of ALS progression collected over 12 months. We observed increased levels of Aβ1-42 (controls: 992.9 ± 358.3 ng/L; ALS: 1277.0 ± 296.6 ng/L; < 0.0001) and increased Aβ1-42/phospho-Tau ratio and Innotest Amyloid Tau Index (IATI) (both < 0.0001). IATI and the phospho-Tau/total Tau ratio correlated positively with ALSFRS-R and weight at baseline. Multivariate analysis revealed that baseline ALSFRS-R was associated with Aβ1-42 and phospho-Tau/total Tau ratio ( = 0.0109 and = 0.0013, respectively). Total Tau and phospho-Tau levels correlated negatively with ALSFRS-R variation at months 6 and 9, respectively ( = 0.02 and = 0.04, respectively). Phospho-Tau/total Tau ratio correlated positively with ALSFRS-R variation at month 9 ( = 0.04). CSF levels of Aβ1-42 could be used as a complementary tool to ALS diagnosis, and total Tau and phospho-Tau levels may help establishing the prognosis of ALS. Further studies merit exploring the pathophysiological mechanisms associated with these markers. Despite their lack of specificity, phospho-Tau/total Tau and Aβ1-42 should be combined to other biological and clinical markers in order to improve ALS management.
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http://dx.doi.org/10.3390/ijms21082911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216266PMC
April 2020

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

J Psychiatry Neurosci 2018 08;43(5):318-326

From the School of Psychiatry, University of New South Wales, Randwick, NSW, Australia (Quidé); Neuroscience Research Australia, Randwick, NSW, Australia (Quidé); Inserm U1253 ''Imaging and Brain: iBrain,'' Université de Tours, Tours, France (Cléry, Andersson, Barantin, Dufour-Rainfray, Brizard, El-Hage); Centre d'Accueil des Victimes d'Agressions Sexuelles, Centre Hospitalier Régional d'Orléans, Orléans, France (Descriaud); Service de Médecine Légale, CHRU de Tours, Tours, France (Saint-Martin); Inserm CIC 1415, Centre d'Investigation Clinique, CHRU de Tours, Tours, France (Gissot, El-Hage); Association Départementale d'Aide aux Victimes d'Infractions Pénales d'Indre-et-Loire, ADAVIP 37, France Victimes 37, Tours, France (Carrey Le Bas); Centre d'Accueil des Victimes d'Agressions Sexuelles, Centre Hospitalier de Blois, Blois, France (Osterreicher); and CHRU de Tours, Tours, France (Dufour-Rainfray, Ogielska, El-Hage).

Background: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women.

Methods: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities.

Results: Relative to the control group, the survivor group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivor group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivor group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories.

Limitations: The small sample size was the main limitation of this study.

Conclusion: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158026PMC
August 2018

Validation of metabolomics analysis of human perilymph fluid using liquid chromatography-mass spectroscopy.

Hear Res 2018 09 22;367:129-136. Epub 2018 May 22.

UMR 1253, iBrain. Université de Tours, Inserm, Tours, France. Electronic address:

Although there is some data from animal studies, the metabolome of inner ear fluid in humans remains unknown. Characterization of the metabolome of the perilymph would allow for better understanding of its role in auditory function and for identification of biomarkers that might allow prediction of response to therapeutics. There is a major technical challenge due to the small sample of perilymph fluid available for analysis (sub-microliter). The objectives of this study were to develop and validate a methodology for analysis of perilymph metabolome using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Due to the low availability of perilymph fluid; a methodological study was first performed using low volumes (0.8 μL) of cerebrospinal fluid (CSF) and optimized the LC-HRMS parameters using targeted and non-targeted metabolomics approaches. We obtained excellent parameters of reproducibility for about 100 metabolites. This methodology was then used to analyze perilymph fluid using two complementary chromatographic supports: reverse phase (RP-C18) and hydrophilic interaction liquid chromatography (HILIC). Both methods were highly robust and showed their complementarity, thus reinforcing the interest to combine these chromatographic supports. A fingerprinting was obtained from 98 robust metabolites (analytical variability <30%), where amino acids (e.g., asparagine, valine, glutamine, alanine, etc.), carboxylic acids and derivatives (e.g., lactate, carnitine, trigonelline, creatinine, etc.) were observed as first-order signals. This work lays the foundations of a robust analytical workflow for the exploration of the perilymph metabolome dedicated to the research of biomarkers for the diagnosis/prognosis of auditory pathologies.
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http://dx.doi.org/10.1016/j.heares.2018.05.016DOI Listing
September 2018

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

J Psychiatry Neurosci 2018 Apr 5;43(3):170116. Epub 2018 Apr 5.

From the School of Psychiatry, University of New South Wales, Randwick, NSW, Australia (Quidé); Neuroscience Research Australia, Randwick, NSW, Australia (Quidé); Inserm U1253 ''Imaging and Brain: iBrain,'' Université de Tours, Tours, France (Cléry, Andersson, Barantin, Dufour-Rainfray, Brizard, El-Hage); Centre d'Accueil des Victimes d'Agressions Sexuelles, Centre Hospitalier Régional d'Orléans, Orléans, France (Descriaud); Service de Médecine Légale, CHRU de Tours, Tours, France (Saint-Martin); Inserm CIC 1415, Centre d'Investigation Clinique, CHRU de Tours, Tours, France (Gissot, El-Hage); Association Départementale d'Aide aux Victimes d'Infractions Pénales d'Indre-et-Loire, ADAVIP 37, France Victimes 37, Tours, France (Carrey Le Bas); Centre d'Accueil des Victimes d'Agressions Sexuelles, Centre Hospitalier de Blois, Blois, France (Osterreicher); and CHRU de Tours, Tours, France (Dufour-Rainfray, Ogielska, El-Hage).

Background: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women.

Methods: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities.

Results: Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories.

Limitations: The small sample size was the main limitation of this study.

Conclusion: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.
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http://dx.doi.org/10.1503/jpn.170116DOI Listing
April 2018

Vitamin D is Not a Protective Factor in ALS.

CNS Neurosci Ther 2015 Aug 20;21(8):651-6. Epub 2015 Jun 20.

Unité mixte de recherche U930, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, Tours, France.

Aims: Vitamin D deficiency has been associated with poorer prognosis in ALS. Better understanding of the role of vitamin D in ALS is needed to determine whether trials of systematic supplementation are justified. Our aim was to report vitamin D levels during the course of ALS and to evaluate its relationship with clinical parameters at diagnosis and with disease progression.

Methods: We prospectively collected vitamin D serum concentrations from 125 consecutive ALS patients. Cox proportional hazard models analyzed the relationship between vitamin D concentrations, clinical parameters, and survival.

Results: The mean vitamin D concentration was below our laboratory's lower limit of normal (P < 0.0001) and did not change during the course of the disease. The concentrations were higher in patients with bulbar onset (P = 0.003) and were negatively associated with body mass index (BMI) (P = 0.0095). Models with ALSFRS-R (ALS Functional Rating Scale-Revised) and BMI as a covariates showed that vitamin D concentrations predicted worse prognosis.

Conclusion: The distribution of vitamin D concentrations in our cohort was consistent with previous reports. Surprisingly, we noted a negative effect of higher vitamin D levels on prognosis in ALS. More detailed research is warranted to determine whether manipulation of vitamin D could be beneficial to patients.
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http://dx.doi.org/10.1111/cns.12423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495158PMC
August 2015

[Mass spectrometry for steroid assays].

Ann Biol Clin (Paris) 2015 Jan-Feb;73(1):70-8

Département de biochimie et génétique, CHRU d'Angers, Angers, France.

Steroid hormone measurement, first developed with radioimmunoassay, is now becoming easier with the use of automated platforms of immunoassay. However, some hormones remain uneasily detectable because of their low blood concentration, their structural homology or the presence of interferences. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can be considered as an alternative to immunoassays. This approach allows the simultaneous determination of several parameters thanks to its selectivity led by the detector mass spectrometer and the separate dimension of chromatography liquid. In addition, recourse to UHPLC (ultra high performance liquid chromatography) allows improving selectivity and sensitivity while limiting the samples volumes. The "ready-to-use" kits are now available and added to the "homemade" techniques developed by laboratories, thus giving opportunity for measurement of a wide steroid panel with only one sample. Finally, mass spectrometry methods, including a prior extraction step, allow the use of varied biological fluids (blood, urine, saliva…). Also, several clinical indications could gain from mass spectrometry, especially when hormone levels are low, when several steroids have to be identified, when the sample volume is low. However, this technology represents an important financial investment and in-depth staff training. In addition, some steroids are not easily quantifiable by mass spectrometry. It is likely by immunoassay and mass spectrometry, well-matched technologies, that we could answer the best to clinical questions about steroids.
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http://dx.doi.org/10.1684/abc.2014.0988DOI Listing
March 2016

The Pattern of Brain Amyloid Load in Posterior Cortical Atrophy Using (18)F-AV45: Is Amyloid the Principal Actor in the Disease?

Dement Geriatr Cogn Dis Extra 2014 Sep 11;4(3):431-41. Epub 2014 Nov 11.

CHRU Bretonneau, Université François Rabelais de Tours, France ; INSERM U930, Imagerie et Cerveau, Université François Rabelais de Tours, France.

Background: Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuoperceptual dysfunction and praxis declines. This syndrome is related to a number of underlying diseases, including, in most cases, Alzheimer's disease (AD). The aim of this study was to compare the amyloid load with (18)F-AV45 positron emission tomography (PET) between PCA and AD subjects.

Methods: We performed (18)F-AV45 PET, cerebrospinal fluid (CSF) biomarker analysis and a neuropsychological assessment in 11 PCA patients and 12 AD patients.

Results: The global and regional (18)F-AV45 uptake was similar in the PCA and AD groups. No significant correlation was observed between global (18)F-AV45 uptake and CSF biomarkers or between regional (18)F-AV45 uptake and cognitive and affective symptoms.

Conclusion: This (18)F-AV45 PET amyloid imaging study showed no specific regional pattern of cortical (18)F-AV45 binding in PCA patients. These results confirm that a distinct clinical phenotype in amnestic AD and PCA is not related to amyloid distribution.
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http://dx.doi.org/10.1159/000363761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264487PMC
September 2014

Total protein level in cerebrospinal fluid is stable in elderly adults.

J Am Geriatr Soc 2013 Oct;61(10):1819-21

Nuclear Medicine Laboratory, Centre Hospitalier Régional Universitaire, Tours, France; Université François-Rabelais de Tours, PRES Centre-Val de Loire Université, Tours, France; UMR INSERM U 930 Imagerie et cerveau, Université François-Rabelais de Tours, PRES Centre-Val de Loire Université, Tours, France.

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http://dx.doi.org/10.1111/jgs.12489DOI Listing
October 2013

CSF biomarker variability in the Alzheimer's Association quality control program.

Alzheimers Dement 2013 May;9(3):251-61

Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.

Background: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories.

Methods: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection.

Results: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP).

Conclusions: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.
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http://dx.doi.org/10.1016/j.jalz.2013.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707386PMC
May 2013

Confirmation of the amyloidogenic process in posterior cortical atrophy: value of the Aβ42/Aβ40 ratio.

J Alzheimers Dis 2013 ;33(3):775-80

CHRU de Tours, Tours, France.

Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuo-perceptual dysfunction and praxis declines. This syndrome is related to several underlying diseases, including Alzheimer's disease (AD), sometimes involving an amyloidogenic process. The aims of the study were to 1) define cerebrospinal fluid (CSF) biomarker profiles in PCA patients compared to AD patients and 2) explore the amyloidogenic process through the Aβ(42)/Aβ(40) ratio in PCA patients to elucidate the underlying disease in vivo. CSF biomarker analysis (t-tau, p-tau, Aβ(42), and Aβ(42)/Aβ(40) ratio) and neuropsychological examination were performed in 22 PCA patients and compared with those of age-matched AD patients. Associated clinical neurological signs were investigated (e.g., extrapyramidal motor signs, myoclonus). CSF biomarker profiles did not differ significantly between the PCA and AD groups; 82% of patients with PCA fulfilled the biological criteria for typical AD with abnormal levels of the three markers and 18% of PCA patients presented atypical CSF profiles. All PCA patients with associated clinical neurological signs presented typical AD CSF profiles. The clinical presentations of these patients were similar to other PCA subjects. The Aβ(42)/Aβ(40) ratio for all PCA patients, including those with atypical CSF profiles, was decreased. Most PCA syndromes were associated with CSF biomarkers suggestive of AD, even in cases with associated clinical neurological signs. The amyloidogenic process was confirmed by the decreased Aβ(42)/Aβ(40) ratio for all patients. This analysis avoids misdiagnosis in the presence of physiologically high or low amyloid peptide production rates and provides information in vivo to improve understanding of the underlying disease in PCA.
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http://dx.doi.org/10.3233/JAD-2012-121267DOI Listing
June 2013

Fetal exposure to teratogens: evidence of genes involved in autism.

Neurosci Biobehav Rev 2011 Apr 30;35(5):1254-65. Epub 2010 Dec 30.

UMR INSERM U930, CNRS ERL 3106, Université François Rabelais de Tours, Tours, France.

Environmental challenges during the prenatal period can result in behavioral abnormalities and cognitive deficits that appear later in life such as autism. Prenatal exposure to valproic acid, ethanol, thalidomide and misoprostol has been shown to be associated with an increased incidence of autism. In addition, rodents exposed in utero to some of these drugs show autism-like abnormalities, including brain changes and lifelong behavior dysfunction. Our aim is to summarize current understanding of the relationship between in utero exposure to these drugs and autism in humans and in autism-like animal model phenotypes. It also highlights the importance of these models to understanding the neurobiology of autism, particularly in the identification of susceptibility genes. These drugs are able to modulate the expression of many genes involved in processes such as proliferation, apoptosis, neuronal differentiation and migration, synaptogenesis and synaptic activity. It seems essential to focus research on genes expressed during early neurodevelopment which may be the target of mutations or affected by drugs such as those included in this review.
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http://dx.doi.org/10.1016/j.neubiorev.2010.12.013DOI Listing
April 2011

Study of the serotonin transporter (SLC6A4) and BDNF genes in French patients with non syndromic mental deficiency.

BMC Med Genet 2010 Feb 22;11:30. Epub 2010 Feb 22.

UMR Inserm U930, Université François Rabelais de Tours, Tours, France.

Background: Mental deficiency has been linked to abnormalities in cortical neuronal network connectivity and plasticity. These mechanisms are in part under the control of two interacting signalling pathways, the serotonergic and the brain-derived neurotrophic (BDNF) pathways. The aim of the current paper is to determine whether particular alleles or genotypes of two crucial genes of these systems, the serotonin transporter gene (SLC6A4) and the brain-derived neurotrophic factor gene (BDNF), are associated with mental deficiency (MD).

Methods: We analyzed four functional polymorphisms (rs25531, 5-HTTLPR, VNTR, rs3813034) of the SLC6A4 gene and one functional polymorphism (Val66 Met) of the BDNF gene in 98 patients with non-syndromic mental deficiency (NS-MD) and in an ethnically matched control population of 251 individuals.

Results: We found no significant differences in allele and genotype frequencies in the five polymorphisms studied in the SLC6A4 and BDNF genes of NS-MD patients versus control patients. While the comparison of the patterns of linkage disequilibrium (D') in the control and NS-MD populations revealed a degree of variability it did not, however, reach significance. No significant differences in frequencies of haplotypes and genotypes for VNTR/rs3813034 and rs25531/5-HTTLPR were observed.

Conclusion: Altogether, results from the present study do not support a role for any of the five functional polymorphisms of SLC6A4 and BDNF genes in the aetiology of NS-RM. Moreover, they suggest no epistatic interaction in NS-MD between polymorphisms in BDNF and SLC6A4. However, we suggest that further studies on these two pathways in NS-MD remain necessary.
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http://dx.doi.org/10.1186/1471-2350-11-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837021PMC
February 2010

Behavior and serotonergic disorders in rats exposed prenatally to valproate: a model for autism.

Neurosci Lett 2010 Feb 28;470(1):55-9. Epub 2009 Dec 28.

CHRU de Tours, Tours, France.

In order to explore whether some aspects of the autistic phenotype could be related to impairment of the serotonergic system, we chose an animal model which mimics a potential cause of autism, i.e. rats exposed to valproate (VPA) on the 9th embryonic day (E9). Previous studies have suggested that VPA exposure in rats at E9 caused a dramatic shift in the distribution of serotonergic neurons on postnatal day 50 (PND50). Behavioral studies have also been performed but on rats that were exposed to VPA later (E12.5). Our aim was to test whether VPA exposure at E9 induces comparable behavioral impairments than at E12.5 and causes serotonergic impairments which could be related to behavioral modifications. The results showed significant behavioral impairments such as a lower tendency to initiate social interactions and hyperlocomotor activity in juvenile male rats. The serotonin levels of these animals at PND50 were decreased (-46%) in the hippocampus, a structure involved in social behavior. This study suggests that VPA could have a direct or indirect action on the serotonergic system as early as the progenitor cell stage. Early embryonic exposure to VPA in rats provides a good model for several specific aspects of autism and should help to continue to explore pathophysiological hypotheses.
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http://dx.doi.org/10.1016/j.neulet.2009.12.054DOI Listing
February 2010