Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates.

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.

Towards an improved access to psychiatric rehabilitation: availability and effectiveness at 1-year follow-up of psychoeducation, cognitive remediation therapy, cognitive behaviour therapy and social skills training in the FondaMental Advanced Centers of Expertise-Schizophrenia (FACE-SZ) national cohort.

Psychosocial Interventions (PIs) have shown positive effects on clinical and functional outcomes of schizophrenia (SZ) in randomized controlled trials. However their effectiveness and accessibility remain unclear to date in "real world" schizophrenia. The objectives of the present study were (i) to assess the proportion of SZ outpatients who benefited from PIs between 2010 and 2015 in France after an Expert Center Intervention in a national multicentric non-selected community-dwelling sample; (ii) to assess PIs' effectiveness at 1-year follow-up. 183 SZ outpatients were recruited from FondaMental Advanced Centers of Expertise for Schizophrenia cohort. Baseline and 1-year evaluations included sociodemographic data, current treatments, illness characteristics and standardized scales for clinical severity, adherence to treatment, quality of life, a large cognitive battery, and daily functioning assessment. Only 7 (3.8%) received a PI before the evaluation, and 64 (35%) have received at least one PI during the 1-year follow-up. Having had at least one PI during the follow-up has been associated in multivariate analyses with significantly higher improvement in positive and negative symptoms (respectively p =0.031; p = 0.011), mental flexibility (TMT B, p = 0.029; C-VF, p = 0.02) and global functioning (p =0.042). CBT and SST were associated with higher cognitive improvements, while CRT was associated with clinical improvement. These results have not been demonstrated before and suggest that the effect of each PI is larger than its initial target. The present study has confirmed the PIs' effectiveness in a large sample of community-dwelling SZ outpatients at 1 year follow-up. Efforts to improve access to PI should be reinforced in public health policies.

DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease.

In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a(+/-) mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that deregulation of developmental apoptosis may contribute to the phenotype of patients with imbalanced DYRK1A gene dosage.

Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency.

Mitochondrial complex I dysfunction has long been associated with Parkinson's disease (PD). Recent evidence suggests that mitochondrial involvement in PD may extend beyond a sole respiratory deficit and also include perturbations in mitochondrial fusion/fission or ultrastructure. Whether and how alterations in mitochondrial dynamics may relate to the known complex I defects in PD is unclear. Optic atrophy 1 (OPA1), a dynamin-related GTPase of the inner mitochondrial membrane, participates in mitochondrial fusion and apoptotic mitochondrial cristae remodeling. Here we show that complex I inhibition by parkinsonian neurotoxins leads to an oxidative-dependent disruption of OPA1 oligomeric complexes that normally keep mitochondrial cristae junctions tight. As a consequence, affected mitochondria exhibit major structural abnormalities, including cristae disintegration, loss of matrix density and swelling. These changes are not accompanied by mitochondrial fission but a mobilization of cytochrome c from cristae to intermembrane space, thereby lowering the threshold for activation of mitochondria-dependent apoptosis by cell death agonists in compromised neurons. All these pathogenic changes, including mitochondrial structural remodeling and dopaminergic neurodegeneration, are abrogated by OPA1 overexpression, both in vitro and in vivo. Our results identify OPA1 as molecular link between complex I deficiency and alterations in mitochondrial dynamics machinery and point to OPA1 as a novel therapeutic target for complex I cytopathies, such as PD.

Neurotoxin-based models of Parkinson's disease.

Animal experimentation in the Parkinson's disease (PD) field is a classic example of how the use of animal models to study diseases can have a significant impact on human health. Among the different neurotoxin-based animal models of PD that are presently available, the 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models have been established and validated as useful models for the development of therapeutic strategies aimed to treat motor symptoms and to study alterations of the basal ganglia that occur in this disease. The 6-OHDA rat model and the MPTP primate model have contributed enormously to translate animal experimentation into clinical practice, including pharmacological treatments and deep brain stimulation of the subthalamic nucleus. These models, along with the MPTP mouse model, are helping to elucidate the pathogenic mechanism of neurodegeneration in PD. The roles of oxidative stress, apoptosis, mitochondrial dysfunction, inflammation, and impairment of the protein degradation pathways have also come under careful consideration thanks to these models. The more recently developed paraquat and rotenone rodent models are also contributing to our understanding of neuronal cell death. However, none of the neuroprotective strategies that have worked in the pre-clinical stage have thus far been successfully translated to a clinical setting to treat PD patients. At the same time, the lack of any effective neuroprotective strategy for PD is preventing the validation of any one particular model as a screening tool for such neuroprotective strategies. Therefore, it seems that we are trapped in a vicious circle that casts doubt on the suitability of the neurotoxin-based models for this purpose. Here, we discuss how epidemiological data may help to validate a specific model with data linking a lower risk of developing PD with nutritional/consumption habits or with a specific chronic drug therapy.

[Propositions for the standardized expression of HbA 1c results]. / Propositions pour l'expression standardisée des résultats d'HbA 1c.

The 2007 international consensus about the standardization of HbA(1c) determination and expression of results is progressively implemented in most countries. In France, a common working group of the Société française de biologie clinique (SFBC) and the Société francophone de diabétologie (SFD) has expressed the following recommendations. HbA(1c) results are expressed in percentage of total hemoglobin and in mmol HbA(1c)/mol Hb, but are not converted into estimated average glucose. A table indicating the correspondence between HbA(1c) and estimated average glucose may be given with the results, subject to precautions of interpretation at the individual level.

[Evolutionary comparison of laboratory cardiac and infectious parameters during septic shock: about an original case]. / Evolution comparée des indicateurs biologiques cardiaques et infectieux lors du choc septique: à propos d'une observation originale.

A massive release of troponin Ic and CKMB was described in a patient during septic shock. According to experimental animal models previously described, this release of biological markers by myocardial tissue could be due to an inflammatory process of myocardial tissue during septic shock without myocardial infarction in non cardiac critically ill patients.

[About two cases of massive hypercholesterolemia]. / A propos de deux cas d'hypercholestérolémie massive.

Two patients presented massive hypercholesterolemia related to acquired disease, intrahepatic cholangitis with cholestasis in one and nephrotic syndrome in the second. Comparison of the lipoprotein patterns demonstrated distinctive pathophysiological processes different from those operating in primary causes of hypercholesterolemia.

Energy and nutrient intake of elderly hospitalized patients in a steady metabolic status versus catabolic status.

Protein undernutrition enhances frailty and aggravates intercurrent diseases generally observed in elderly patients. Undernutrition results from insufficient food intake and catabolic status. Daily nutrient intakes were explored for hospitalized geriatric patients. Nutrient intake (carbohydrates, lipids, proteins, and calcium) was determined in randomly selected geriatric patients (n=49) over five consecutive days by weighting food in the plate before and after meals. For each geriatric patient, catabolic status and risk factors of undernutrition were considered. Results were compared between patients in a steady status or catabolic status. In steady status patients, protein, lipid and carbohydrate intake but not calcium intake, met recommended dietary allowances (total caloric intake:1535 +/- 370 Cal/day ; protein:1+/- 0.4 g/kg/day ; carbohydrates:55 +/- 7.7 % ; lipids: 30 +/- 6.3 % ; calcium:918 +/- 341 mg/day) . Patients in catabolic status (cardiopulmonary deficiency , neurologic disease , inflammatory process) had lower total caloric intake, lower protein intake and dramatically lower calcium intake (total caloric intake : 1375 +/- 500 Cal/day ; protein :0.9 +/- 0.4 g/kg/day ; carbohydrates : 54 +/- 8.3 % ; lipids : 31 +/-6.2 % ; calcium : 866 +/- 379 mg/day). Nutrient intake was lower in elderly patients hospitalized in short stay care units, perhaps due to failure to recognize suitable nutrient requirements. Protein-caloric undernutrition should be diagnosed early during hospitalization in order to allow appropriate dietary supplementation. However the incidence of protein undernutrition among elderly patients as a cause or a consequence of adverse pathophysiological processes remains a cause of debate.

[Unexpected occurence of hemoglobin Athens-Georgia]. / Révélation inattendue de l'hémoglobine Athens-Georgia.

The following report concerned a 47 year old Caucasian diabetic patient. Routine HPLC of HbA1c (Variant II Biorad Laboratories - hemoglobin A1c program) resulted only in the evidence of HbF (1%) and increase in HbA1c (10%). Considering the presence of HbF a standard agarose gel electrophoresis of patient's hemoglobin was performed and revealed the presence of Hb Athens-Georgia. Consequently the occurrence of HbF during determination of HbA1c by HPLC should lead to perform a standard hemoglobin electrophoresis in order to explore an hidden, unsuspected and clinically silent occurrence of rare Hb variant or additional unsuspected increase in HbA2.

Native protein glycoxidation and aging.

Structural and functional alterations of proteins are observed during aging. Glycation of long half-life proteins, involving reducing carbohydrates, leads to the formation of intra and intermolecular cross-links and the production of free radicals. These processes depend on the amount of glucose available and on molecular oxygen which contributes to the production of free radicals. These processes are observed without dysfunction of carbohydrate metabolism and progress with age. However, whether this process is a primary cause or a consequence of aging remains a question of debate. Prevention of excessive glycoxidation could be a goal of recommendations designed to control the tissular alterations occurring in aging.

Changes in glycation of fibrous type I collagen during long-term in vitro incubation with glucose.

The course of glycation of calf skin fibrous type I collagen was monitored in vitro under physiological conditions during an 8-week incubation period in order to take into account the long half-life of this protein. The formation of glycated compounds was measured by determining fructosamine, pentosidine, and carboxymethyllysine content. The incubation conditions were as physiological as possible in sterile saline phosphate buffer, except glucose concentration. With incubation medium containing 200 mmol glucose, fibrous collagen underwent solubilization; in addition an increase in fructosamine, pentosidine, and carboxymethyllysine content in both solubilized and remaining insoluble collagen was noticed. There was a spontaneous, restricted, and time-dependent native glycated state of collagen; high concentration glucose enhanced the formation of glycated compounds and induced changes in solubility and glycoxidated products. The production of pentosidine during incubation without glucose should be considered as an event resulting from the initial fructosamine. Whereas the production of carboxymethyllysine during long-term incubation with glucose provided indirect proof of an additional oxidative process after early glycated product formation. These experimental observations provide insight into the in vivo context of advanced glycation end product formation in chronic hyperglycemia and aging.

In vitro glycoxidation of insoluble fibrous type I collagen: solubilization and advanced glycation end products.

The deleterious effects of glycoxidation are dependent on the half-life of proteins. Collagen, the main component of extracellular matrices, is a long live protein and thus may be sensitive to the glycoxidation process. We incubated calf skin fibrous type I collagen in PBS at 37 degrees C with glucose. The fibrous type I collagen was solubilized and an increase in the amount of advanced glycation end products of the solubilized fraction was observed. As there was no bacterial contamination and no proteolytic activities in the incubation medium, the solubilization of fibrous type I collagen is probably due to the speculative production of the free radicals in our experimental conditions. To test this hypothesis, fibrous type I collagen was incubated in PBS with AAPH (2,2'azo-bis 2-aminodinopropane) a free radicals generator. AAPH induced a dramatic and dose dependent solubilization of fibrous type I collagen.

Serum pentosidine as an indicator of Alzheimer's disease.

Pentosidine, an advanced glycation end product (AGE), was assayed by HPLC in serum proteins from patients with Alzheimer type dementia (AD), patients with diabetes mellitus (D), and healthy (C) age-matched old subjects (mean age from each group = 84 years). Serum pentosidine was significantly different between the three groups despite similar renal function (serum creatinine < 160 micromol/L). In all groups of patients, pentosidine was independent of glycated hemoglobin (HbA1C) and the early glycation marker fructosamine and appeared to be an independent marker, mainly bound to serum albumin. Pentosidine could be an important factor useful for the diagnosis of Alzheimer's disease.

Nutritional markers, acute phase reactants and tissue inhibitor of matrix metalloproteinase 1 in elderly patients with pressure sores.

BACKGROUND: Loss of collagen and elastin is observed in the elderly. In geriatric inpatients, chronic protein malnutrition could induce susceptibility to additional morbidity such as pressure sores. OBJECTIVE: The purpose of this study was to explore the relationship between nutritional and inflammatory status and the production of tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). METHODS: Chronically ill elderly inpatients, without or with pressure sores, were enrolled. Nutritional protein markers, acute phase reactants, and TIMP-1 were determined, and changes in these biological parameters were compared. RESULTS: Chronic inflammatory process and protein malnutrition were observed in all enrolled patients. The severity of these two pathophysiological processes was independent of the occurrence of pressure sores. The serum prealbumin and albumin levels were lower in patients with pressure sores than in those without. In addition, the general increase in the TIMP-1 level was independent of the occurrence of pressure sores. The TIMP-1 level was mainly related to the prognostic inflammatory and nutritional index. CONCLUSIONS: The general increase in acute-phase reactants observed in the elderly could be related to the intercurrent diseases. The generally low serum albumin level, lowest in patients with pressure sores, may be considered evidence of protein malnutrition and hypercatabolism. Regarding the morbidity, the increase in TIMP-1 levels could be explained as an adaptive process to prevent intrinsic protein expenditure of extracellular matrices.

[A patient with white matter involvement and superficial hemosiderosis of the central nervous system]. / Atteinte de la substance blanche et hémosidérose marginale du névraxe.

We present a patient with a superficial siderosis and a white matter involvement on MRI and a demyelinating pattern on visual evoked potentials. White matter involvement is supposed to be secondary to vascular modifications induced by superficial siderosis.

Synergy between ascorbate and alpha-tocopherol on fibroblasts in culture.

Ascorbate and tocopherol are important antioxidants that protect cells against oxidative stress. The interaction of ascorbate and alpha-tocopherol in cells is difficult to detect as both ascorbate and alpha-tocopherol are unstable in vitro in a biological medium. We examined the interactions between human dermal fibroblasts, ascorbate and alpha-tocopherol to determine the effects of the vitamins on growth and cell viability. The interaction of ascorbate and alpha-tocopherol was studied in a fibroblast culture medium during 48h. Ascorbate and alpha-tocopherol were detected by fluorimetry after high-performance liquid chromatography (HPLC). Cell growth and cell viability were studied by cell numeration after trypan blue staining. The ascorbate concentration fell in presence of alpha-tocopherol in cell culture medium under all experimental conditions, with or without cells. Ascorbate partly protected alpha-tocopherol but only in presence of cells. Cell viability was preserved by alpha-tocopherol whereas ascorbate enhanced fibroblast growth. The synergy between ascorbate and alpha-tocopherol corresponds to a consumption of ascorbate which spares alpha-tocopherol but only in presence of cells.

Ipsilateral and contralateral subthalamic activity after unilateral dopaminergic lesion.

Unilateral lesions of the dopaminergic nigral neurons in rats are currently used as a model of Parkinson's disease. However, several neurochemical studies have questioned the possible influence of the lesioned side on the contralateral non-lesioned side. To address this question, electrophysiological recordings in the ipsilateral and contralateral subthalamic nucleus was performed on anaesthetized rats, 3, 7 and 14 days after induction of a unilateral dopaminergic lesion. At these three times, the mean discharge rate of the subthalamic neurons recorded ipsilateral to the lesion was increased by 85, 176 and 127%, respectively, whereas this rate was decreased by 16, 27 and 43%, respectively, in the opposite subthalamic nucleus. This result emphasizes the importance of interhemispheric regulation of this structure, contrasting with the unilateralized current model of the functional organization of the basal ganglia.

Metabolic effects of nigrostriatal denervation in basal ganglia.

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.