Combination of white matter hyperintensities and Aß burden is related to cognitive composites domain scores in subjective cognitive decline: the FACEHBI cohort.

BACKGROUND: To explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aß) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD). METHODS: Two hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI), 18F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables. RESULTS: Adjusted multiple linear regression models showed that FreeSurfer (B - .245; 95% CI - .1.676, - .393, p = .016) and ß burden (SUVR) (B - .180; 95% CI - 2.140, - .292; p = .070) were associated with face-name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face-name associative performance indicated that those individuals with either higher WMH load or higher Aß burden showed the worst performance on the face-name associative memory CCs domain score. CONCLUSIONS: Our results suggest that increased WMH load and increased Aß are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.

Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundació ACE Healthy Brain Initiative (FACEHBI).

BACKGROUND: Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aß) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aß species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results. METHODS: The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(18F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aß40 and Aß42 peptides. The association between Aß40 and Aß42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aß levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aß plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis. RESULTS: FBB-PET global SUVR correlated weakly but significantly with Aß42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R2 = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aß measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aß FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aß measurements (p value for interaction = 0.105). CONCLUSION: Brain and plasma Aß levels are partially correlated in individuals diagnosed with SCD. Aß plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

FACEHBI: A Prospective Study of Risk Factors, Biomarkers and Cognition in a Cohort of Individuals with Subjective Cognitive Decline. Study Rationale and Research Protocols.

BACKGROUND: Long-term longitudinal studies with multimodal biomarkers are needed to delve into the knowledge of preclinical AD. Subjective cognitive decline has been proposed as a risk factor for the development of cognitive impairment. Thus, including individuals with SCD in observational studies may be a cost-effective strategy to increase the prevalence of preclinical AD in the sample. OBJECTIVES: To describe the rationale, research protocols and baseline characteristics of participants in the Fundació ACE Healthy Brain Initiative (FACEHBI). DESIGN: FACEHBI is a clinical trial (EudraCT: 2014-000798-38) embedded within a long-term observational study of individuals with SCD. SETTING: Participants have been recruited at the memory clinic of Fundació ACE (Barcelona) from two different sources: patients referred by a general practitioner and individuals from an Open House Initiative. PARTICIPANTS: 200 individuals diagnosed with SCD with a strictly normal performance in a comprehensive neuropsychological battery. MEASUREMENTS: Individuals will undergo an extensive neuropsychological protocol, risk factor assessment and a set of multimodal biomarkers including florbetaben PET, structural and functional MRI, diffusion tensor imaging, determination of amyloid species in plasma and neurophthalmologic assessment with optical coherence tomography. RESULTS: Two hundred individuals have been recruited in 15 months. Mean age was 65.9 years; mean MMSE was 29.2 with a mean of 14.8 years of education. CONCLUSIONS: FACEHBI is a long-term study of cognition, biomarkers and lifestyle that has been designed upon an innovative symptom-based approach using SCD as target population. It will shed light on the pathophysiology of preclinical AD and the role of SCD as a risk marker for the development of cognitive impairment.

Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene.

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10(-)(9)).

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

Prefrontal cortex volume reduction on MRI in preclinical Huntington's disease relates to visuomotor performance and CAG number.

PURPOSE: To investigate grey matter volumes on magnetic resonance imaging (MRI) in preclinical Huntington's disease (HD), and their relationship to neuropsychology and CAG number. MATERIAL AND METHODS: Twenty preclinical HD carriers and 21 healthy controls matched for age, sex, and educational level were included in this study. Clinical (UHDRS), and detailed neuropsychological assessments, and 3D IR SPGR axial MR acquisition. Calculation of global, segmented (SIENAX), and focal (voxel based morphometry, VBM) grey matter volumes was carried out. An analysis of variance (ANOVA) and a general linear model for VBM analysis were used to compare preclinical HD carriers and controls. Small volume correction was used, and clusters at p<0.05 were considered significant. Correlation analysis (VBM) with neuropsychology, and CAG number was also performed. RESULTS: Preclinical HD carriers showed, compared to controls, smaller global volumes of the brain (1279+/-6 vs. 1331+/-46, p=0.003), total (666+/-48 vs. 698+/-34, p=0.020) and cortical grey matter (551+/-44 vs. 577+/-32, p=0.035). When compared to the controls, preclinical carriers showed focal volume losses, which were more prominent in the left prefrontal cortex, cerebellum, and right posterior temporal cortex. Preclinical HD performed slower in a visuomotor integration task, the 15-Objects test, than controls (t (1,25.02)=3.69; p=0.001: pre-HD: 69.55+/-28.86; controls: 45.79+/-8.38). A correlation was found between volume loss in the prefrontal cortex, visuomotor performance, and CAG number. CONCLUSION: Preclinical HD carriers show grey matter volume reduction involving the prefrontal cortex, which relates to the visuomotor performance and CAG number. This suggests that regionally selective neuronal loss/dysfunction occurs prior to the clinical onset of symptoms.

Utilidad de las baterías neuropsicológicas estandarizadas en sujetos adultos con síndrome de Down y demencia / The Usefulness of standard neuropsychological testing for adults with Down syndrome and dementia

(SD) tienen un riesgo aumentado de desarrollar la enfermedad de Alzheimer (EA). Puesto que en el SD se parte de un nivel intelectual menor que en la población general, a veces resulta difícil objetivar si existe o no, en el envejecimiento, una reducción de sus capacidades para cumplir los criterios diagnósticos de EA. El «Mini-MentalState Examination» (MMSE) y el «Severe ImpairmentBattery» (SIB) son pruebas cognitivas estandarizadas ampliamente utilizadas para detectar demencia en la población general. Escasos estudios han utilizado el MMSE y la SIB en sujetos con SD con sospecha de demencia. El objetivo del presente estudio consistió en analizar la utilidad del MMSE y la SIB en la valoración de las funciones cognitivas de sujetos con SD. Método: Se administró el MMSE y la SIB a 45 sujetos con SD (16 con EA y 29 sin demencia) y el cuestionario «Dementia Questionnaire for Mentally Retarded Persons» (DMR) a sus cuidadores. Resultados: Los sujetos con SD y demencia mostraron una mayor alteración que los sujetos con SD sin demencia en la DMR-social y DMR-total, pero no se hallaron diferencias significativas entre ambos grupos en el rendimiento de la SIB, MMSE ni DMR-cognitivo. Las puntuaciones en la SIB correlacionaron significativamente con las del MMSE, DMR-total, DMR-cognitivo y DMR-social. El rendimiento en el MMSE correlacionó significativamente con el del DMR-total, DMR-cognitivo y SIB. Conclusiones: El MMSE y la SIB son herramientas útiles para el seguimiento de las funciones cognitivas en sujetos con SD y deterioro cognitivo o demencia (AU)

Background: Subjects with Down syndrome (DS) have an increased risk of Alzheimer’s disease (AD). As intellectual ability is lower in DS subjects than among the general population, it is difficult to determine whether cognition has deteriorated with age to the point of fulfilling AD diagnostic criteria. The Mini-Mental State Examination (MMSE) and the Severe Impairment Battery (SIB) are standard cognitive tests widely used to assess dementia in the general population. There are few studies using the MMSE and the SIB on subjects with DS where dementia is suspected. The aim of the present study was to analyse the appropriateness of the SIB and the MMSE in the cognitive assessment of aging subjects with DS. Methods: The SIB and the MMSE were administered to 45 subjects with DS (16 with Alzheimer’s disease and 29 without dementia), and the DMR questionnaire was given to their caregivers. Results: DS subjects with dementia had higher impairment levels than DS subjects without dementia in their social and total DMR scores, but no significant differences were found between the two groups in the SIB and MMSE scores or in cognitive DMR performance. Overall, SIB scores correlated significantly with MMSE results, total DMR, cognitive DMR, and social DMR. MMSE performance correlated significantly with total and cognitive DMR scores as well as SIB score. Conclusion: The SIB and the MMSE are useful assessment tools in monitoring cognitive function among subjects with DS and cognitive loss or dementia (AU)

Pleiotropic effects of statins and related pharmacological experimental approaches.

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects," and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.

Decreased frontal choline and neuropsychological performance in preclinical Huntington disease.

OBJECTIVES: To study metabolic brain changes in preclinical carriers of Huntington disease (PreHD) using proton magnetic resonance spectroscopy (1H-MRS) and to examine their relationship to neuropsychological performance. METHODS: Seventeen subjects with PreHD and 17 controls, matched for age and education, were studied. Frontal cortex and basal ganglia 1H-MRS, and a detailed neuropsychological battery, including visuomotor integration and speed, and memory, frontal, and visuospatial tests were performed. Statistical analysis included Student t-test and Pearson correlations (significance p < 0.05). RESULTS: Frontal choline-containing compounds (CHO) were decreased in PreHD [t (32) = -2.834, p = 0.008]. Subjects with PreHD performed worse than controls in the 15-Objects test [t (32) = 4.077, p = 0.000], Luria motor alternances [t (32) = -2.094, p = 0.044], and Symbol Digit tests [t (32) = -2.136, p = 0.040]. Decreased frontal CHO in PreHD correlated to slowing in visuomotor tasks (the 15-Objects test: r = -0.60, p = 0.000, and the Symbol Digit: r = 0.37, p = 0.047). CONCLUSION: As choline-containing compounds relate to membrane turnover, membrane dysfunction antedating neuronal death is suggested to occur in the frontal cortex in preclinical carriers of Huntington disease. This dysfunction may be responsible for some of the neuropsychological deficits observed.

Pleiotropic effects of statins and related pharmacological experimental approaches.

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects", and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.

Regulación de la expresión de caveolina-1 en macrófagos por agonistas PPAR / Regulation of caveolin-1 expression in macrophages by PPAR agonists

Introducción. La activación o la sobreexpresión del receptor activado por proliferadores peroxisómicos * (PPAR*) induce la expresión de caveolina-1 en diferentes tipos celulares. El objetivo de este estudio ha sido evaluar si los agonistas PPAR regulan la expresión de la caveolina-1 en macrófagos, y explorar los posibles mecanismos implicados. Material y métodos. Se diferenciaron monocitos THP-1 por exposición a PMA durante 24 h y, posteriormente, se trataron con rosiglitazona a diferentes dosis y durante distintos períodos. Los valores de ARNm se determinaron por la reacción de la transcriptasa inversa acoplada a la reacción en cadena de la polimerasa (RT-PCR), y la expresión de la proteína mediante western-blot. Resultados. El tratamiento con la rosiglitazona aumentó los valores de ARNm y de proteína de caveolina-1 de forma dependiente de la dosis y el tiempo en macrófagos THP-1. Esta inducción no se observó en presencia de inhibidores de la transcripción o de la síntesis de novo de proteínas. El incremento de la expresión de caveolina-1 producido por rosiglitazona no se relaciona con el estado de diferenciación celular y parece ser dependiente de la activación PPAR, ya que la presencia del antagonista PPAR GW9662 lo anuló por completo. Por último, se ha identificado un elemento de respuesta a proliferadores peroxisómicos (PPRE) funcional en el promotor del gen de la caveolina-1, que se activa por el tratamiento con rosiglitazona en macrófagos THP-1. Conclusiones. La rosiglitazona incrementa la expresión de caveolina-1 en macrófagos, a través de la activación de los PPAR y, probablemente, como consecuencia de la unión al PPRE identificado en la secuencia del promotor del gen de la caveolina-1 (AU)

Introduction. Peroxisome proliferator-activated receptor * (PPAR*) activation or overexpression induce caveolin-1 expression in several cell types. The aim of this study was to ascertain whether PPAR agonists could also regulate the caveolin-1 gene in macrophages, and to investigate the mechanisms involved. Materials and methods. PMA-treated THP-1 monocytes were incubated with rosiglitazone at different concentrations and for different periods of time. MRNA levels were determined by RT-PCR and protein expression by Western blot. Results. Our experiments demonstrated that rosiglitazone dose- and time-dependently increased caveolin-1 mRNA and protein in THP-1 macrophages. This induction was not observed in the presence of transcription inhibitors or de novo protein synthesis. We also showed that the increase in caveolin-1 elicited by rosiglitazone was not related to macrophage differentiation. This inductive effect seems to be dependent on PPAR activation, since the PPAR antagonist GW9662 abolished it. Finally, we identified a functional peroxisome proliferator response element (PPRE) in the caveolin-1 promoter, which was activated upon rosiglitazone treatment in THP-1 macrophages. Conclusions. PPAR activators, such as the PPAR* agonist rosiglitazone, increase caveolin-1 expression in macrophages. This effect appears to be mediated by PPAR activation, possibly by the binding of activated PPAR to the PPRE identified in the caveolin-1 promoter (AU)

Acyl coenzyme A:cholesterol acyltransferase inhibitors as hypolipidemic and antiatherosclerotic drugs.

Acyl coenzyme A:cholesterol acyltransferase (ACAT) is the enzyme that catalyzes the conversion of intracellular cholesterol into cholesteryl esters. Two ACAT isoforms, termed ACAT1 and ACAT2, have been described. ACAT1 is ubiquitously found, with high expression levels in macrophages, adrenals, sebaceous glands and foam cells from human atherosclerotic lesions. In contrast, ACAT2 expression is restricted to the intestine and the liver of mice and non-human primates. The reaction catalyzed by ACAT is essential for intestinal cholesterol absorption, synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins, and intracellular storage of cholesterol. Therefore, ACAT inhibitors would theoretically reduce plasma cholesterol levels by blocking cholesterol absorption from the diet and by reducing hepatic VLDL synthesis. Moreover, ACAT inhibition could limit the accumulation of cholesteryl esters in the cytoplasm of macrophages, thus reducing the formation of foam cells. In view of these attractive possibilities, a great deal of molecules with ACAT inhibitory properties have been synthesized in the last 20 years. However, only a few of them have reached clinical studies, mainly due to unexpected side effects. On the other hand, most of the compounds assayed in humans have not shown substantial hypolipidemic efficacy. The present article focuses on the current knowledge of the pharmacology of ACAT inhibitors, and, specifically, on the different pharmacological approaches used to evaluate these compounds as hypolipidemic and antiatherosclerotic agents.

Sexual dimorphism in lipid metabolic phenotype associated with old age in Sprague-Dawley rats.

PURPOSE: Aged male rats show a decrease in liver PPARalpha. We aimed to determine if the sexual dimorphism in lipid metabolism observed in the PPARalpha-/- mouse is also present in senescent rats. RESULTS: Eighteen-month old rats were obese and presented high plasma NEFA concentrations. Old male rats were more hypercholesterolemic and hyperleptinemic than females, presenting a higher content in hepatic triglycerides and cholesteryl esters, while 18-month old females were more hypertriglyceridemic than males. Although PPARalpha expression and binding activity was reduced in liver from old male and female rats, the mRNA for a PPARalpha target gene, such as CPT-I, was reduced in old males (-56%), while increased by 286% in old females. LXRalpha protein was increased, and its binding activity was decreased in livers of old males, while livers of old females showed an increase in DGAT1 (2.6-fold) and DGAT2 (4.9-fold) mRNA, with respect to 3-month old animals. The increases in DGAT1 and DGAT2 mRNAs matched in old females those of plasma (3.1-fold) and liver triglycerides (5.0-fold). CONCLUSIONS: These features disclose a marked sexual dimorphism in lipid metabolism associated to old age in rats that can be partially attributed not only to an age-related decrease in liver PPARalpha expression, but also to changes in other hepatic transcription factors and enzymes, such as liver X receptor alpha (LXRalpha) and diacylglycerol acyltransferases (DGAT).

Increase in hepatic expression of SREBP-2 by gemfibrozil administration to rats.

It is well known that gemfibrozil increases the biliary output of cholesterol and phospholipids, but we have little knowledge about the impact these changes have on liver cholesterol and phospholipid biosynthetic pathways. In the present study, no changes were detected in liver lipids and CTP:phosphocholine cytidylyltransferase after gemfibrozil administration to rats. On the contrary, 3-hydroxy-3-methylglutaryl-CoA reductase mRNA (9.9-fold) and Rd activity (16.7-fold) and phosphatidate phosphohydrolase activity (1.7-fold) increased, while plasma apo B-cholesterol (40%) and triglyceride (43%) levels decreased. As a part of a compensatory homeostatic response, we report for the first time that gemfibrozil administration to rats increased the hepatic sterol regulatory element binding protein-2 (SREBP-2) mRNA (2.9-fold) and mature protein (2.2-fold) levels. An early increase in the transcriptional activity of SREBP-2 elicited by gemfibrozil administration might be responsible for the observed changes in HMG-CoA reductase, phosphatidate phosphohydrolase, and SREBP-2 expression.

Effects of bilateral subthalamic stimulation on cognitive function in Parkinson disease.

BACKGROUND: Chronic bilateral subthalamic deep brain stimulation (STN-DBS) is known to improve motor function in patients with Parkinson disease (PD). However, the possible effects of STN-DBS on neuropsychological functions have been studied less. OBJECTIVE: To investigate the effects of STN-DBS on neuropsychological functions in PD. DESIGN: Before-after trial. PATIENTS AND METHODS: Fifteen consecutive patients were assessed before and 3 months after implantation of stimulators for STN-DBS (postsurgical assessment with the stimulators switched on). Both assessments were performed with patients in a drug-free condition. The neuropsychological battery consisted of tests measuring memory and visuospatial and frontal functions. RESULTS: The comparison between presurgical and postsurgical performance showed a moderate deterioration in verbal memory and prefrontal and visuospatial functions, and a moderate improvement in a prefrontal task and obsessive-compulsive traits. The motor state improved in all patients. CONCLUSION: Therapy with STN-DBS improves motor symptoms in PD without any clinically relevant neuropsychological deterioration.

Bezafibrate reduces mRNA levels of adipocyte markers and increases fatty acid oxidation in primary culture of adipocytes.

The molecular mechanisms by which peroxisome proliferator-activated receptor (PPAR) activation by fibrates reduces fat deposition and improves insulin sensitivity are not completely understood. We report that exposure of a rat primary culture of adipocytes for 24 h to the PPAR activator bezafibrate increased the mRNA levels of crucial genes involved in peroxisomal and mitochondrial beta-oxidation. The mRNA levels of the peroxisomal beta-oxidation rate-limiting enzyme acyl-CoA oxidase and of the muscle-type carnitine palmitoyl transferase I (M-CPT-I), which determines the flux of mitochondrial beta-oxidation, increased by 1.6-fold (P < 0.02) and 4.5-fold (P = 0.001), respectively. These changes were accompanied by an increase in the transcript levels of the uncoupling protein-2 (UCP-2; 1.5-fold induction; P < 0.05) and UCP-3 (3.7-fold induction; P < 0.001), mitochondrial proteins that reduce ATP yield and may facilitate the oxidation of fatty acids. Furthermore, bezafibrate increased the mRNA levels of the fatty acid translocase (2-fold induction; P < 0.01), suggesting a higher fatty acid uptake into adipocytes. In agreement with these changes, bezafibrate caused a 1.9-fold induction (P < 0.02) in 9,10-[(3)H]palmitate oxidation. Moreover, bezafibrate reduced the mRNA expression of several adipocyte markers, including PPARgamma (30% reduction; P = 0.05), tumor necrosis factor-alpha (33% reduction; P < 0.05), and the ob gene (26% reduction). In contrast, adipocyte fatty acid binding protein mRNA levels increased (1.5-fold induction; P < 0.01), pointing to a mobilization of fatty acids to mitochondria and peroxisomes. The reduction of the adipocyte markers caused by bezafibrate was accompanied by an increase in the mRNA levels of the preadipocyte marker Pref-1 (1.6-fold induction; P < 0.01). Some of the changes observed in the primary culture of rat adipocytes also were studied in the epididymal white adipose tissue of bezafibrate-treated rats for 7 days. In vivo, M-CPT-I mRNA levels increased (4.5-fold induction; P = 0.001) in epididymal white adipose tissue of bezafibrate-treated rats. Similarly, fatty acid translocase (2.6-fold induction; P = 0.002) and Pref-1 (5.6-fold induction) mRNA levels increased, although differences in the latter were not significant because of huge individual variations. These results indicate that exposure of adipocytes to bezafibrate, independent of its hepatic effects, increases the degradation of fatty acids, reducing their availability to synthesize triglycerides. As a result, some degree of dedifferentiation of adipocytes to preadipocyte-like cells is achieved. These changes may be involved in the reduction in fat depots and in the improvement of insulin sensitivity observed after bezafibrate treatment.

Uncoupling protein-3 mRNA up-regulation in C2C12 myotubes after etomoxir treatment.

Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters that uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane. Treatment of C2C12 myotubes for 24 h with 40 microM etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase I (CPT-I), up-regulated uncoupling protein 3 (UCP-3) mRNA levels (2-fold induction), whereas UCP-2 mRNA levels were not modified. Etomoxir treatment also caused a 2.5-fold induction in M-CPT-I (muscle-type CPT-I) mRNA levels. In contrast, other well-known peroxisome proliferator-activated receptor alpha (PPAR alpha) target genes, such as acyl-CoA oxidase and medium-chain acyl-CoA dehydrogenase, were not affected, suggesting that this transcription factor was not involved in the effects of etomoxir. Since it has been reported that CPT-I inhibition by etomoxir leads to a further increase in ceramide synthesis, we test the possibility that ceramides were involved in the changes reported. Similarly to etomoxir, addition of 20 microM C(2)-ceramide to C2C12 myotubes for 3, 6 and 9 h resulted in increased UCP-3 and M-CPT-I mRNA levels. These results indicate that the effects on UCP-3 mRNA levels could be mediated by increased ceramide synthesis.

MRI atrophy parameters related to cognitive and motor impairment in Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) show specific neuropsychological deficits in attention, memory, visuospatial or frontal lobe functions, which can arise from degeneration of different cerebral structures. OBJECTIVE: The aim of the present study was to analyze the role of focal degeneration (basal ganglia and substantia nigra) and diffuse cerebral atrophy (ventricular enlargement) in motor/cognitive impairment in PD. PATIENTS AND METHODS: We administered to 14 patients with advanced PD the following tests: Purdue Pegboard, Rey's Auditory-Verbal Learning test (RAVLT), Benton's Line Orientation, Trail Making, phonemic verbal fluency and Stroop test. Ventricular system, caudate and putamen nuclei and pars compacta of the substantia nigra were quantitatively measured by magnetic resonance imaging. Correlation analyses were carried out. RESULTS: The results showed that ventricular enlargement is negatively correlated with the performance on RAVLT and Stroop test. No relationship was found between caudate atrophy and cognitive deficits. Degeneration of putamen nucleus was found to be associated with motor deficits. CONCLUSION: Memory and frontal impairment are related to diffuse cerebral degeneration and the motor deficit is related to degeneration of the putamen nucleus.