Association of a MIND Diet with Brain Structure and Dementia in a French Population.

BACKGROUND: Adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, which combines higher consumption of vegetables, berries, nuts, whole grains, olive oil, fish, beans and poultry, with lower consumption of meat, sugars and saturated fats, is a promising strategy to prevent dementia. However, evidence in populations with non-US food culture, especially from Europe, is limited. OBJECTIVES: To evaluate the association of a French-adapted MIND diet score with gray matter volumes, white matter microstructure and incident dementia. DESIGN AND SETTING: This longitudinal study included participants from the population-based Three-City Bordeaux cohort (≥65 years), with a follow-up from June 2001 to February 2018. PARTICIPANTS: Dementia-free participants at dietary assessment, in 2001-2002, who underwent systematic detection of incident dementia (over up to 7 visits). A subset of the cohort was included in an ancillary MRI study in 2010-2011. MEASUREMENTS: A French-adapted MIND diet score (range, 0-15) was computed from a 148-item Food Frequency Questionnaire and a 24-hour recall administered at home. Incident dementia and its subtypes were adjudicated by an expert committee; and gray matter volumes and white matter microstructure were assessed by 3D-T1 MRI and diffusion-MRI. RESULTS: Among 1,412 participants (mean age, 75.8 [SD, 4.8]; 63% women), followed for a median of 9.7 years (maximum 16.3 years), 356 (25.2%) developed incident dementia. In multivariable-adjusted Cox model, a higher French MIND diet score was associated with lower risks of dementia and AD (hazard ratios for 1-point of score = 0.89 [95% confidence interval, 0.83-0.95] and 0.88 [0.81-0.96], respectively). In Tract-Based Spatial Statistics analysis of 175 participants included in the MRI sub-study, a higher MIND diet score was associated with lower diffusivity values in the splenium of the corpus callosum (P < .05 after Family-Wise Error-correction). In contrast, there was no significant association of the adapted MIND diet score with gray matter volumes in Voxel-Based Morphometry analysis. CONCLUSION: In this cohort of French older adults, higher adherence to the French MIND diet was associated with a lower dementia risk and with preserved white matter microstructure. These results provide further evidence for a role of the MIND diet in the prevention of dementia.

Co-Occurrence of Geriatric Syndromes and Diseases in the General Population: Assessment of the Dimensions of Aging.

OBJECTIVES: The co-occurrence of multiple medical or psycho-social conditions (geriatric syndromes (GS) and age-related diseases) is a growing concern in older people. Given the diversity of these conditions and their complex interactions, our aim was to determine whether they could be structured into synthetic dimensions in order to facilitate the management of multimorbidity. DESIGN: The underlying structure of 10 GSs and 8 age-related diseases was identified using a multiple correspondence analysis (MCA), and confronted to subjective and objective health outcomes. SETTING: community residents from Bordeaux City (France) older than 75 years in 2010. PARTICIPANTS: 630 adults aged 75+ years who lived in Bordeaux and participated in the 10-year follow-up of the Three-City study. MEASUREMENTS: GSs included physical frailty, cognitive impairment and dementia, dependency, depressive symptoms, polymedication, thinness, falls, sensory deficit, social isolation, incontinence. Age-related diseases were cancer, cardiac diseases, peripheral vascular diseases, diabetes, hypertension, pulmonary diseases, osteoporosis, other chronic diseases. Association of the MCA-derived independent dimensions was assessed with 10-year visit subjective health and well-being, and with incident death and entry into institution during the remaining cohort follow-up. RESULTS: Most of the participants (82%) had at least two age-related syndromes or diseases. The MCA structured the 18 conditions into three major dimensions: Degradation (D) driven by GS, Vascular (V), and Psychosocial (P) representing 68.7%, 7.4%, and 5.7% of the total variance, respectively. Dimension D was a strong predictor of future death and institutionalization. Dimensions D and P were strongly associated with current well-being. CONCLUSIONS: This work confirmed that multimorbidity is very common among older adults, and demonstrated the essential role of GS as manifestations of aging, even more than age-related diseases.

Relationships between emotional disorders, personality dimensions, and binge eating disorder in French obese adolescents.

PURPOSE: Binge eating disorder (BED) is associated with higher psychopathology, including emotional and personality disorders, in the adult population, whether or not they are obese; although few data are available on adolescents, particularly among obese adolescents. OBJECTIVE: To explore the association of both emotional disorders and personality dimensions with BED in obese adolescents. METHODS: The sample consisted of 115 French adolescents enrolled at a clinical unit for the multidisciplinary care of their overweight or obesity. BED was defined using the Binge Eating Scale (BES). Emotional disorders and personality dimensions were assessed using the following tools: Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Junior Temperament and Character Inventory (JTCI); impulsivity was determined by the Barratt Impulsiveness Scale (BIS) and the Toronto Alexithymia Scale (TAS). Associations between emotional disorders (BDI/BAI) and personality dimensions (TAS/BIS/JTCI), considered first separately and then jointly with BED were determined with multivariate analysis. RESULTS: More severe depression (ß=0.27, CI [0.06; 0.48], P=0.011), a higher level of excess weight (ß=1.91, CI [0.22; 3.59], P=0.027), older age (ß=1.28, CI [0.43; 2.14], P=0.003), and greater cooperativeness (ß=0.36, CI [0.07; 0.66], P=0.017) were independently significantly associated with the presence of BED. CONCLUSIONS: This cross-sectional study underlines the co-occurrence of emotional and personality disorders with BED. This points out the importance of a multidisciplinary approach and the relevance of a joint diagnosis of binge eating, emotional disorders, and personality dimensions in obese adolescents, for better prevention and treatment of pediatric obesity.

Dietary patterns in french home-living older adults: Results from the PRAUSE study.

The aim of the present study was to provide descriptive dietary patterns of home-living older adults, and to examine their association with sociodemographic and 'diet-related' variables, and health and psychological factors. Dietary patterns were analyzed using separately cluster analysis for men (N=151,Mage=72.72, SD=8.80, range=56-97) and women (N=251, Mage=76.74, SD=9.95, range=55-97) in 402 older adults aged 55 years and over. Cluster analyses showed four distinct dietary profiles for each gender. In older men, the four distinct dietary clusters were associated with any differences in sociodemographic and 'diet-related' variables, cognitive function, and health and psychological factors. Likewise, in older women, the four distinct dietary clusters were associated with any differences in sociodemographic and 'diet-related' variables'. However in older women, results showed that the cluster 1 "high fish-fruit-vegetable" was associated with a better cognitive function, a better self-rated health and no depressive symptoms, whereas cluster 3 "moderate ready meals" was associated with cognitive decline, slight depression, and poor perceived health. Results emphasize the interest to take into consideration health and psychological factors associated with dietary patterns to better target the vulnerability of individuals and enable an effective prevention.

Ginkgo Biloba Extract Consumption and Long-Term Occurrence of Death and Dementia.

OBJECTIVES: To study the benefit of Ginkgo Biloba Extract (GBe) consumption on the long term risk of dementia and death in elderly people. DESIGN: The Paquid study is a population-based cohort with regular follow-up screenings up to twenty-two years and systematic detection of incident cases of dementia. Statistical analysis was conducted with an illness-death model dealing with interval censoring of dementia and competing risk of death. SETTING: The sample was randomly selected from electoral rolls in two administrative areas of southwestern France in 1988-1989. PARTICIPANTS: 3,777 subjects aged 65 years or older at baseline who were living at home. MEASUREMENT: Participants were visited at home by a trained psychologist at baseline in 1988/1989, and then again approximately every two years. Drug consumption for the treatment of cognitive or neurosensory impairment was collected at baseline. Participants were classified as GBe consumers, other drug (OD) consumers and untreated controls (UC) for this motive. RESULTS: After adjustment for sociodemographic factors and cognitive measures at baseline the risk for dementia was not significantly different in GBe consumers and UC (Hazard Ratio (HR)=1.21, 95% Confidence Interval (95% CI)=0.95-1.55, p=0.42) and it was of the same magnitude but significantly increased in the OD group versus UC (HR=1.25, 95% CI=1.06-1.46, p=0.004). With the same adjustment, the risk of dying in non-demented subjects was reduced in GBe consumers versus UC (HR=0.67, 95% CI=0.49-0.93, p=0.02) while it was the same as the reference group in OD consumers. The mean lifetimes without dementia was of 11.2 years in the UC group (95% CI=10.9-11.5), 11.1 years in the GBe group (10.2-11.9) and 9.1 years for the OD group (8.7-9.6). CONCLUSION: GBe consumers have a lower risk of dying before dementia and a longer lifetime without dementia than participants taking other drugs for the same indication.

Dietary patterns in French home-living older adults: Results from the PRAUSE study.

The aim of the present study was to provide descriptive dietary patterns of home-living older adults, and to examine their association with sociodemographic and 'diet-related' variables, and health and psychological factors. Dietary patterns were analyzed using separately cluster analysis for men (N=151,Mage=72.72, SD=8.80, range=56-97) and women (N=251, Mage=76.74, SD=9.95, range=55-97) in 402 older adults aged 55 years and over. Cluster analyses showed four distinct dietary profiles for each gender. In older men, the four distinct dietary clusters were associated with any differences in sociodemographic and diet-related variables, cognitive function, and health and psychological factors. Likewise, in older women, the four distinct dietary clusters were associated with any differences in sociodemographic and 'diet-related' variables'. However in older women, results showed that the cluster 1 "high fish-fruit-vegetable" was associated with a better cognitive function, a better self-rated health and no depressive symptoms, whereas cluster 3 "moderate ready meals" was associated with cognitive decline, slight depression, and poor perceived health. Results emphasize the interest to take into consideration health and psychological factors associated with dietary patterns to better target the vulnerability of individuals and enable an effective prevention.

Poor nutritional status is associated with a higher risk of falling and fracture in elderly people living at home in France: the Three-City cohort study.

UNLABELLED: Falling and fractures are a public health problem in elderly people. The aim of our study was to investigate whether nutritional status is associated with the risk of falling or fracture in community-dwelling elderly. Poor nutritional status was significantly associated with a higher risk of both falling and fractures. INTRODUCTION: Nutrition could play a role to prevent falls and fractures. The purpose of this study is to investigate whether a poor nutritional status is associated with the risk of falling and of fracture in community dwelling elderly. METHODS: Baseline nutritional status of participants was assessed using the Mini Nutritional Assessment (MNA). After a follow-up of 12 years, 6040 individuals with available data for falls and 6839 for fracture were included. People who presented the outcomes at baseline were excluded. Cox models were used to evaluate the associations between nutritional status and the risks of fall or fracture. RESULTS: The frequency of poor nutritional status (MNA ≤ 23.5), at baseline, was respectively 12.0% in the "fall study sample" and 12.8% in the "fracture study sample." Incident fall and fracture over 12 years were reported in 55.8 and 18.5% of the respective samples, respectively. In multivariate models controlled for sociodemographic data and several baseline health indicators, poor nutritional status was significantly associated with a higher risk of falling (hazard ratio (HR) = 1.66, 95% confidence interval (95% CI) 1.35-2.04 in men and HR = 1.20, 95% CI 1.07-1.34 in women) and with a higher risk of fracture (HR = 1.28, 95% CI 1.09-1.49). CONCLUSION: Poor nutritional status was associated with a higher risk of both falling and fractures in French elderly community-dwellers. Early screening and management of the nutritional status may be useful to reduce the frequency of these events in older people.

Walking and psychomotor speed in the elderly: concordance, correlates and prediction of death.

OBJECTIVES: To investigate the concordance between walking (WS) and psychomotor speed (PS), correlates of both tasks, and their capacity to predict mortality in the elderly. DESIGN, SETTING AND PARTICIPANTS: Seven-year cohort study of 1,365 community-dwelling subjects aged 65-95 years, participating in the Bordeaux sample of the Three City Study, a French prospective cohort designed to evaluate the risk of cognitive decline attributable to vascular risk factors. MEASUREMENTS: Participants completed a battery of cognitive assessments including time to complete Trail Making Test A used as a PS measure, and a measure of WS. Socio-demographic determinants, co-morbidities, functional and cognitive evaluation, and incident mortality were taken into account. RESULTS: Mean age was 75.7 (SD ± 5.4) years. WS and TMT-A speed have very low concordance (kappa coefficient=.05). The correlates of each measure were different: mostly clinical co-morbidities for WS, and mostly cognition and function for TMT-A speed. However, TMT-A speed and WS are both independent predictors of death after seven years of follow-up. CONCLUSION: WS and TMT-A speed could be considered as two different dimensions of age-related slowness, but both performances were associated with higher risk of mortality.

Adherence to a Mediterranean diet and risk of fractures in French older persons.

UNLABELLED: Prevention of fractures is a considerable public health challenge. In a population-based cohort of French elderly people, a diet closer to a Mediterranean type had a borderline significant deleterious effect on the risk of fractures, in part linked to a low consumption of dairy products and a high consumption of fruits. INTRODUCTION: Higher adherence to the Mediterranean diet (MeDi) is linked to a lower risk of several chronic diseases, but its association with the risk of fractures is unclear. Our aim was to investigate the association between MeDi adherence and the risk of fractures in older persons. METHODS: The sample consisted of 1,482 individuals aged 67 years or older, from Bordeaux, France, included in the Three-City Study in 2001-2002. Occurrences of hip, vertebral and wrist fractures were self-reported every 2 years over 8 years, and 155 incident fractures were recorded. Adherence to the MeDi was evaluated at baseline by a MeDi score, on a 10-point scale based on a food frequency questionnaire and a 24-h recall. Multivariate Cox regression tests were performed to estimate the risk of fractures according to MeDi adherence. RESULTS: Higher MeDi adherence was associated with a non-significant increased risk of fractures at any site (hazard ratio [HR] per 1-point increase of MeDi score = 1.10, P = 0.08) in fully adjusted model. Among MeDi components, higher fruits consumption (>2 servings/day) was significantly associated with an increased risk of hip fractures (HR = 1.95, P = 0.04), while low intake of dairy products was associated with a doubled risk of wrist fractures (HR = 2.03, P = 0.007). An inverse U-shaped association between alcohol intake and risk of total fracture was observed (HR high vs. moderate = 0.61, P for trend = 0.03). CONCLUSIONS: Greater MeDi adherence was not associated with a decreased risk of fractures in French older persons. The widely recognized beneficial effects of the MeDi do not seem to apply to bone health in these people.

Nutrient patterns and risk of fracture in older subjects: results from the Three-City Study.

UNLABELLED: We investigated the association between nutrient patterns and risk of fractures in 1,482 older subjects. Patterns associated with higher intakes of Ca, P, vitamin B12, proteins and unsaturated fats, and moderate alcohol intake, provided by diets rich in dairies and charcuteries, were related to a lower risk of wrist and hip fractures. INTRODUCTION: The purpose of this study was to investigate the relationship between patterns of nutrient intake and the risk of fractures in older subjects. METHODS: Among 1,482 participants from the Bordeaux sample of the Three-City (3C) Study who completed a 24-h dietary recall and a food frequency questionnaire, we examined the association between patterns of nutrient intake derived from principal component analysis and 8-year incidence of self-reported fractures of the hip, the wrist, and the vertebrae. RESULTS: A "nutrient-dense" pattern rich in Ca and P, iron, vitamins B including B12, vitamins C and E, alcohol, proteins, and unsaturated fats, and characterized by a higher consumption of fruits and vegetables, meats and fish, cheese and milk, charcuteries, cereals, rice, pasta, and potatoes, was associated with a 19% (95% CI 2-34%, P=0.03) lower risk of wrist fractures. The same pattern was associated with a 14% (95% CI 2-25%) lower risk of fractures at any site. A "south-western French" pattern rich in Ca, P, vitamins D and B12, retinol, alcohol, proteins, and fats-including unsaturated fats; poor in vitamins C, E, and K, carotenes, folates, and fibers; and related to a higher consumption of cheese, milk, and charcuterie and a lower consumption of fruits and vegetables was related to a 33% lower risk of hip fractures (95% CI 3-39%, P=0.03). CONCLUSIONS: Higher intakes of Ca, P, vitamin B12, proteins, and unsaturated fats and moderate alcohol, provided by dietary patterns rich in cheese, milk, and charcuteries, were related to a lower risk of wrist and hip fractures in our cohort.

Dietary patterns: a novel approach to examine the link between nutrition and cognitive function in older individuals.

Cognitive decline may lead to dementia whose most frequent cause is Alzheimer's disease (AD). Among the many potential risk factors of cognitive decline and AD, diet raises increasing interest. Most studies considered diet in the frame of a single nutrient approach with inconsistent results. A novel approach to examine the link between nutrition and cognitive function is the use of dietary patterns. The aim of the present review was to update and complete the body of knowledge about dietary patterns in relationship with various cognitive outcomes in the elderly. Two approaches can be used: a priori and a posteriori patterns. A priori patterns are defined by the adhesion to a pre-defined healthy diet using a score such as the Mediterranean diet (MeDi) score, the Healthy Eating Index, the Canadian Healthy Eating Index, the French National Nutrition and Health Programme (Programme National Nutrition Santé) Guideline Score (PNNS-GS), the Recommended Food Score (RFS) and Dietary Approaches to Stop Hypertension (DASH). MeDi score, RFS, PNNS-GS and DASH have been associated with lower risks of cognitive impairment, cognitive decline, and dementia or AD. Principal components analysis, reduced rank regression and clustering methods allow the identification of 'healthy' patterns associated with lower risk of cognitive decline. However, some studies did not report any associations with cognitive outcomes and results are discordant especially regarding MeDi and the risk of dementia. Several methodological challenges should be overcome to provide a higher level of evidence supporting the development of nutritional policies to prevent cognitive decline and AD.

Olive oil consumption, plasma oleic acid, and stroke incidence: the Three-City Study.

OBJECTIVE: To determine whether high olive oil consumption, and high plasma oleic acid as an indirect biological marker of olive oil intake, are associated with lower incidence of stroke in older subjects. METHODS: Among participants from the Three-City Study with no history of stroke at baseline, we examined the association between olive oil consumption (main sample, n = 7,625) or plasma oleic acid (secondary sample, n = 1,245) and incidence of stroke (median follow-up 5.25 years), ascertained according to a diagnosis validated by an expert committee. RESULTS: In the main sample, 148 incident strokes occurred. After adjustment for sociodemographic and dietary variables, physical activity, body mass index, and risk factors for stroke, a lower incidence for stroke with higher olive oil use was observed (p for trend = 0.02). Compared to those who never used olive oil, those with intensive use had a 41%(95% confidence interval 6%-63%, p = 0.03) lower risk of stroke. In the secondary sample, 27 incident strokes occurred. After full adjustment, higher plasma oleic acid was associated with lower stroke incidence (p for trend = 0.03). Compared to those in the first tertile, participants in the third tertile of plasma oleic acid had a 73% (95% confidence interval 10%-92%, p = 0.03) reduction of stroke risk. CONCLUSIONS: These results suggest a protective role for high olive oil consumption on the risk of stroke in older subjects.

Dietary omega 3 polyunsaturated fatty acids and Alzheimer's disease: interaction with apolipoprotein E genotype.

Epidemiological studies suggest a protective role of omega-3 poly-unsaturated fatty acids (n-3 PUFA) against Alzheimer's disease (AD). However, most intervention studies of supplementation with n-3 PUFA have yielded disappointing results. One reason for such discordant results may result from inadequate targeting of individuals who might benefit from the supplementation, in particular because of their genetic susceptibility to AD. The ε4 allele of the apolipoprotein E gene (ApoE) is a genetic risk factor for late-onset AD. ApoE plays a key role in the transport of cholesterol and other lipids involved in brain composition and functioning. The action of n-3 PUFA on the aging brain might therefore differ according to ApoE polymorphism. The aim of this review is to examine the interaction between dietary fatty acids and ApoE genotype on the risk for AD. Carriers of the ε4 allele tend to be the most responsive to changes in dietary fat and cholesterol. Conversely, several epidemiological studies suggest a protective effect of long-chain n-3 PUFA on cognitive decline only in those who do not carry ε4 but with inconsistent results. An intervention study showed that only non-carriers had increased concentrations of long-chain n-3 PUFA in response to supplementation. The mechanisms underlying this gene-by-diet interaction on AD risk may involve impaired fatty acids and cholesterol transport, altered metabolism of n-3 PUFA, glucose or ketones, or modification of other risk factors of AD in ε4 carriers. Further research is needed to explain the differential effect of n-3 PUFA on AD according to ApoE genotype.

Metabolic syndrome and cognitive decline in French elders: the Three-City Study.

OBJECTIVE: To examine associations between metabolic syndrome (MetS) and its individual components with risk of cognitive decline on specific cognitive functions. METHODS: Participants were 4,323 women and 2,764 men aged 65 and over enrolled in the longitudinal Three-City Study. Cognitive decline, defined as being in the worst quintile of the distribution of the difference between baseline score and either 2- or 4-year follow-up, was assessed by the Mini-Mental State Examination (MMSE, global cognitive function), the Isaacs Set Test (IST, verbal fluency), and the Benton Visual Retention Test (BVRT, visual working memory). MetS was defined by National Cholesterol Education Program-Adult Treatment Panel III criteria (at least 3 of 5 cardio-metabolic abnormalities: hypertension, high waist circumference, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, hyperglycemia). Proportional hazards models were adjusted for age, gender, educational level, center, baseline cognitive score, APOE4 genotype, and other potential confounders. RESULTS: MetS at baseline was associated with an increased risk of cognitive decline on MMSE (hazard ratio [HR] = 1.22 [1.08-1.37]; p = 0.001) and BVRT (HR = 1.13 [1.01-1.26]; p = 0.03) but not on IST (HR = 1.11 [0.95-1.29]; p = 0.18). Among MetS components, hypertriglyceridemia and low HDL cholesterol were significantly associated with higher decline on MMSE; diabetes, but not elevated fasting glycemia, was significantly associated with higher decline on BVRT and IST. CONCLUSIONS: MetS as a whole and several of its components had a negative impact on global cognitive decline and specific cognitive functions in older persons.

Fish, docosahexaenoic acid and Alzheimer's disease.

Cognitive decline in the elderly, particularly Alzheimer's disease (AD), is a major socio-economic and healthcare concern. We review here the literature on one specific aspect of diet affecting AD, that of the omega3 fatty acids, particularly the brain's principle omega3 fatty acid - docosahexaenoic acid (DHA). DHA has deservedly received wide attention as a nutrient supporting both optimal brain development and for cardiovascular health. Our aim here is to critically assess the quality of the present literature as well as the potential of omega3 fatty acids to treat or delay the onset of AD. We start with a brief description of cognitive decline in the elderly, followed by an overview of well recognized biological functions of DHA. We then turn to epidemiological studies, which are largely supportive of protective effects of fish and DHA against risk of AD. However, biological studies, including blood and brain DHA analyses need careful interpretation and further investigation, without which the success of clinical trials with DHA may continue to struggle. We draw attention to some of the methodological issues that need resolution as well as an emerging mechanism that may explain how DHA could be linked to protecting brain function in the elderly.

Decreased expression of retinoid nuclear receptor (RAR alpha and RAR gamma) mRNA determined by real-time quantitative RT-PCR in peripheral blood mononuclear cells of hypothyroid patients.

In vivo assessment of the cellular impact of thyroid hormones on target tissues might be of help for physiological studies and to evaluate the consequences of various diseases of the thyroid gland in humans. Given the tenuous relationship between retinoid and tri-iodothyronine (T3) status and that retinoids have also intracellular roles, the aim of this study was to determine the effect of hypothyroidism on the expression of T3 nuclear receptors (TR) and retinoic acid nuclear receptors (RAR, RXR) in human peripheral blood mononuclear cells (PBMC). Using real time RT-PCR, we quantified the relative amount of mRNA of the thyroid (TR alpha and TR beta) and retinoid (RAR alpha, RAR gamma, and RXR alpha) nuclear receptors in PBMC of euthyroid (n = 22) compared with hypothyroid (n = 22) subjects. Classical plasma parameters (free T3 (FT3), free thyroxine (T4) (FT4), thyroid-stimulating hormone (TSH), retinol (ROH), retinol-binding protein (RBP) and transthyretin (TTR)) were also measured. In hypothyroid subjects, the concentration of TSH was elevated, and dramatically low T3 and T4 concentrations were associated with a decrease in the expression of TR beta. Expression of RAR alpha and RAR gamma significantly decreased in hypothyroid versus control subjects, while an increased concentration of ROH was emphasised by hypothyroidism. These results first indicated that primary hypothyroidism induces hypoactivation of the retinoid nuclear pathway in PBMC, which was not predicted by the plasma ROH level. Further investigations will be necessary to evaluate these parameters in very small changes in thyroid hormone production such as mild (subclinical) hypothyroidism.

Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells.

BACKGROUND: Inadequate retinoid status has often been described as occurring with aging. Moreover, subclinical hypothyroid status has also been evoked in the elderly. Several studies performed in animals have described the crucial incidence of age-related hypo-functioning of retinoid and thyroid signalling pathways, particularly in the brain. OBJECTIVE: The aim of the present study was to clarify whether aging modifies retinoid and thyroid signalling in humans. METHODS: Using real-time RT-PCR the relative amount of mRNA of the retinoid (RARalpha, RARgamma and RXRalpha) and thyroid (TRalpha and TRbeta) nuclear receptors in peripheral blood mononuclear cells (PBMC) of young (24-57 years old, n = 22) compared with elderly (69-90 years old, n = 24) healthy subjects was quantitated. Classical plasma parameters used to characterize the retinoid and thyroid status - retinol (ROH), retinol-binding protein (RBP), free triiodothyronine (FT3) and thyroxine (FT4), thyroid-stimulating hormone (TSH) and transthyretin (TTR) - were also assessed. RESULTS: RARgamma expression was significantly decreased in elderly versus young subjects while no modification of the retinoid-related plasma parameters ROH and RBP were emphasized by aging. Concerning thyroid criteria, the elderly exhibited an increase in TSH concentration (+39%) without significant modifications of FT3 and FT4, which indicated an age-related sub-clinical hypothyroidism. Concurrently, the amount of TR mRNA (alpha as well as beta subtypes) was significantly decreased in the elderly. CONCLUSION: These data constitute the first evidence of an age-related hypo-activation of the retinoid and thyroid nuclear pathways in PBMC. Further study of the possible association between the expression of the retinoid and thyroid nuclear receptors and age-related cognitive alterations in humans would be interesting.

Differential effect of retinoic acid and triiodothyronine on the age-related hypo-expression of neurogranin in rat.

Given the important role of retinoids and thyroid hormone for optimal brain functioning and the tenuous relationship between retinoic acid (RA) and triiodothyronine (T3) signalings, we compared the effects of RA or T3 administrations on RA and T3 nuclear receptors (RAR, RXR and TR) and on their target genes, neuromodulin (GAP43) and neurogranin (RC3) in 24-month-old rats. Quantitative real time PCR and western blot analysis allowed us to verify that retinoid and thyroid signalings and GAP43 and RC3 expression are affected by age. By in situ hybridization we observed a decreased expression of RC3 in hippocampus, striatum and cerebral cortex. RARbeta, RXRbeta/gamma and GAP43 were up-regulated by RA as well as T3 treatment. The abundance of TRalpha/beta mRNA and RC3 expression were only increased by T3 administration in the whole brain. This up-regulator effect of T3 on RC3 was only observed in the striatum. During aging, T3 become a limiting factor alone able to correct the age-related concomitant hypo-activation of retinoid and thyroid signalings and alterations of synaptic plasticity.

Retinoic acid reverses the PTU related decrease in neurogranin level in mice brain.

Recent data have shown that fine regulation of retinoid mediated gene expression is fundamentally important for optimal brain functioning in aged mice. Nevertheless, alteration of the thyroid hormone signalling pathway may be a limiting factor, which impedes retinoic acid (RA) from exerting its modulating effect. Mild hypothyroidism is often described in the elderly. Thus, in the present study, it was of interest to determine if RA exerts its neurological modulating effect in mild hypothyroidism. To obtain further insight into this question, mice were submitted to a low propylthiouracyl (PTU) drink (0.05%) in order to slightly reduce the serum level of triiodothyronine (T3). A quantitative evaluation of RA nuclear receptors (RAR, RXR), T3 nuclear receptor (TR) and of neurogranin (RC3, a RA target gene which codes for a protein considered as a good marker of synaptic plasticity) in PTU treated mice injected with vehicle or RA or T3 was carried out. The PTU-related decrease in expression of RAR, RXR and RC3 was restored following RA or T3 administration, as observed in aged mice. The amount of TR mRNA, which was not affected in PTU treated mice, was increased only after T3 treatment as observed in overt hypothyroidism. These results suggest that neurobiological alterations observed in aged mice are probably related to RA and T3 signalling pathway modifications associated, in part, with mild changes in thyroid function.