Hypertension and changes in cognitive function in a Mediterranean population.

Background: Severe cognitive decline is one of the major public health problems in developed countries. Finding modifiable risk factors could become essential to develop strategies to prevent or delay dementia progression and stop its rising incidence.Objective: Our aim was to investigate the association between hypertension and cognitive function and to assess whether better adherence to the Mediterranean diet may modify this association.Methods: A subsample of 764 participants from the 'Seguimiento Universidad de Navarra' (SUN) cohort older than 55 years was evaluated with the Spanish Telephone Interview for Cognitive Status (TICS-m) at two-time points, separated by 6 years. Multivariable-adjusted linear regression models were used to prospectively assess the association between hypertension -also according to adherence to the Mediterranean diet- and 6-y changes in cognitive function.Results: The adjusted between-group difference in the 6-year change of the TICS-m score between hypertensive participants and their non-hypertensive counterparts was -0.36 (95% CI -0.70, -0.02). This association was stronger among participants with a lower adherence to the Mediterranean diet [-0.62 (95% CI: -1.09, -0.15)] but the differences between hypertensive and non-hypertensive participants were no longer significant among participants with a higher baseline adherence to the Mediterranean diet.Conclusion: In this Mediterranean cohort, hypertension was inversely associated with cognitive function, but an attenuation of this detrimental association by a moderate/high adherence to the Mediterranean diet was suggested.

Coffee consumption and breast cancer risk in the SUN project.

INTRODUCTION: Breast cancer prevalence is growing worldwide. Many factors, such as diet and lifestyle could be determinants of the incidence of breast cancer. Coffee has been extensively studied in relation to several chronic diseases because of its multiple effects in health maintenance and its elevated consumption. We studied the relationship between coffee intake and breast cancer risk in the SUN (Seguimiento Universidad de Navarra) prospective cohort. MATERIALS AND METHODS: We evaluated 10,812 middle-aged, Spanish female university graduates from the SUN Project, initially free of breast cancer. Coffee consumption was assessed with a 136-item validated food-frequency questionnaire (FFQ). Incident breast cancer cases were confirmed by a trained oncologist using medical records and by consultation of the National Death Index. We fitted Cox regression models to assess the relationship between baseline categories of coffee consumption and the incidence of breast cancer during follow-up. We stratified the analysis by menopausal status. RESULTS: During 115,802 person-years of follow-up, 101 new cases of breast cancer were confirmed. Among postmenopausal women, more than 1 cup of coffee per day was associated with a lower incidence of breast cancer (HR 0.44; 95% confidence interval: 0.21, 0.92) in the fully adjusted model, compared to women who consumed one cup of coffee or less per day. We observed no significant differences in regard to premenopausal women. CONCLUSION: Even though the number of cases was low, slight indications of an inverse association between coffee consumption and breast cancer risk among postmenopausal women were observed. Further longitudinal studies are warranted to confirm this finding.

Sugar-sweetened and artificially-sweetened beverages and changes in cognitive function in the SUN project.

Background: Sugar-sweetened beverages (SSB) and artificially-sweetened beverages (ASB) have been inconsistently associated with declines in cognitive function. Because of their low caloric content and replacement of sugar, ASB are often seen as 'healthy' alternatives to SSB. Objective: We longitudinally assessed the association between the consumption of SSB or ASB and cognitive function. Design: A subsample of the 'Seguimiento Universidad de Navarra' (SUN) cohort of university graduates aged over 55 years old was evaluated with the Spanish Telephone Interview for Cognitive Status (STICS-m) at two-time points, separated by 6 years. Consumption of SSB and ASB was appraised using a validated food-frequency questionnaire. Linear regression models were fitted, adjusting for potential confounders, including cardiometabolic variables, with the change in the STICS-m score at year 6 as the dependent variable. Results: A significant association between the consumption of SSB and changes in cognitive function as measured by the STICS-m was observed in the total sample, with a change of -0.43 (95% CI -0.85, -0.02, p = 0.04) in those that consumed >1 beverage/month compared to never/seldom consumers. The association was not significant for the consumption of ASB, but point estimates showed negative values, suggesting declines in cognition. Conclusions: Only the consumption of SSB, but not ASB, was significantly associated with a decline in cognitive function after 6 years. Further longitudinal studies are needed to explore the relationship between these beverages and cognitive function and the potential mechanisms through which they might be harmful.

Validation study of a Spanish version of the modified Telephone Interview for Cognitive Status (STICS-m) / Validación de la versión en español de la Telephone Interview for Cognitive Status modificada

Objective: To compare the Spanish version of the modified Telephone Interview of Cognitive Status (STICS-m) with the Mini-Mental State Examination (MMSE) and predict its ability to detect the development of dementia. Method: 106 participants in a dietary intervention trial underwent face-to-face evaluation with the MMSE, and phone interview with the STICS-m. The correlation between STICS-m and MMSE was assessed with the intraclass correlation coefficient (ICC) of consistency. Secondly, 932 participants over 55 years old from the "Seguimiento Universidad de Navarra" cohort were evaluated with the STICS-m and data on dementia diagnosis were gathered (median follow-up time of 6.5 years). A logistic regression model evaluated the association between STICS-m score or 2-year changes in STICS-m score and risk of developing dementia, adjusting for ApoE, age and years of university education. Results: The ICC between the MMSE and the STICS-m was 0.31 (95% confidence interval [95%CI]: 0.13-0.48). The adjusted odds ratio (OR) for the development of dementia for each additional point in the baseline STICS-m score was 0.85 (95%CI: 0.72-1.02; p=0.084). When considering the 2-year change in the STICS-m score as exposure, the OR for the development of dementia was 0.79 (95%CI: 0.67-0.93; p=0.006). Conclusions: The weak correlation between the STICS-m and the MMSE reflects moderate-low concurrent validity. Even so, the STICS-m can be regarded as an useful tool in the epidemiological setting since increasing scores appear to be able to predict a lower risk of developing dementia

Objetivo: Estudiar la correlación de la Telephone Interview for Cognitive Status modificada en español (STICS-m) con el Mini-Mental State Examination (MMSE) y predecir la capacidad de la primera para detectar el desarrollo de demencia. Método: Ciento seis sujetos de un estudio de intervención dietética fueron evaluados personalmente con el MMSE y por teléfono con la STICS-m. La correlación entre ambos se midió con el coeficiente de correlación intraclase (CCI) de consistencia. Además, 932 participantes mayores de 55 años de la cohorte "Seguimiento Universidad de Navarra" fueron evaluados con la STICS-m. Durante una mediana de seguimiento de 6,5 años, se recogió información sobre el desarrollo de demencia. Mediante regresión logística se estudió la asociación entre la puntuación de la STICS-m o el cambio a 2 años en la puntuación y el riesgo de desarrollar demencia, ajustando por apolipoproteína E, edad y años de educación universitaria. Resultados: El CCI entre el MMSE y la STICS-m fue de 0,31 (intervalo de confianza del 95% [IC95%]: 0,13-0,48). La odds ratio (OR) ajustada para el desarrollo de demencia para cada punto adicional en la puntuación basal de la STICS-m fue de 0,85 (IC95%: 0,72-1,02; p=0,084). Al considerar el cambio en la puntuación a los 2 años como variable independiente, la OR fue de 0,79 (IC95%: 0,67-0,93; p=0,006). Conclusiones: La correlación débil entre la STICS-m y el MMSE refleja solo una moderada-baja validez concurrente. Aun así, la STICS-m puede considerarse útil en el contexto epidemiológico, ya que aumentos en la puntuación parecen predecir un menor riesgo de desarrollar demencia

Validation study of a Spanish version of the modified Telephone Interview for Cognitive Status (STICS-m).

OBJECTIVE: To compare the Spanish version of the modified Telephone Interview of Cognitive Status (STICS-m) with the Mini-Mental State Examination (MMSE) and predict its ability to detect the development of dementia. METHOD: 106 participants in a dietary intervention trial underwent face-to-face evaluation with the MMSE, and phone interview with the STICS-m. The correlation between STICS-m and MMSE was assessed with the intraclass correlation coefficient (ICC) of consistency. Secondly, 932 participants over 55 years old from the "Seguimiento Universidad de Navarra" cohort were evaluated with the STICS-m and data on dementia diagnosis were gathered (median follow-up time of 6.5 years). A logistic regression model evaluated the association between STICS-m score or 2-year changes in STICS-m score and risk of developing dementia, adjusting for ApoE, age and years of university education. RESULTS: The ICC between the MMSE and the STICS-m was 0.31 (95% confidence interval [95%CI]: 0.13-0.48). The adjusted odds ratio (OR) for the development of dementia for each additional point in the baseline STICS-m score was 0.85 (95%CI: 0.72-1.02; p=0.084). When considering the 2-year change in the STICS-m score as exposure, the OR for the development of dementia was 0.79 (95%CI: 0.67-0.93; p=0.006). CONCLUSIONS: The weak correlation between the STICS-m and the MMSE reflects moderate-low concurrent validity. Even so, the STICS-m can be regarded as an useful tool in the epidemiological setting since increasing scores appear to be able to predict a lower risk of developing dementia.

Better Adherence to the Mediterranean Diet Could Mitigate the Adverse Consequences of Obesity on Cardiovascular Disease: The SUN Prospective Cohort.

Strong observational evidence supports the association between obesity and cardiovascular events. In elderly high-risk subjects, the Mediterranean diet (MedDiet) was reported to counteract the adverse cardiovascular effects of adiposity. Whether this same attenuation is also present in younger subjects is not known. We prospectively examined the association between obesity and cardiovascular clinical events (myocardial infarction, stroke or cardiovascular death) after 10.9 years follow-up in 19,065 middle-aged men and women (average age 38 year) according to their adherence to the MedDiet (<6 points or ≥6 points in the Trichopoulou's Mediterranean Diet Score). We observed 152 incident cases of cardiovascular disease (CVD). An increased risk of CVD across categories of body mass index (BMI) was apparent if adherence to the MedDiet was low, with multivariable-adjusted hazard ratios (HRs): 1.44 (95% confidence interval: 0.93-2.25) for ≥25 - <30 kg/m² of BMI and 2.00 (1.04-3.83) for ≥30 kg/m² of BMI, compared to a BMI < 25 kg/m². In contrast, these estimates were 0.77 (0.35-1.67) and 1.15 (0.39-3.43) with good adherence to MedDiet. Better adherence to the MedDiet was associated with reduced CVD events (p for trend = 0.029). Our results suggest that the MedDiet could mitigate the harmful cardiovascular effect of overweight/obesity.

TREM2 is associated with the risk of Alzheimer's disease in Spanish population.

Two recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD). Rs75932628-T is a rare nonsynonymous variant (p.R47H) that confers a high risk of AD with an effect size similar to that of the APOE ɛ4 allele. However, this association has not been replicated in any independent studies to date. The allelic frequency of rs75932628 varies according to the population from 0.02% to 0.63% among healthy controls. In an attempt to replicate the association between rs75932628-T and AD risk, we genotyped rs75932628 in a cohort of 504 AD subjects and 550 healthy controls from a Spanish population. Rs75932628-T showed a minor allele frequency of 0.3% among this cohort. Interestingly, in our study, rs75932628-T was found exclusively in 1.4% of AD cases (7/504), including 4 early-onset AD cases, and in none of the controls (n = 0/550). Here, we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD.

Selective brain gray matter atrophy associated with APOE ε4 and MAPT H1 in subjects with mild cognitive impairment.

The aim of our study was to elucidate whether specific patterns of gray matter loss were associated with apolipoprotein E ε4 (APOE ε4) and microtubule-associated protein tau (MAPT)-H1) genetic variants in subjects with mild cognitive impairment (MCI) at a baseline visit. Gray matter voxel-based morphometry analysis of T1 magnetic resonance imaging scans were performed in 65 amnestic-MCI subjects. MCI APOE ε4 carriers compared with non-carriers showed increased brain atrophy in right hippocampus and rostral amygdala, superior and middle temporal gyrus, and right parietal operculum, including inferior frontal gyrus, inferior parietal, and supramarginal gyrus. MAPT-H1/H1 MCI carriers showed an increased bilateral atrophy in superior frontal gyri (including frontal eye fields and left prefrontal cortex) and precentral gyrus but also unilateral left atrophy in the inferior temporal gyrus and calcarine gyrus. In addition, MCI subjects carrying both APOE ε4 and MAPT-H1/H1 variants showed gray matter loss in the supplementary motor area and right pre- and postcentral gyri. The effect of APOE ε4 on gray matter loss in right hippocampus suggests that, at least in some AD sub-types, the neuronal vulnerability could be increased in the right hemisphere. The pattern of frontal gray matter loss observed among MCI MAPT H1/H1 carriers has also been found in other tauopathies, suggesting that MCI may share etiological factors with other tauopathies. Frontal and parietal cortex vulnerability was found when adding MAPT H1/H1 and APOE ε4 effects, suggesting a synergistic effect of these variants. These results could be due to changes in APOE ε4 and MAPT expression.

Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort.

INTRODUCTION: Some familial Alzheimer's disease (AD) cases are caused by rare and highly-penetrant mutations in APP, PSEN1, and PSEN2. Mutations in GRN and MAPT, two genes associated with frontotemporal dementia (FTD), have been found in clinically diagnosed AD cases. Due to the dramatic developments in next-generation sequencing (NGS), high-throughput sequencing of targeted genomic regions of the human genome in many individuals in a single run is now cheap and feasible. Recent findings favor the rare variant-common disease hypothesis by which the combination effects of rare variants could explain a large proportion of the heritability. We utilized NGS to identify rare and pathogenic variants in APP, PSEN1, PSEN2, GRN, and MAPT in an Ibero-American cohort. METHODS: We performed pooled-DNA sequencing of each exon and flanking sequences in APP, PSEN1, PSEN2, MAPT and GRN in 167 clinical and 5 autopsy-confirmed AD cases (15 familial early-onset, 136 sporadic early-onset and 16 familial late-onset) from Spain and Uruguay using NGS. Follow-up genotyping was used to validate variants. After genotyping additional controls, we performed segregation and functional analyses to determine the pathogenicity of validated variants. RESULTS: We identified a novel G to T transition (g.38816G>T) in exon 6 of PSEN1 in a sporadic early-onset AD case, resulting in a previously described pathogenic p.L173F mutation. A pathogenic p.L392V mutation in exon 11 was found in one familial early-onset AD case. We also identified a novel CC insertion (g.10974_10975insCC) in exon 8 of GRN, which introduced a premature stop codon, resulting in nonsense-mediated mRNA decay. This GRN mutation was associated with lower GRN plasma levels, as previously reported for other GRN pathogenic mutations. We found two variants in MAPT (p.A152T, p.S318L) present only in three AD cases but not controls, suggesting that these variants could be risk factors for the disease. CONCLUSIONS: We found pathogenic mutations in PSEN1, GRN and MAPT in 2.33% of the screened cases. This study suggests that pathogenic mutations or risk variants in MAPT and in GRN are as frequent in clinical AD cases as mutations in APP, PSEN1 and PSEN2, highlighting that pleiotropy of MAPT or GRN mutations can influence both FTD and AD phenotypic traits.

Genetic variation in APOE cluster region and Alzheimer's disease risk.

We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimer's disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE ε4. Rs5158 (APOC4 intron 1) and rs10413089 (3' to APOC2) showed a trend toward an increase in AD risk independently from APOE ε4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk.

Cingulate epileptogenesis in hypothalamic hamartoma.

Hypothalamic hamartoma (HH) is a relatively rare cause of epilepsy, mainly affecting children. Nearly all patients develop gelastic seizures, often followed by other focal seizure types. Our case illustrates the mechanisms of epileptogenesis in HH. The patient developed gelastic attacks as a baby, and secondarily generalized seizures and drop attacks at 9 years of age. Magnetic resonance imaging (MRI) confirmed the presence of a HH. Presurgical assessment with intracranial electroencephalography (EEG) monitoring recorded gelastic seizures with generalized epileptiform activity. Functional stimulation of the hamartoma provoked gelastic attacks. Single pulse electrical stimulation (SPES) was used to identify epileptogenic cortex. SPES of the left cingular cortex provoked generalized responses similar to the spontaneous generalized discharges. Our results suggest that long-standing history of epilepsy in patients with HH may be related to additional sources of epileptogenic activity. Electrical stimulation performed in this patient provided additional data to favor the hypothesis of secondarily epileptogenesis in the cingulate gyrus independently from the primary origin in the HH.

LINGO1 gene analysis in Parkinson's disease phenotypes.

BACKGROUND: Parkinson's disease (PD) and essential tremor (ET) may share some etiopathogenic factors. A genome-wide association study has shown that LINGO1 gene variants are associated with increased risk of ET. We hypothesized that LINGO1 variants could increase susceptibility to PD. METHODS: A large series of PD subjects and healthy controls were genotyped for rs9652490 and rs11856808 LINGO1 single nucleotide polymorphisms (SNPs). RESULTS: We found an increased frequency of the rs11856808(T/T) genotype in PD compared with controls (odds ratio = 1.46; corrected P value = 0.02). A recessive genetic model was the best fit for rs11856808 influence on PD (recessive gene action test: corrected P value = 0.01). Stratification analysis showed that rs11856808(T/T) genotype frequency was higher in the tremor-dominant PD and the classical PD (C-PD) subgroups (recessive gene action test for the C-PD subgroup: corrected P value = 0.004). DISCUSSION: Our results indicate that LINGO1 variants could increase risk of PD, specifically those presenting the non-rigid-akinetic phenotypes, which suggests that LINGO1 may have a role in the etiology of tremor in PD at least in the Spanish population.

Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease.

Recent genome-wide association studies of Parkinson's disease have nominated 3 new susceptibility loci (PARK16-18) and confirmed 2 known risk genes (MAPT and SNCA) in populations of European ancestry. We sought to replicate these findings. We genotyped single-nucleotide polymorphisms in each of these genes/loci in 1445 Parkinson's disease patients and 1161 controls from northern Spain. Logistic regression was used to test for association between genotype and Parkinson's disease under an additive model, adjusting for sex, age, and site. We also performed analyses stratified by age at onset. Single-nucleotide polymorphisms in MAPT (rs1800547; P = 3.1 × 10(-4) ) and SNCA (rs356219; P = 5.5 × 10(-4) ) were significantly associated with Parkinson's disease. However, none of the markers in PARK16-18 associated with Parkinson's disease in the overall sample, or in any age stratum, with P values ranging from .09 to .88. Although our data further validate MAPT and SNCA as Parkinson's disease susceptibility genes, we failed to replicate PARK16, PARK17, and PARK18. Potential reasons for the discordance between our study and previous genome-wide association studies include effects of population structure, power, and population-specific environmental interactions. Our findings suggest that additional studies of PARK16-18 are necessary to establish the role of these loci in modifying risk for Parkinson's disease in European-derived populations. © 2011 Movement Disorder Society.

The effect of MAPT H1 and APOE ε4 on transition from mild cognitive impairment to dementia.

Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio =1.45; 95% CI=1.04-2.02; p=0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio=1.47; 95% CI= 1.06-2.04; p=0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio=2.24, 95% CI =1.40-3.58; p=0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-ß and tau brain deposition.