Obesity, diabetes and their metabolic correlates in middle-aged adults with Down syndrome.

BACKGROUND: Obesity in adults without Down syndrome is associated with an adverse metabolic profile including high prevalence of pre-diabetes and diabetes, high levels of insulin, non-high-density lipoprotein (HDL) cholesterol, leptin and high-sensitivity C-reactive protein (hsCRP) and low levels of HDL and adiponectin. We examined whether obesity in middle-aged adults with Down syndrome is also related to an adverse metabolic profile. METHODS: This cross-sectional study included 143 adults with Down syndrome, with a mean age of 55.7 ± 5.7 years and 52.5% women. Body mass index (BMI) was classified as underweight (BMI < 18.5 kg/m2 ), normal (BMI 18.5-24.9 kg/m2 ), overweight (BMI 25-29.9 kg/m2 ) and obese (BMI ≥ 30 kg/m2 ). Diabetes was ascertained by history or by haemoglobin A1c (HbA1c) as normal glucose tolerance (HbA1c < 5.7%), pre-diabetes (HbA1c 5.7-6.4%) and diabetes (HbA1c ≥ 6.5%). We measured non-fasting lipids, hsCRP, insulin, adiponectin and leptin. RESULTS: The majority of the sample had an overweight (46.9%) or obesity (27.3%) status. However, there was a relatively low prevalence of pre-diabetes (9.8%) and diabetes (6.9%). Overweight and obesity status were not associated with lower HDL and adiponectin and higher insulin, non-HDL cholesterol and hsCRP as expected in adults without Down syndrome. However, overweight and obesity were strongly associated with higher leptin (P < 0.001). CONCLUSIONS: The only metabolic correlate of obesity in middle-aged adults with Down syndrome was high leptin levels. Our findings are limited by non-fasting laboratory tests but suggest that middle-aged adults with Down syndrome do not have the adverse metabolic profile related to obesity found in adults without Down syndrome.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

Estrogen receptor α variants affect age at onset of Alzheimer's disease in a multiethnic female cohort.

BACKGROUND/AIMS: Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer's disease (AD) in women of different ethnicities. We examined the influence of ESR1 polymorphisms on age at onset of AD in a multiethnic cohort of women. METHODS: Among 1,436 women participating in the Washington Heights Inwood Columbia Aging Project, association with age at AD onset was assessed for 41 single-nucleotide polymorphisms (SNPs) on the ESR1 gene using Cox proportional hazard models, adjusting for presence of an APOE ε4 allele, years of education, and body mass index. RESULTS: Six SNPs in self-identified White women were protectively associated with delayed age of AD onset in this self-identified group, including the two restriction fragment length polymorphisms PvuII (rs2234693) and XbaI (rs9340799) (HR range = 0.420-0.483). Two separate SNPs were found to affect age of AD onset in self-identified Black women. CONCLUSIONS: ESR1 polymorphisms affect age of onset of AD in women, and risk alleles vary by ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid environmental or cultural risk factors mediating the SNP effect on risk for AD.

Aromatase variants modify risk for Alzheimer's disease in a multiethnic female cohort.

BACKGROUND/AIMS: Few studies of gene variants that affect estrogen activity investigate their association with risk for Alzheimer's disease (AD) in women of different ethnicities. We investigated the influence of CYP19 polymorphisms on risk for AD in a multiethnic cohort of women, with individual ethnicity assessed by genetic population ancestry informative markers (AIMs) as well as by self-identified ethnicity. METHODS: Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project, association with risk for AD was assessed for 41 single nucleotide polymorphisms (SNPs) on the CYP19 gene using multivariable logistic regression, adjusting for age, presence of an APOE ε4 allele, years of education, and body mass index. RESULTS: Risk for AD was associated with 6 SNPs in women of predominantly Caucasian AIMs-defined ancestry. Of these, 2 were also associated with decreased risk of AD in women of admixed/Hispanic AIMs ancestry. Two separate SNPs were found to be protective in women of predominantly African AIMs-based ancestry. CONCLUSIONS: CYP19 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry. These effects are possibly due to linkage disequilibrium patterns or differences in the prevalence of comorbid risk factors mediating the SNP effect on risk for AD by group.

Type 2 diabetes and late-onset Alzheimer's disease.

BACKGROUND/AIMS: To confirm in a cohort recruited in 1999-2001 our finding in a cohort recruited in 1992-1994 relating type 2 diabetes (T2D) to late-onset Alzheimer's disease (LOAD). METHODS: Participants were 1,488 persons aged 65 years and older without dementia at baseline from New York City. T2D was ascertained by self-report. Dementia and LOAD were ascertained by standard research procedures. Proportional hazard regression was used for analyses relating T2D and LOAD. RESULTS: The prevalence of T2D was 17%. There were 161 cases of dementia and 149 cases of LOAD. T2D was related to dementia (hazard ratio = 1.7; 95% confidence interval = 1.4-2.9) and LOAD (1.6; 1.0-2.6) after adjustment for age, sex, education, ethnic group and apolipoprotein E ε4. This association was weaker when only AD - excluding cases of mixed dementia - was considered (hazard ratio = 1.3; 95% confidence interval = 0.8-2.2). CONCLUSION: T2D is associated with LOAD. Cerebrovascular disease may be an important mediator.

Plasma beta-amyloid and duration of Alzheimer's disease in adults with Down syndrome.

OBJECTIVES: To investigate the relation of plasma levels of Abeta peptides (Abeta1-40 and Abeta1-42) and apolipoprotein E (APOE) genotype to dementia status, and the duration of Alzheimer's disease (AD) in adults with Down syndrome (DS). METHODS: Adults with DS were recruited from community settings and followed up for a mean period of 6.7 years. Plasma levels Abeta1-40 and Abeta1-42 and APOE genotype were determined at the last visit. RESULTS: There were 83 nondemented participants and 44 participants with prevalent AD. Overall, plasma levels of Abeta1-42, Abeta1-40 and the ratio Abeta1-42/Abeta1-40 did not differ significantly between the adults with DS. Among demented participants, the mean level of Abeta1-40 was significantly lower (157.0 vs. 195.3) and the ratio of Abeta1-42/Abeta1-40 was significantly higher (0.28 vs. 0.16) in those with more than 4 years duration of dementia than in those with 4 or fewer years' duration of dementia. This pattern was generally similar in those with and without an APOE epsilon4 allele. CONCLUSIONS: There is an association between plasma Abeta peptide levels and the duration of AD in older persons with DS. The predictive and diagnostic roles of Abeta1-42 and Abeta1-40 measurements for AD, however, remain controversial. Change in Abeta peptide levels with onset of AD and with the duration of dementia may account for a lack of difference between prevalent cases and nondemented individuals and for variation in the predictive power of Abeta peptide levels.

Antigen-antibody reactions in rat brain sites induce transient changes in drinking behavior.

The septum or hypothalamus of rat brain was injected through implanted cannulas with antibody against membrane antigens in the rat brain or with antibody against exogenous soluble antigens (such as ovalbumin) followed by the specific antigen. Both immunological systems produced a moderate but highly significant decrease in drinking by thirsty rats. This phenomenon is suggested as an experimental model for behavioral disorders resulting from nondegenerative, immunological processes in the brain.

Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down syndrome.

OBJECTIVE: Virtually all adults with Down syndrome (DS) have neuropathological manifestations of Dementia in Alzheimer's disease (DAD) but not all develop clinical psychopathology. The effect of allelic variants of Apolipoprotein (APOE) gene in development and progression of DAD and mortality in persons with DS is examined. METHODS: Recruited participants with DS underwent two to 14 sequential assessments over a follow up period of 6 years on average and their APOE genotype determined. Dementia status was confirmed as recommended by the Working Group for the Establishment of Criteria for the Diagnosis of Dementia in Individuals with Intellectual Disability. RESULTS: APOE genotype results were available for 252 individuals. Participants with APOE epsilon 4 allele had significantly higher risk of developing DAD (HR = 1.8, 95% CI: 1.12-2.79), had an earlier onset of DAD (55.0 vs 57.0 years; p = 0.0027) and a more rapid progression to death compared with participants with epsilon 3 allele (4.2 years vs. 5.4 years, respectively, p = 0.048). In non-demented persons with DS, epsilon 4 allele was associated with earlier death by 17 years (mean survival age, 55.7 vs. 72.7 years; HR = 5.9, 95% CI: 1.7-21.3). CONCLUSIONS: This study highlights the relationship of APOE genotype to morbidity and mortality in persons with DS which has important clinical implications. We recommend screening for APOE genotype in persons with DS to identify those at risk of DAD and premature death. Further research is required to investigate the underlying reasons for the early mortality in non-demented DS persons with an epsilon 4 allele.

Body mass index, dementia, and mortality in the elderly.

OBJECTIVES: To explore the association between body mass index and mortality in the elderly taking the diagnosis of dementia into account. DESIGN: Cohort study. SETTING: cohort study of aging in Medicare recipients in New York City. PARTICIPANTS: 1,452 elderly individuals 65 years and older of both genders. MEASUREMENTS: We used proportional hazards regression for longitudinal multivariate analyses relating body mass index (BMI) and weight change to all-cause mortality. RESULTS: There were 479 deaths during 9,974 person-years of follow-up. There were 210 cases of prevalent dementia at baseline, and 209 cases of incident dementia during follow-up. Among 1,372 persons with BMI information, the lowest quartile of BMI was associated with a higher mortality risk compared to the second quartile (HR=1.5; 95% CI: 1.1,2.0) after adjustment for age, gender, education, ethnic group, smoking, cancer, and dementia. When persons with dementia were excluded, both the lowest (HR=1.9; 95% CI=.3,2.6) and highest (HR=1.6; 95% CI: 1.1,2.3) quartiles of BMI were related to higher mortality. Weight loss was related to a higher mortality risk (HR=1.5; 95% CI: 1.2,1.9) but this association was attenuated when persons with short follow-up or persons with dementia were excluded. CONCLUSION: The presence of dementia does not explain the association between low BMI and higher mortality in the elderly. However, dementia may explain the association between weight loss and higher mortality.

An improved method for detecting telomere size differences in T-lymphocyte interphases from older people with Down syndrome with and without mild cognitive impairment.

Telomere size (quantified by fluorescence intensity and physical lengths) in short-term T-lymphocyte cultures from adults with Down syndrome (DS) with and without mild cognitive impairment (MCI-DS) or dementia was compared. For these studies, dementia status was determined based on longitudinal assessments employing a battery of cognitive and functional assessments developed to distinguish adult-onset impairment from preexisting developmental disability. In the course of our studies using a MetaSystems Image Analyzer in combination with ISIS software and a Zeiss Axioskop 2, we found that Fluorescein isothiocyanate (FITC) telomere fluorescence referenced to chromosome 2-identified FITC probe fluorescence as a nontelomere standard (telomere/cen2 ratio) showed great promise as a biomarker of early decline associated with Alzheimer's disease (AD) in this high-risk population. We have now obtained a cen (2) CY3 probe that can clearly be distinguished from the blue-green FITC interphase telomere probe, providing a clear distinction between telomere and centromere fluorescence in both interphase and metaphase. We used FITC/CY3 light intensity ratios to compare telomere length in interphases in adults with DS with and without MCI-DS or dementia. Five age-matched female and five age-matched male pairs (n = 10) all showed clear evidence of telomere shortening associated with clinical progression of AD (P < 0.002 - P < 0.000001), with distributions of mean values for cases and controls showing no overlap. We also examined the time needed for microscopy using interphase versus metaphase fluorescence preparations. With interphase preparations, examination time was reduced by an order of magnitude compared with metaphase preparations, indicating that the methods employed herein have considerable practical promise for translation into broad diagnostic practice.

Unbalanced placental expression of imprinted genes in human intrauterine growth restriction.

Imprinted genes control fetal and placental growth in mice and in rare human syndromes, but the role of these genes in sporadic intrauterine growth restriction (IUGR) is less well-studied. We measured the ratio of mRNA from a maternally expressed imprinted gene, PHLDA2, to that from a paternally expressed imprinted gene, MEST, by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the PHLDA2/MEST mRNA ratio in IUGR (p=0.0001). Altered expression of PHLDA2 and MEST was not accompanied by changes in DNA methylation within their imprinting centers, and immunohistochemistry showed PHLDA2 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae. We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays. In this series six imprinted genes were differentially expressed by ANOVA with a Benjamini-Hochberg false discovery rate of 0.05, with increased expression of PHLDA2 and decreased expression of MEST, MEG3, GATM, GNAS and PLAGL1 in IUGR placentae. At lower significance, we found IGF2 mRNA decreased and CDKN1C mRNA increased in the IUGR cases. We confirmed the significant reduction in MEG3 non-translated RNA in IUGR placentae by Northern blotting. In addition to imprinted genes, the microarray data highlighted non-imprinted genes acting in endocrine signaling (LEP, CRH, HPGD, INHBA), tissue growth (IGF1), immune modulation (INDO, PSG-family genes), oxidative metabolism (GLRX), vascular function (AGTR1, DSCR1) and metabolite transport (SLC-family solute carriers) as differentially expressed in IUGR vs. non-IUGR placentae.

Dementia of the Alzheimer's type and accelerated aging in Down syndrome.

This case study, of a woman with Down syndrome and dementia of the Alzheimer's type (DAT), follows the course of her decline over an 11-year period until death at age 57. Detailed neuropathological findings are also presented. This case illustrates features of premature aging that are typically associated with Down syndrome, and the progressive changes in memory and cognition that are usually associated with DAT. Although the subject's cardiovascular condition and thyroid disorder were treated, they may have contributed to the decline of her memory. This case shows the difficulty in diagnosing dementia in an individual with mental retardation who suffered comorbid episodes of depression and psychosis.

Risk of epilepsy in offspring of affected women: association with maternal spontaneous abortion.

BACKGROUND: Previously, the authors found that risk of spontaneous abortion was increased in the pregnancies of women with epilepsy compared with their same-sex siblings, which could have implications for risk of epilepsy in their offspring. An association between a history of spontaneous abortion in the mother and risk of epilepsy in her live-born offspring may arise through selective loss of fetuses with a genetic susceptibility to epilepsy or through intrauterine environmental factors that may predispose the mother to a spontaneous abortion and to epilepsy in her live-born children. METHOD: The authors examined the relation of a history of spontaneous abortion to the risk of idiopathic or cryptogenic epilepsy in 791 live-born offspring of 385 women with cryptogenic localization-related epilepsy (probands) ascertained from voluntary organizations. A semistructured telephone interview with probands and additional family informants, supplemented by medical record review, was used to obtain information on seizures and other risk factors in probands and relatives. RESULTS: Live-born offspring of women with a history of spontaneous abortion were four or five times as likely to develop epilepsy as were children of women without (12.8% versus 4.7%; rate ratio = 4.6, 95% CI: 2.3-9.0). Cumulative incidence of epilepsy was 21.9% in offspring of women with a history of spontaneous abortion and a family history of epilepsy, compared with 4.7% in offspring of women with neither risk factor. CONCLUSIONS: These results suggest that a history of spontaneous abortion is associated with increased risk of epilepsy in live-born offspring and may be a marker for genetic susceptibility for epilepsy in the mother.

Earlier onset of Alzheimer's disease in men with Down syndrome.

BACKGROUND: Virtually all individuals with Down syndrome (DS) have neuropathologic changes characteristic of Alzheimer's disease (AD) beginning at 40 years of age. Few studies have examined factors that influence age at onset of AD in DS. We investigated whether sex differences in age at onset and risk of AD among adults with DS are similar to those observed in the general population and whether the effect of sex on risk of AD is modified by apolipoprotein E (APOE) genotype. METHODS: A community-based sample of 111 adults with cytogenetically confirmed DS (34 to 71 years of age) was ascertained through the New York State Developmental Disabilities system. A semistructured interview with caregivers and review of medical records was used to ascertain the presence or absence of AD. APOE genotyping was carried out without knowledge of the subject's medical history or clinical diagnosis. RESULTS AND CONCLUSIONS: Both male gender and the presence of an APOE epsilon4 allele were associated with an earlier onset of AD. Compared with women, men with DS were three times as likely to develop AD. Compared with those with the APOE 3/3 genotype, adults with DS with the 3/4 or 4/4 genotypes were four times as likely to develop AD. No individual with an APOE epsilon2 allele developed AD. No evidence of interaction of sex and APOE genotype was found in risk of AD. The higher risk of AD in men may be related to differences in hormonal function between men and women with DS that are distinct from those in the general population.

Specificity of the fivefold increase in AD in mothers of adults with Down syndrome.

BACKGROUND: In a previous study, the authors found that the risk of AD among mothers who were 35 years or younger when their children with Down syndrome (DS) were born was five times that of mothers of children with other forms of mental retardation. The current study investigated the specificity of the familial aggregation of DS and AD by examining whether mothers who gave birth to children with DS before age 35 are also at increased risk of other age-related neurologic or medical disorders. METHODS: The authors used survival methods to compare cumulative incidence and relative risk of AD, other dementias, and common age-related disorders in parents of 200 adults with DS and parents of 252 adults with other forms of mental retardation. RESULTS: Mothers who were < or =35 years of age when their children with DS were born were four to five times as likely to develop AD as control mothers (rate ratio = 4.8, 95% CI 2.1, 11.2), whereas risk of AD among mothers who were >35 years when their children with DS were born was not significantly increased (rate ratio = 1.8, 95% CI 0.6, 5.1). Risk of AD among fathers of probands with DS was similar to that of control fathers, and did not vary by age at proband birth. Risk of other dementias and of other age-related medical condition was similar among mothers and fathers of probands with DS and control parents, regardless of age at proband birth. CONCLUSION: These findings suggest that the increased risk of AD among mothers who gave birth to children with DS before age 35 appears to represent a specific vulnerability to AD, as opposed to other age-related degenerative disorders.

Reliability of seizure classification using a semistructured interview.

Methods for standardized classification of epileptic seizures are important for both clinical practice and epidemiologic research. In this study, we developed a strategy for standardized classification using a semistructured telephone interview and operational diagnostic criteria. We interviewed 1,957 adults with epilepsy ascertained from voluntary organizations. To confirm and expand the seizure history, we also interviewed a first-degree relative for 67% of subjects and obtained medical records for 59%. Three lay reviewers used all available information to classify seizures. To assess reliability, each reviewer classified a sample of subjects assigned to the others. In addition, an expert physician classified a sample of subjects assigned to two of the reviewers. Agreement was "moderate-substantial" for generalized-onset seizures, both for the comparisons between pairs of lay reviewers and for the neurologist versus lay reviewers. Agreement was "substantial-almost perfect" for partial-onset seizures, both for pairs of lay reviewers and for the neurologist versus lay reviewers. These results suggest that seizures can be reliably classified by lay reviewers, using operational criteria applied to symptoms ascertained in a semistructured telephone interview.

Psychopharmacological activity of immune complexes in rat brain is complement dependent.

Sprague-Dawley male rats implanted with chronic indwelling cannulae at the perifornical hypothalamus eat excessively during the sixth hour following administration of exogenous immune-complexing reactants to the brain site. Rabbit anti-HSA was injected, followed in 30 min by a 20-fold excess of antigen. Anaphylatoxin C5a has also been shown to induce excessive intake, an effect similar to that of norepinephrine at this brain site. If the anaphylatoxins or other byproducts or consequence of the complement cascade were responsible for the immune complex effect, interference with the initiation of the cascade or with the conversion of C3 to C3a and C3b should abolish the behavioral response. These experiments demonstrate that immune complexes formed with the non-complement-fixing F(ab')2 fragment of the rabbit anti-HSA do not induce eating, and that normally active IgG antibody complexes do not induce eating if the site has been pretreated with goat anti-rat C3. This latter treatment had no effect, however, on the ability of the animals to respond to norepinephrine or to C5a. We conclude that the immune complex effect is complement dependent.

Effect of immune complex-forming reactants on catecholamine-modulated behaviors in the rat hypothalamus.

Injection of immune complex-forming reactants via implanted cannulae to the perifornical hypothalamus stimulated eating in sated rats and increased the eating response to exogenous norepinephrine (NE). Immune complex-induced eating was not seen after carbamyl choline injection, and immune complex treatment had no effect on water intake under any of the test conditions. The effects of immune complex activity occurred only 6 hours after administration, a time associated with heavy polymorphonuclear leukocyte infiltration of the cannula site. Immune complex activity mimics that following NE injection of this site. Because the immune complex-forming reactants are not specific to any neural antigen, we propose that their effects are indirectly mediated by anaphylatoxins produced by activation of the complement cascade.

Anaphylatoxin C5a modulation of an alpha-adrenergic receptor system in the rat hypothalamus.

C5a anaphylatoxin injected via implanted cannulae into the perifornical region of the hypothalamus stimulated eating in sated rats. C5a also attenuated carbamyl choline-induced drinking, and carbamyl choline inhibited C5a-induced eating, a mutual inhibition characteristic of the adrenergic-cholinergic interactions at this site. The increased food intake induced by C5a was also reversed by phentolamine, an alpha-adrenergic antagonist. Granulocytes infiltrating as a result of C5a-mediated leukotaxis did not arrive at the site in time to influence C5a activity. We propose that C5a in some way activates an alpha-adrenergic receptor system in the hypothalamus, and that anaphylatoxins could mediate neuropsychiatric symptoms sometimes associated with immune complex diseases affecting the central nervous system.