Antonia M. W. Coppus

Survival in Elderly Persons with Down Syndrome

The longer life expectancy now experienced by persons with Down syndrome (DS) makes it necessary to know the factors influencing survival in older persons with this syndrome. In a prospective longitudinal cohort study of dementia and mortality, 506 persons with DS aged 45 and older were followed for a mean of 4.5 years (range 0.0–7.6 years). Cognitive and social functioning were tested at baseline and annual follow‐up. The diagnosis of dementia was determined according to a standardized protocol. Cox proportional hazards modeling was used for survival analysis.

Plasma β amyloid and the risk of Alzheimer's disease in Down syndrome.

Extracellular deposition of amyloid beta peptide (Aβ) has been implicated as a critical step in the pathogenesis of Alzheimers disease (AD). In Down syndrome (DS), Alzheimers disease is assumed to be caused by the triplication and overexpression of the gene for amyloid precursor protein (APP), located on chromosome 21. Plasma concentrations of Aβ1-40 and Aβ1-42 were determined in a population based study of 506 persons with DS, who were screened annually for dementia. We used Cox proportional hazards models to determine the risk of dementia. Demented persons with DS have a significantly higher plasma Aβ1-40 concentration than the nondemented (p = 0.05). Those with the highest concentrations of Aβ1-40 and Aβ1-42 have a higher risk to develop dementia. The risk to develop dementia during follow-up (mean 4.7 years) increased to 2.56 (95% confidence interval, 1.39-4.71) for Aβ1-42 and 2.16 (95% confidence interval, 1.14-4.10) for Aβ1-40. High plasma concentration of plasma Aβ1-40 and Aβ1-42 are determinants of the risk of dementia in persons with DS.

Behavioural and psychological symptoms of dementia in Down syndrome: Early indicators of clinical Alzheimer's disease?

Behavioural and Psychological Symptoms of Dementia (BPSD) are a core symptom of dementia and are associated with suffering, earlier institutionalization and accelerated cognitive decline for patients and increased caregiver burden. Despite the extremely high risk for Down syndrome (DS) individuals to develop dementia due to Alzheimers disease (AD), BPSD have not been comprehensively assessed in the DS population. Due to the great variety of DS cohorts, diagnostic methodologies, sub-optimal scales, covariates and outcome measures, it is questionable whether BPSD have always been accurately assessed. However, accurate recognition of BPSD may increase awareness and understanding of these behavioural aberrations, thus enabling adaptive caregiving and, importantly, allowing for therapeutic interventions. Particular BPSD can be observed (long) before the clinical dementia diagnosis and could therefore serve as early indicators of those at risk, and provide a new, non-invasive way to monitor, or at least give an indication of, the complex progression to dementia in DS. Therefore, this review summarizes and evaluates the rather limited knowledge on BPSD in DS and highlights its importance and potential for daily clinical practice.

Early age at menopause is associated with increased risk of dementia and mortality in women with Down syndrome.

In a prospective longitudinal cohort study of dementia and mortality in persons with Down syndrome aged 45 years and older, 85 postmenopausal women were followed for a mean follow-up time of 4.3 years (range 0.0 to 7.4 years). The effect of age at menopause on age at diagnosis of dementia and survival was estimated using correlation analysis and Cox Proportional Hazard Model. We found a significant correlation between age at menopause and age at diagnosis of dementia (rho=0.52; p< 0.001), and between age at menopause and age at death (rho=0.49; p=0.01). Early age at menopause is associated with a 1.8 fold increased risk of dementia: Hazard Ratio (HR): 1.82 (95%Confidence Interval (CI): 1.31-2.52) and with risk of death: HR: 2.05 (95%CI: 1.33-3.16). Our study suggests that age at menopause in women with Down syndrome is a determinant of age at onset of dementia and mortality.

Plasma amino acids and neopterin in healthy persons with Down’s syndrome

SummaryIn persons with Down’s syndrome (DS) immunological abnormalities as well as hypothyroidism and Alzheimer type dementia are frequently observed. In addition, the activity of the enzyme cystathionine beta-synthase (CBS) is over-expressed which results in an altered homocysteine metabolism.In the present study, 48 older healthy DS persons without signs of dementia, psychiatric or somatic comorbidity and free of medication were analyzed for plasma levels of amino acids, neopterin and monoaminergic metabolites. Data were compared with those obtained from age and sex matched healthy controls.It was found that the spectrum of amino acids showed widespread differences in that levels of nearly all essential amino acids were lower in DS patients as compared to healthy controls. In addition, a significantly lower methionine and higher taurine concentration were observed which is in accordance with a disturbed homocysteine metabolism. With respect to the monoamine metabolites, the concentration of 5-hydroxyindoleacetic acid was not altered whereas that of homovanillic acid was significantly increased. Finally, the concentration of the immune activation marker neopterin was increased in persons with DS.It is concluded that healthy DS persons of older age show extensive biochemical abnormalities suggesting a compromised homocysteine metabolism, an activated cell-mediated immune response and an enhanced turnover of dopamine.

The impact of apolipoprotein E on dementia in persons with Down's syndrome

Apolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Downs syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-based sample of persons with DS (n=425), demented and non-demented. There was evidence that APOE epsilon4 is correlated with the rate of decline in the social competence rating scale (SRZ) (p=0.04). In our population, we found overall a modest but not statistical significant effect on the prevalence of dementia (OR=1.57, 95%CI: 0.87-2.82). We did observed a significant long-term effect on the incidence of dementia (HR=4.66, 95%CI: 1.35-16.14), but for those with a follow-up less than 3 years the risk was not significantly increased: HR=0.83 (95%CI 0.35-1.94). When pooling our data in a meta-analysis, the APOE epsilon4 allele shows a 1.59-fold (95%CI: 1.19-2.12) increase in risk of dementia in persons with DS. We conclude that APOE is influencing the risk of dementia in persons with DS.

Serum MHPG Strongly Predicts Conversion to Alzheimer's Disease in Behaviorally Characterized Subjects with Down Syndrome.

BACKGROUND Down syndrome (DS) is the most prevalent genetic cause of intellectual disability. Early-onset Alzheimers disease (AD) frequently develops in DS and is characterized by progressive memory loss and behavioral and psychological signs and symptoms of dementia (BPSD). Predicting and monitoring the progression of AD in DS is necessary to enable adaptive caretaking. OBJECTIVE Reliable blood biomarkers that aid the prediction of AD are necessary, since cerebrospinal fluid sampling is rather burdensome, particularly for people with DS. Here, we investigate serum levels of eight biogenic amines and their metabolites in relation to dementia staging and probable BPSD items. METHODS Using RP-HPLC with electrochemical detection, (nor)adrenergic (NA/A and MHPG), serotonergic (5-HT and 5-HIAA), and dopaminergic (DA, HVA, and DOPAC) compounds were quantified in the serum of DS subjects with established AD at baseline (n = 51), DS subjects without AD (n = 50), non-demented DS individuals that converted to AD over time (n = 50), and, finally, healthy non-DS controls (n = 22). RESULTS Serum MHPG levels were significantly lower in demented and converted DS subjects (p < 0.0001) compared to non-demented DS individuals and healthy controls. Those subjects with MHPG levels below median had a more than tenfold increased risk of developing dementia. Furthermore, significant correlations were observed between monoaminergic serum values and various probable BPSD items within each DS group. CONCLUSION Decreased serum MHPG levels show great potential as biomarker to monitor and predict conversion to AD in DS. Moreover, significant monoaminergic alterations related to probable BPSD items, suggesting that monoaminergic dysregulation is an underlying biological mechanism, and demonstrating the need to develop a validated rating scale for BPSD in DS.

Alzheimer's disease and Down's syndrome: Treating two paths to dementia☆

Successful therapy of dementia, like any disease, depends upon understanding its pathogenesis. This review contrasts the dominant pathways to dementia which differ in Alzheimers disease (AD) and in Downs syndrome (DS). Impaired clearance of neurotoxic amyloid beta peptides (Abeta) leads to dementia in AD. In DS over-production of Abeta plays the dominant role in the development of dementia. It follows, therefore, that the therapy of AD and DS should reflect a different balance between the dominant agent that inhibits the synthesis of Abeta in the brain in AD and increase the clearance of Abeta from the cerebrospinal DS.

Neopterin and the risk of dementia in persons with Down syndrome

Persons with Down syndrome show an altered immune response and an increased susceptibility to Alzheimers disease. In a prospective study, we examined whether the plasma neopterin level, a marker for cell-mediated immune activation and inflammation, is associated with an increased risk of dementia in persons with Down syndrome. Plasma concentrations of neopterin were determined in a population-based study of 394 persons with Down syndrome, who were screened annually for dementia. We used Cox proportional hazards model to determine risk of dementia. Demented persons with Down syndrome have a significantly (p=0.05) higher plasma neopterin concentration than the non-demented. In the non-demented without autoimmune disorders, in those with a plasma level of neopterin above median, the risk to develop dementia increased to 1.83 (95% confidence interval: 1.04-3.20). High plasma neopterin level is an independent determinant of the risk of dementia in persons with Down syndrome.

Serum NGAL is Associated with Distinct Plasma Amyloid-β Peptides According to the Clinical Diagnosis of Dementia in Down Syndrome

BACKGROUND The majority of people with Down syndrome (DS) develop dementia due to Alzheimers disease (AD). Neuropathological features are characterized by an accumulation of amyloid-β (Aβ) deposits and the presence of an activated immune response. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a newly identified (neuro)inflammatory constituent in AD. OBJECTIVE This study examines NGAL as an inflammatory marker in DS and its associations with plasma Aβ peptides according to the follow-up clinical diagnosis of dementia. METHODS Baseline serum NGAL and plasma Aβ40, Aβ42, Aβ(n40), and Aβ(n42) were quantified in 204 people with DS. The diagnosis of dementia in DS was established by follow-up clinical assessments. The following study groups were characterized: DS with AD at baseline (n = 67), DS without AD (n = 53), and non-demented DS individuals that converted to AD (n = 84). Serum NGAL was analyzed in 55 elderly non-DS, non-demented people. RESULTS Serum NGAL levels were significantly increased in DS subjects compared to non-DS people. Serum NGAL levels were not associated with clinical dementia symptoms in DS. However, NGAL was positively associated with Aβ42 and Aβ(n42) in demented DS individuals and with Aβ40 and Aβ(n40) in the non-demented DS group. NGAL was negatively associated with Aβ42/Aβ40 and Aβ(n42)/Aβ(n40) ratios in converted DS subjects. These associations persisted for Aβ(n40), Aβ42/Aβ40, and Aβ(n42)/Aβ(n40) after adjusting for demographics measures, apolipoprotein E ε4 allele, platelets, and anti-inflammatory medication. CONCLUSION Serum NGAL levels are increased in DS and associated with distinct species of Aβ depending on the progression of dementia as diagnosed by baseline and follow-up clinical assessments.