Alain D. Dekker

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.

Epigenetics: the neglected key to minimize learning and memory deficits in Down syndrome.

Down syndrome (DS) is the most common genetic intellectual disability, caused by the triplication of the human chromosome 21 (HSA21). Although this would theoretically lead to a 1.5 fold increase in gene transcription, transcript levels of many genes significantly deviate. Surprisingly, the underlying cause of this gene expression variation has been largely neglected so far. Epigenetic mechanisms, including DNA methylation and post-translational histone modifications, regulate gene expression and as such might play a crucial role in the development of the cognitive deficits in DS. Various overexpressed HSA21 proteins affect epigenetic mechanisms and DS individuals are thus likely to present epigenetic aberrations. Importantly, epigenetic marks are reversible, offering a huge therapeutic potential to alleviate or cure certain genetic deficits. Current epigenetic therapies are already used for cancer and epilepsy, and might provide novel possibilities for cognition-enhancing treatment in DS as well. To that end, this review discusses the still limited knowledge on epigenetics in DS and describes the potential of epigenetic therapies to reverse dysregulated gene expression.

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

BACKGROUNDnDown 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.nnnOBJECTIVEnReliable 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.nnnMETHODSnUsing 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).nnnRESULTSnSerum 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.nnnCONCLUSIONnDecreased 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.

Neuropsychiatric Disturbances in Alzheimer's Disease: What Have We Learned from Neuropathological Studies?

Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer’s disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients’ secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.

Aging rather than aneuploidy affects monoamine neurotransmitters in brain regions of Down syndrome mouse models

Altered concentrations of monoamine neurotransmitters and metabolites have been repeatedly found in people with Down syndrome (DS, trisomy 21). Because of the limited availability of human post-mortem tissue, DS mouse models are of great interest to study these changes and the underlying neurobiological mechanisms. Although previous studies have shown the potential of Ts65Dn mice – the most widely used mouse model of DS – to model noradrenergic changes, a comprehensive monoaminergic characterization in multiple brain regions has not been performed so far. Here, we used RP-HPLC with electrochemical detection to quantify (nor)adrenergic (NA, adrenaline and MHPG), dopaminergic (DA, HVA and DOPAC), and serotonergic compounds (tryptophan, 5-HT and 5-HIAA) in ten regionally dissected brain regions of Ts65Dn mice, as well as in Dp1Tyb mice – a novel DS mouse model. Comparing young adult aneuploid mice (2.5–5.5 months) with their euploid WT littermates did not reveal generalized monoaminergic dysregulation, indicating that the genetic overload in these mice barely affected the absolute concentrations at this age. Moreover, we studied the effect of aging in Ts65Dn mice: comparing aged animals (12–13 months) with their younger counterparts revealed a large number of significant changes. In general, the (nor)adrenergic system appeared to be reduced, while serotonergic compounds were increased with aging. Dopaminergic alterations were less consistent. These overall patterns appeared to be relatively similar for Ts65Dn and WT mice, though more observed changes were regarded significant for WT mice. Similar human post-mortem studies are necessary to validate the monoaminergic construct validity of the Ts65Dn and Dp1Typ mouse models.

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

BACKGROUNDnThe 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.nnnOBJECTIVEnThis 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.nnnMETHODSnBaseline 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.nnnRESULTSnSerum 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.nnnCONCLUSIONnSerum 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.

Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome

Down syndrome (DS), present in nearly six million people, is associated with an extremely high risk to develop Alzheimers disease (AD). Amyloid‐β and tau pathology are omnipresent from age 40 years onward, but clinical symptoms do not appear in all DS individuals. Dementia diagnostics is complex in this population, illustrating the great need for predictive biomarkers. Although blood biomarkers have not yet proven useful, cerebrospinal fluid (CSF) biomarkers (low amyloid‐β42, high t‐tau, and high p‐tau) effectively contribute to AD diagnoses in the general population and are increasingly used in clinical practice. Surprisingly, CSF biomarkers have been barely evaluated in DS. Breaking the taboo on CSF analyses would finally allow for the elucidation of its utility in (differential) diagnoses and staging of disease severity. A sensitive and specific biomarker profile for AD in DS would be of paramount importance to daily care, adaptive caregiving, and specific therapeutic interventions.

Phosphorylation of AMPA-type glutamate receptors: the trigger of epileptogenesis?

Epilepsy is a common neurological disease characterized by changes in consciousness, recurrent unprovoked seizures, and signs of abnormal neurological activity. Epilepsy, present in ∼40 different types, affects ∼50–65 million people in the world, mostly young children and people older than 65

DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20u2009mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.

Changing Paradigms in Down Syndrome: The First International Conference of the Trisomy 21 Research Society.

Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) in humans with an incidence of ∼1:1,000 live births worldwide. It is caused by the presence of an extra copy of all or a segment of the long arm of human chromosome 21 (trisomy 21). People with DS present with a constellation of phenotypic alterations involving most organs and organ systems. ID is present in all people with DS, albeit with variable severity. DS is also the most frequent genetic cause of Alzheimers disease (AD), and ∼50% of those with DS will develop AD-related dementia. In the last few years, significant progress has been made in understanding the crucial genotype-phenotype relationships in DS, in identifying the alterations in molecular pathways leading to the various clinical conditions present in DS, and in preclinical evaluations of potential therapies to improve the overall health and well-being of individuals with DS. In June 2015, 230 scientists, advocates, patients, and family members met in Paris for the 1st International Conference of the Trisomy 21 Research Society. Here, we report some of the most relevant presentations that took place during the meeting.