University of Groningen
Down & Alzheimer
Dekker, Alain Daniel
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Publication date: 2017
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Dekker, A. D. (2017). Down & Alzheimer: Behavioural biomarkers of a forced marriage. Rijksuniversiteit Groningen.
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Summary, General Discussion
& Future Implications
Summary
Down syndrome & Alzheimer’s disease
Alzheimer’s disease (AD) is the major threat to elderly people with Down syndrome (DS). Behind their friendly faces, a devastating accumulation of pathology is ongoing in the brain. Not late in life, but already from birth onwards. The extremely high risk for AD, i.e. 68-80% develops dementia by age 65, relates to the additional third chromosome 21 (hence: trisomy 21) that genetically characterizes DS. Chromosome 21 encodes the amyloid precursor protein (APP), which enzymes cleave into ‘sticky’ amyloid-β (Aβ) peptides. The additional copy of chromosome 21 causes overproduction of APP, and thus of Aβ peptides that subsequently aggregate and deposit in amyloid plaques. Abnormal Aβ production and aggregation is thought to initiate the cascade of pathological processes in AD, including the formation of neurofibrillary tangles, which, together with amyloid plaques, constitute the two characteristic hallmarks of AD that were first described by Alois Alzheimer in 1906.
In DS, a remarkable discrepancy is observed. From the age of 40 onwards, DS brains have a full-blown AD neuropathology. Some individuals are diagnosed with dementia a few years later, while others remain free of dementia symptoms until their sixties or seventies. This highly variable time window between the presence of pathology and the onset of symptoms makes the prediction of those at risk for dementia very hard. In daily care for people with DS, it is of utmost importance to adapt the level of caregiving based on personal needs. The earlier symptoms of dementia are recognized, the more adequate caregiving can be optimized to the situation.
But how to achieve an early diagnosis of dementia in DS? Pre-existing intellectual disability (ID), (challenging) behaviour and trisomy 21-related co-morbidities complicate the diagnosis. In contrast to the general population, PET scans for amyloid pathology do not seem useful in DS as practically every person will be amyloid-positive regardless of clinical symptoms. Which other options can we explore to aid early detection? In the context of this dissertation, we adopted the behavioural perspective. The (highly variable level of) ID complicates the identification of cognitive changes. Behaviour, however, is more pronounced and observed on a daily basis by caregivers.
Behavioural and Psychological Symptoms of Dementia (BPSD)
Behavioural and Psychological Symptoms of Dementia (BPSD) is an umbrella term referring to a broad range of behavioural changes related to the presence of dementia. In the general population, thousands of studies have been conducted in this domain. Surprisingly, BPSD in DS have not received much interest. In chapter 2 we summarized and evaluated all existing literature about this. Which symptoms change most in demented (DS+AD) compared to non-demented (DS) individuals? A wide range of different approaches has been undertaken, making the comparison of studies quite difficult. For instance, more than twenty sub-optimal scales (not specifically designed for behaviour) were used in various, often small-sized DS cohorts that were, not infrequently, compared to illogical control groups. Far from being standardized or consistent, a few patterns in
time (BPSD onset in relation to diagnosis of dementia) could be distilled. Frontal lobe symptoms, such as apathy and disinhibition appeared to be early, possibly predictive of dementia, while agitation, activity disturbances and psychotic symptoms seemed to present later in the disease. Whether changes in anxiety, sleep disturbances, depressive symptoms and eating/drinking could differentiate between DS and DS+AD was inconclusive. Consequently, we identified the need for a validated scale for BPSD that comprehensively evaluates the wide range of behavioural symptoms, taking the specific complexity of pre-existing behaviour in DS into account.
Following our advice, we established a multidisciplinary consortium in The Netherlands and Europe to develop such a scale in a series of consecutive rounds. Based on literature, existing scales and clinical experiences within the consortium, 83 behavioural items were identified and categorized in twelve clinically defined clusters: anxiety & nervousness, sleep disturbances, irritability, obstinacy, agitation & stereotypical behaviour, aggression, apathy & aspontaneity, depressive symptoms, delusions, hallucinations, disinhibition & sexual behaviour, and eating and drinking. Using a systematic interview, informants of 281 individuals identified behavioural changes over time, comparing behaviour in the last six months to characteristic behaviour present in the past. These changes were evaluated in three diagnostic groups: DS, DS with questionable dementia (DS+Q), i.e. not yet meeting the dementia criteria, and DS+AD. Between groups, evident changes were observed in anxiety, sleep disturbances, agitation and stereotypical behaviour, aggression, apathy, depressive symptoms and eating/drinking behaviour. Changes primarily concerned increased frequencies or severities, while decreases were hardly noted. For most items, the proportion of individuals presenting such an increase was highest in the DS+AD group, intermediate in the DS+Q group and lowest in the DS group. Interestingly, a substantial proportion of DS+Q individuals already showed increases in anxiety, sleep disturbances, apathy and depressive symptoms. Such early changes may serve as alarm signals for those at risk to develop dementia. Psychotic symptoms (delusions and hallucinations) and disinhibited behaviour were not evidently altered between groups. Concerning the reliability of the BPSD-DS scale, we demonstrated (very) good interrater, test-retest and internal consistency reliability measures. Application of the scale in daily care allows for the systematic assessment of BPSD, which contributes to understanding among caregivers, and enables timely (adaptive) caregiving and therapeutic interventions.
Impaired monoaminergic neurotransmission
BPSD are thus omnipresent in DS+AD. What could be the underlying causes of these alterations? In addition to studying behavioural symptoms, this dissertation also investigated changes in monoamine neurotransmitter systems, which are associated with BPSD. Apart from a few rather limited studies in the last century, monoamine neurotransmitters – (nor)adrenaline, dopamine and serotonin – and their metabolites did not receive much attention in the context of DS+AD. We started our study at the level of an easily obtainable biological sample: blood. In chapter 4, reversed-phase high-performance liquid chromatography was used to quantify (nor)adrenergic, dopaminergic and serotonergic compounds in serum of 151 elderly DS individuals (>45 years) and 22
healthy non-DS controls. Three DS groups were distinguished: DS, DS+AD and converters, i.e. individuals who were non-demented at the (single) moment of blood sampling, but converted to DS+AD within 3-7 years (clinical follow-up). The most remarkable results were found for the major (nor)adrenergic metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). Serum MHPG levels were significantly lower in DS than in non-DS controls. Moreover, MHPG levels were strongly reduced in DS+AD vs DS, but, importantly, also in converters, even after accounting for the (confounding) use of psychoactive medication. Serum MHPG concentrations thus appeared to be altered years before the clinical diagnosis of dementia was established, illustrating the potential of MHPG as a predictive marker for conversion to AD in DS.
Concentrations in blood, however, are subject to peripheral influences. Cerebrospinal fluid (CSF), which is in more direct contact with the brain, therefore receives vast attention as source of biomarkers for AD in the general population. Would MHPG be altered in CSF of DS individuals? Not more than a mere handful of very small-sized CSF studies has been conducted in DS. Even the CSF biomarker profile for AD (low Aβ42, high total-tau and phosphorylated-tau), repeatedly demonstrated to be sensitive and specific in the general population, was not thoroughly studied in DS. In chapter 5, we summarized the available literature on CSF AD biomarkers in DS and identified possible reasons for this taboo on lumbar punctures. Consequently, we made a plea not to exclude this high-risk population for such studies, because a sensitive and specific panel of AD biomarkers would be of tremendous value to diagnose and care for DS individuals. A perfect example of leaving the choice for a lumbar puncture up to people with DS and their caregivers, is provided by our colleagues in Barcelona. Within the Down Alzheimer Barcelona Neuroimaging Initiative, CSF sampling was found to be feasible and safe, and more than 20% of DS individuals and their caregivers consented to lumbar punctures.
In chapter 6, these CSF samples, enriched with plasma samples, were analysed for monoamines and metabolites and compared between DS, DS with prodromal AD (DS+pAD, similar to DS+Q in chapter 3) and DS+AD. In addition, we managed to establish one of the largest collections of post-mortem brain regions (cortical and limbic regions, basal ganglia, locus coeruleus and cerebellum) of DS and DS+AD cases, as well as of early-onset AD (EOAD) patients and healthy non-DS controls in the general population (chapter 6). Surprisingly, MHPG levels in CSF, plasma and brain tissue were not evidently reduced in DS+AD vs DS. Instead we noted a pronounced overall reduction in noradrenergic and serotonergic compounds in DS+AD vs EOAD brains and to a lesser extent in DS vs non-DS control brains. CSF/plasma concentrations were hardly altered between diagnostic groups. Interestingly, DS and DS+AD presented a rather similar monoaminergic profile. This could, in part, relate to the early deposition of amyloid pathology. Trisomy 21 itself has been associated with reduced monoaminergic levels, which can be further impaired by accumulating Aβ pathology. Indeed, the DS brains (without a pathologic AD diagnosis) studied here already presented high amyloid burden, suggesting that the monoaminergic system might be affected long before full-blown AD-pathology is present.
Down syndrome mouse models
Hitherto, we investigated monoaminergic alterations in human samples (chapter 4 and 6): blood (serum/plasma), CSF and brain. Animals studies may strongly aid the study of underlying neurobiological mechanisms. But to do so, we first needed to establish whether monoaminergic alterations in animal models for DS reflect the deficits observed in the human condition. Ts65Dn, the most widely used mouse model for DS, is trisomic for approximately 50% of the genes homologous to the human chromosome 21, but also for 60 genes that are not homologous. The novel Dp1Tyb mouse model has been created to exclude the effect of these irrelevant triplicated genes. In Ts65Dn, Dp1Tyb and wild-type mice (littermates) we regionally dissected ten brain regions and compared their monoaminergic profiles (chapter 7). Comparing young adult Ts65Dn or Dp1Tyb mice with their euploid (not trisomic) littermates did not show generalized changes, suggesting that the additional genetic material in these mice barely exerted a monoaminergic effect. Subsequently, we investigated the impact of ageing in Ts65Dn mice. Comparing mice of 12-13 months with those aged 2.5-5.5 months yielded substantial changes in Ts65Dn, but also in wild-type littermates. Specifically, (nor)adrenergic compounds were impaired with ageing, while the serotonergic system was generally increased. Dopaminergic alterations were less consistent. In contrast to other studies, we did not find a generalized monoaminergic impairment in trisomic mice compared to wild-type littermates. Since these mouse models do not develop AD neuropathology either, their value in the study of monoaminergic impairment in DS+AD needs further examination.
Lipocalin-2
In addition to amyloid and tau pathology, neuroinflammation is involved in AD. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is one of the more recently identified inflammatory factors in AD. Previously, serum NGAL levels were found to correlate with age in DS and increase in adult and elderly persons with DS compared to non-DS controls. To evaluate whether NGAL concentrations related to the clinical status of dementia, we quantified NGAL in serum of elderly DS, DS+AD and converters, as well as in non-DS controls (chapter 8). Serum NGAL levels were significantly increased in DS vs non-DS, but were not associated with the dementia status. However, serum NGAL levels were significantly associated with distinct Aβ species in the groups. Resembling the absence of monoaminergic differences between DS and DS+AD, the early presence of Aβ pathology in DS may also explain the lack of altered serum NGAL levels. Since all individuals were aged over 45 years, full-blown AD neuropathology is likely present. The consistently increased pro-inflammatory NGAL levels across the diagnostic groups, and the correlation to Aβ species may suggest that serum NGAL reflects the progression of pathology rather than clinical symptoms.
Epigenetic editing
Until now we described the symptomatic/diagnostic side of the coin focusing on behavioural changes and the identification of possible (BPSD-associated) biomarkers. But what about the other side of the coin, i.e. preventing AD? In the general population, clinical trials aimed at stopping the disease, for instance by reducing Aβ plaques load, have
largely failed. In chapter 9 we provided a brand-new perspective related to a technique called epigenetic editing. Epigenetics is a booming field investigating the ‘regulation layer’ on top of the genetic code. Epigenetic marks such as DNA methylation of histone modifications regulate gene expression but do not alter the DNA itself. Epigenetics has been largely neglected in DS so far. Notwithstanding, existing literature points at epigenetic dysregulation, possibly explaining the large variation in the DS population despite their similar genetic background (trisomy 21). In chapter 9, we further hypothesize about the application of epigenetic editing, that is the targeting of epigenetic enzymes with desired properties (stimulating or repressing gene expression) to genes of interest using specific lab-engineered DNA binding domains. In DS, the third copy of the APP gene is the culprit that elicits a devastating cascade of events. Epigenetic editing has proven its value in cancer research, and it is about time to investigate its value in DS. Could specifically targeting APP and repressing its expression back to normal levels prevent or delay AD in DS? The answer remains to be elucidated, but it is a hopeful thought.
Figure 10.1: Schematic overview of the core studies conducted in this dissertation. The two core lines of inquiry
in this dissertation, i.e. BPSD and monoaminergic alterations, are depicted. The white numbers in black circles indicate the chapters describing the specific parts.
Taken together, Figure 10.1 schematically summarizes the main studies in this dissertation, consisting of two main research lines: BPSD and monoaminergic alterations. We have developed the novel BPSD-DS scale and validated it in currently the largest
behaviourally characterized DS cohort. The proportion of individuals presenting an increased frequency/severity of BPSD was highest in the demented group and lowest in the non-demented group. Specifically, DS+AD individuals presented pronounced increases in anxiety, sleep disturbances, agitation and stereotypical behaviour, aggression, apathy, depressive symptoms and eating/drinking behaviour. Furthermore, monoaminergic impairment associated with BPSD was investigated in blood, CSF and post-mortem brain samples. Although the potential diagnostic value of serum MHPG in relation to the clinical status of dementia could not be confirmed in plasma/CSF, an overall monoaminergic deficit (especially impairment of the noradrenergic system) became apparent in brain tissue of DS/DS+AD compared to early-onset AD patients and healthy controls in the general population.
General discussion &
future implications
Whereas specific results are discussed and contextualized in each respective chapter, this section provides a bird’s-eye view on the research conducted in this dissertation, putting it into a general perspective, and importantly, highlighting future implications.
BPSD-DS scale
Given the heterogeneity of dementia symptoms, including cognitive, functional and behavioural changes, it has been recognized that a broad range of assessments is needed to capture these changes in DS (Lautarescu et al., 2017). In most studies, cognitive and functional decline has been the primary focus, and a comprehensive tool to evaluate BPSD in DS was lacking. Consequently, we decided to develop a behavioural evaluation scale adapted for DS. BPSD are associated with a reduced quality of life and increased suffering for the person as well as increased caregiver burden, causing it to be a major concern in daily care. Since the start of the BPSD-DS study, we noted high consent rates. Informants were very willing to participate and regularly drove large distances to attend the interviews. This enabled us to complete a total of 281 assessments, currently one of the largest well-characterized DS cohorts in the world. Individuals with, among others, different ID severities, living situations and co-morbidities were included, causing the cohort to be representative of the contemporary situation in DS care. Therefore, we may assume that the results described in chapter 3 are generalizable to the larger DS population.
Identification of frequency and severity changes in DS, DS+Q and DS+AD demonstrated pronounced differences between groups for anxiety, sleep disturbances, agitation and stereotypical behaviour, aggression, apathy, depressive symptoms and eating/drinking (chapter 3). The DS+AD group consistently presented the highest proportion of individuals with an increased frequency/severity. In a substantial proportion
of those with questionable dementia increases in anxiety, sleep disturbances, apathy and depressive symptoms were noted, suggesting that these symptoms change early and may serve as ‘alarm signals’ for those at risk. Whereas a dementia diagnosis cannot be established purely on behavioural assessment (McKhann et al., 2011), evaluation of BPSD can strongly aid the diagnostic process. Based on the sum of frequency change scores, we identified two off scores for the discrimination of the groups. Frequency change cut-off scores ≥11 (DS vs DS+Q/DS+AD) and ≥18 (DS/DS+Q vs DS+AD) most optimally discriminated between groups with a sensitivity and specificity over 80%. As such, the BPSD-DS may serve as a useful tool to aid clinicians in their diagnostic work-up.
On the individual level, the BPSD-DS scale identifies personal frequency and severity changes. Various caregivers provided feedback, stating that the interview had been useful for them. Behavioural symptoms that change little by little over a longer period of time may be unnoticed on a daily basis. The scale forces informants to take some distance, go back in time and semi-quantifiably score life-long typical behaviour and behaviour over the last six months to identify alterations. BPSD-DS outcomes are of added value to the medical file or client dossier. In the context of (possible) dementia, combined information on cognitive, functional and behavioural changes is important to identify someone’s personal needs. Although we did not explore this, documented information on behavioural alterations might be valuable in substantiating the required level of support/care, including governmental financial support (Dutch: Indicatiestelling Wet Langdurige Zorg, Centrum indicatiestelling zorg (CIZ), 2016). Importantly, a comprehensive assessment of BPSD (frequency, severity and caregiver burden) enables stakeholders to develop a management plan, which – indispensably – has a multidisciplinary nature.
Management options for BPSD are numerous and may be both pharmacological and non-pharmacological (Gauthier et al., 2010). Non-pharmacological approaches, also including caregiver training and environmental management – particularly important as most DS individuals live in group homes or attend day-care – are generally first in line. If needed, non-pharmacological therapies are followed by, or go together with, the prescription of psychoactive medication (Keller et al., 2016; Seitz et al., 2012). A wide variety of (personally tailored) management strategies and treatment options is available, but it is not within the scope of this dissertation to discuss best practices herein. Whether evidence-based or not, one could argue that any therapy increasing quality of life and reducing suffering for the individual may serve useful from the individual perspective.
The behavioural results found on group level may aid caregivers in recognizing and understanding (possibly early) changes related to dementia. Caregivers are often not familiar with the typical manifestation of decline, which may erroneously cause changes to be attributed to ID instead of dementia (Janicki and Keller, 2015). Indeed, Iacono et al. (2014) reported that most care staff had limited understanding of AD in DS and often responded ad hoc or adopted a trial-and-error approach based on knowledge of, and experience with the disability rather than dementia. For instance, caregivers sometimes misinterpret apathetic symptoms as laziness or opposition (Deb et al., 2007; Landes et al., 2005). Awareness that the occurrence of apathy is generally increased in DS+AD may prevent symptoms being perceived as laziness. Consequently, the approach towards the
person may change: rather than making someone participate in (group) activities, e.g. at a day-care center or in a group home, a less demanding approach is likely adopted.
BPSD are a key reason for referral to specialists (Lawlor, 2002). Among referrals to Dutch ID outpatient clinics, 51% has been referred because of behavioural and psychiatric problems (Ewals and Huisman, 2016). In the BPSD-DS scale, caregiver burden was scored and found to increase from DS to DS+Q to DS+AD (chapter 3). Therefore, monitoring signs of caregiver burden is not trivial. Early consideration enables timely counselling or referral to community-based services, reducing the risk of caregivers suffering from overstrain or burnout (Keller et al., 2016). Education and training is essential in this respect. Anticipatory guidance about changes that may lie ahead has been recommended, enabling caregivers to prepare for upcoming challenges in daily care (Keller et al., 2016). Moreover, being aware of potential behavioural changes can contribute to (earlier) recognition of symptoms. Whereas specialized training about advanced dementia in people with ID has been recommended (McCallion et al., 2017), also less formal forms of education are useful. A great example is the Dementia Table (Dementietafel) initiative in The Netherlands (Overbeek and Thoolen, 2016; Werkgroep Dementietafel Groningen, 2017). Dementia Tables are special evenings for familial and professional caregivers about ageing and dementia in people with ID. In addition to expert presentations on different aspects of the disease, these evenings provide a platform for sharing experiences. This is perceived as very helpful: caregivers realize and feel they are not the only one encountering difficulties.
Importantly, adults with DS often live with their parents or siblings, who, due to their often old(er) age, may no longer be capable of intensifying care when the situation demands this. Consequently, a crisis situation may arise. Ambulatory care may provide relief, but continuous care is likely needed with progression of the disease (Keller et al., 2016). It is unlikely, however, that the necessary level of care can be offered at home. BPSD often lead to institutionalisation (Finkel, 2000; O’Donnell et al., 1992). Otherwise, a large proportion of DS individuals lives in group homes or assisted living facilities. People either age in their homes (the level of care being adapted to the situation as far as possible) or move to specifically adapted homes depending on the required level of care (Keller et al., 2016). If living with relatives or in a group home becomes increasingly difficult for the individual, but also for the environment, when is the ‘right’ moment to decide about moving to a dementia-friendly home? A complicated issue for all stakeholders involved. Systematic evaluation of BPSD using the novel scale will clearly demonstrate increasing frequencies, severities and caregiver burden, which may objectively aid the decision process. Further validation is still required in this regard.
To facilitate the implementation of the BPSD-DS scale in daily care, the scale will be optimized based on the results and experiences so far. Certain items were less relevant than others. Delusions and hallucinations, for example, were barely altered between groups, suggesting that the actual twelve items on delusions and hallucinations could be reduced in number. Furthermore, a digital application (for tablet and/or computer) of the scale would save a lot of paper work, automatically signal missing items and calculate scores, and yield an overall report of changes by just pressing the button. A digital version could be coupled to a research database. With consent, anonymized data could be
included in such a database, aiding further (validation) studies. As described in chapter 2 and 3, longitudinal approaches are needed to establish the evolution of BPSD over time, ideally from baseline to an MCI-like state to the different stages of AD (Esbensen et al., 2017). Whereas the current cross-sectional study compared typical behaviour with behaviour in the last six months, a follow-up study would compare the last six months with the last six months in the previous assessment. Regardless of the location, a digital application could easily retrieve previous scores and compare these to current results.
Monoaminergic impairment
In addition to the study of behavioural changes, we also examined alterations in monoaminergic neurotransmission associated with BPSD. Monoaminergic alterations in AD are extensively summarized in two excellent reviews by Simic et al. (2017) and Trillo et al. (2013). Figure 10.1 depicts the consecutive steps we took in characterizing the monoaminergic profile in DS and DS+AD samples. First, we analysed serum samples (chapter 4). A remarkable decrease in MHPG concentrations was found in demented and converted DS individuals compared to their non-demented counterparts. To confirm the potential of decreased serum MHPG levels as a biomarker for AD in DS, new analyses in other cohorts were needed. Subsequently, we went a step closer to the brain: CSF (chapter 6). In these unique samples, enriched with plasma samples, we were not able to confirm the potential of MHPG. Simultaneously, we collected post-mortem brain samples to investigate monoaminergic alterations at the source (chapter 6), but we could not confirm the MHPG findings either. Notwithstanding, another pattern became evident in brain samples: noradrenergic and serotonergic impairment in DS (vs non-DS controls) and DS+AD (vs EOAD). Indeed, in serum we had already observed decreased levels of NA, MHPG and 5-HT in DS vs non-DS controls.
While both DS vs DS+AD groups thus showed a fairly similar monoaminergic profile, an overall impairment was observed in DS/DS+AD compared to the general population (chapter 6). The analysed samples were obtained from elderly DS individuals who likely present omnipresent AD pathology, also the ones that were clinically not diagnosed with dementia (high Aβ load). This may explain the absence of evident differences between the DS groups. In the absence of AD pathology, studies on foetal material (Whittle et al., 2007) found monoaminergic changes related to the trisomy 21 itself. We, therefore, hypothesize that monoamine neurotransmitters are affected by trisomy 21 from the start, while further impairment presents later in life due to (early) accumulation of Aβ pathology. Whether Aβ pathology indeed causes (early) alterations in monoaminergic neurotransmission remains to be elucidated.
Well-characterized samples (mainly CSF and post-mortem brain tissue) from DS individuals are extremely scarce, especially for younger cases (further discussed in the next section), making it fairly impossible to study (early) monoaminergic changes in relation to Aβ accumulation. Collecting samples from young to older DS individuals (wide age range, thus with progressive neuropathology) is vital for further studies. Good clinical documentation is essential: (longitudinal) sampling would ideally coincide with the administration of the BPSD-DS scale to link behavioural changes to monoaminergic alterations, resembling the attempts in chapter 4 and studies in the general population
(Vermeiren et al., 2016, 2014, 2013). Furthermore, in vivo imaging of monoamines offers a promising future avenue. PET tracers for monoaminergic receptors, transporters and enzymes (e.g. monoamine oxidase) have been used in multiple brain studies, summarized in Jones et al. (2012). For instance, neuroimaging of NA transporters in the locus coeruleus and projection areas using [11C]methylreboxetine (Pietrzak et al., 2013) in DS individuals at
different ages may provide insights into the progression of noradrenergic impairment. Combining such studies with imaging of AD pathology would be invaluable. In recent years, studies have shown the feasibility of performing amyloid PET studies in DS using [11C]Pittsburgh compound B (Annus et al., 2016; Lao et al., 2016), [18F]florbetaben (Jennings et al., 2015) and [18F]florbetapir (Matthews et al., 2016; Rafii et al., 2015;
Sabbagh et al., 2015).
In addition, we examined the monoaminergic profiles in ten brain regions of Ts65Dn and Dp1Tyb mice to establish whether these DS mouse models demonstrate similar impairments as the human condition (chapter 7). Remarkably, the effect of aneuploidy was limited, while pronounced monoaminergic changes were found with ageing. The latter, however, was seen in both Ts65Dn and wild-type mice, thus questioning the validity and utility of the model in studying monoaminergic deficits. A main limitation is the absence of extensive AD pathology in DS mouse models (Wiseman et al., 2015). Consequently, development of new animal models integrating DS and AD phenotypes, thus combining neurodevelopmental and neurodegenerative deficits, would be very worthwhile. Such DS+AD models would offer new possibilities to study monoaminergic alterations in relation to the complex interplay between overexpressed chromosome 21 genes and AD pathology.
Shortcomings and related opportunities in DS+AD research
Studying the forced marriage of trisomy 21 with the genetically-induced accumulation of AD pathology has been pioneering work until now. Among dementia researchers and funding agencies an apparent lack of interest for DS has been noticeable, while DS researchers mainly focused on paediatrics and genetics in the last decades. However, DS+AD receives more attention in recent years, demonstrated by an increasing number of publications and the establishment of international working groups such as the Professional Interest Area (PIA) on Down Syndrome and Alzheimer’s Disease by the American Alzheimer’s Association, the Trisomy 21 Research Society (T21RS) (Delabar et al., 2016), and the Down Syndrome and Other Genetic Developmental Disorders Network of the European College of Neuropsychopharmacology (ECNP). Despite these efforts, DS+AD research is truly lagging behind dementia research in the general population. The path to discoveries lies open as many (basic) questions on DS+AD have not been answered yet. This dissertation highlighted that BPSD (chapter 2 and 3), CSF studies (chapter 5 and 6) and epigenetics (chapter 9) have been largely neglected in DS+AD.
An important aspect underlying the underrepresentation of people with DS, or ID in general, in (bio)medical (dementia) research relates to ethics. The prevalent idea that people with ID are vulnerable and require protection may result in being too restrictive when it comes down to research participation. McDonald and Keys (2008) describe the tension between self-determination for people with ID on the one hand, and the
necessary level of protection on the other hand. They report that researchers and members of institutional review boards are the “key decision-makers” deciding about research participation, thus possibly limiting self-determination of potential participants (McDonald and Keys, 2008). It is a thin line between protection and discrimination, i.e. restricting access to research. In chapter 5 we have argued that “rather than deciding for DS individuals and their caregivers and relatives beforehand, researchers and clinicians could apply a ‘you never know, until you ask’ approach”. On the provision that crystal clear information is provided and the research setting is optimized to ID, our experience is that people are very willing to participate. Colleagues from the University of Cambridge addressed ethical and methodological challenges in the context of amyloid PET imaging, emphasizing, among others, the need to adapt and optimize procedures as much as possible, i.e. tailor them to people with DS and their caregivers (d’Abrera et al., 2013). This does not only apply to neuroimaging studies, but to DS research in general. An extensive description on ethics guidelines for multicenter ID studies, including study design and consent, is provided in Dalton and McVilly (2004).
In recent years, our close collaborators in Barcelona showed that (relatively invasive) CSF sampling and PET imaging were feasible and safe in DS, and substantial consent rates were achieved (Carmona-Iragui et al., 2017, 2016; Fortea et al., 2016). Their pragmatic approach is a beautiful example of integrating care and research. Combining forces, the Catalan Down Syndrome Foundation and the Sant Pau hospital now jointly offer an integrated health plan for DS individuals, also giving them the possibility to participate in clinical research (Blesa et al., 2015). In contrast, DS studies including CSF sampling or PET imaging are barely performed in The Netherlands. Importantly, the aim is not to have lumbar punctures or PET scans from every person. Our concern, however, is that we, as a research community, may – by overprotecting – deny people with DS the possibility to participate in (bio)medical research. “No research about them, without them” is a motto frequently heard at symposia. Consequently, that means asking people and their caregivers whether they want to participate, rather than deciding for them.
In The Netherlands, the first country to have ID medicine as a medical specialty (since 2000), the number of (multidisciplinary) outpatient clinics for people with ID has increased strongly in the last two decades (Ewals and Huisman, 2016). For DS, regional Down18+ outpatient clinics have been established as well. However, scientific research related to these clinics is limited: approximately 15% of the ID physicians participate in studies or development of guidelines (Ewals and Huisman, 2016). Moreover, many outpatient clinics are part of ID care organizations, thus not being connected to an (academic) hospital. For instance, blood samples obtained for standard laboratory tests are often discarded after use, while they would be a valuable source for future (biomarker) studies. Stimulating the integration of clinical care and scientific research, the basic principle of academic hospitals, would enlarge possibilities.
Indeed, establishing repositories with clinically well-characterized biological samples is of utmost importance. Large scale standardized biobanking initiatives are common in the general population – such as the Dutch Parelsnoer Institute (Aalten et al., 2014) – but have not included DS material, unfortunately. Worldwide large collections of samples and neuroimaging data are available from AD patients in the general population
and efforts are undertaken to standardize sampling and classification procedures (Blennow et al., 2015; Montine et al., 2012; O’Bryant et al., 2015). In contrast, DS+AD research is still a developing field with only limited access to well-documented samples. Metaphorically speaking, the field of AD research is a high-speed train going increasingly faster, whereas the field of DS+AD research is still a slow train regularly stopping for longer periods of time because part of the infrastructure needs to be constructed first.
In chapter 6, for example, we tried to establish a large collection of post-mortem DS brain samples for monoaminergic characterization. In major European brain banks, foetal tissue (abortion material) was broadly available, while DS+AD samples were scarce and DS tissues without AD pathology (younger DS cases) were virtually absent. While dementia and other neurodegenerative disorders are a key priority of biobanks, DS+AD samples are (still) not actively recruited. In the absence of recently acquired post-mortem material, we obtained samples included in tissue repositories over the last 25 years. Over this period of time, procedures have evolved, causing samples to be differently classified. Therefore, we re-assessed all DS brains (chapter 6) according to the latest, revised National Institute on Ageing-Alzheimer’s Association consensus guidelines, also known as the ‘ABC scoring’ system (Montine et al., 2012). Although the need for standardized repositories for DS(+AD) samples is recognized (Hartley et al., 2015), such initiatives are still in its infancy.
Moreover, the (clinical) characterization of samples differed from site to site. In the general population validated measures like the Mini-Mental State Examination (Folstein et al., 1975) and Neuropsychiatric Inventory (Cummings et al., 1994) are broadly applied throughout the world. In contrast, there is no consensus on diagnostic procedures for dementia in people with DS or ID in general (Elliott-King et al., 2016; Keller et al., 2016), causing substantial variation in clinical documentation of samples. In Europe, for instance, virtually every center applies different procedures. That is why the main DS+AD research centers meet a few times per year to discuss standardization efforts related to clinical research initiatives. However, opinions differ and various tools are not available in local languages, making this a long-winded work. Caution is required with respect to the pitfalls of overregulation. Instead of overloading people with large series of changes, a step-by-step approach is most feasible, such as jointly implementing a (novel) method, like we have done in the development and validation of the BPSD-DS scale.
Broad support from people on the shop floor (clinicians and caregivers) is of utmost importance for success. Within the BPSD-DS study, we experienced the success of a bottom-up approach. Instead of an executive board deciding on contribution to the study (top-down), we contacted clinicians and ‘orthopedagogen’ directly (bottom-up). If they were positive and willing to participate, they subsequently convinced their own executive board of the importance of the project. Consequently, the study was broadly supported and people were truly motivated to contribute and think along. Introducing this typically Dutch ‘polder model’ to (European) standardization efforts may facilitate implementation, while top-down decisions from experts maneuvering themselves in key decision-making positions may hamper progress.
Recommendations for future studies – a summary
Based on the results, strengths and limitations reported in this dissertation, we identified a number of core recommendations for future initiatives. In summary, this concerns:
• Optimization and development of a digital application of the BPSD-DS scale. • Implementation of the BPSD-DS scale in daily care.
• Longitudinal study of BPSD in DS, establishing the temporal (individual) evolution of behavioural changes over time. Staging of AD severity would be worthwhile in this context.
• Standardized (multicenter) biobanking of blood, CSF and brain tissue samples from clinically well-characterized individuals.
• Establishing the link between monoaminergic alterations and behavioural changes by correlating of monoaminergic concentrations with outcomes of the BPSD-DS scale.
• PET imaging of monoaminergic neurotransmission in relation to AD neuropathology in DS.
• Development of animal models that model both trisomy 21 and AD neuropathology.
• An epigenetic proof-of-principle study using epigenetic editing (repression) of the
APP gene in cultured neurons derived from induced pluripotent stem cells of
adult DS individuals (e.g. Shi et al., 2012).
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Epilogue
‘Due to new prenatal testing, the prevalence of DS will decrease strongly, so why do you study AD in DS anyway?’ This question, which we got on a few occasions, refers to stories in the press suggesting that non-invasive prenatal testing (NIPT), a recent screening method for trisomies based on DNA methylation (introduced in chapter 9), causes the screening out of DS from society. Although the clinical, social and ethical implications of NIPT are not within the reach of this dissertation (e.g. reviewed in: Griffin et al., 2017), they may affect public opinion towards DS research.
Although any change in the number of babies born with DS will not affect dementia research until four or five decades, it is very questionable whether DS will ‘disappear’ from society anyway. Besides mothers who choose not to have prenatal testing, mounting evidence suggests that NIPT is not necessarily the precursor of abortion. Many women use the test as source of information about their baby’s health, and a UK study showed that 31% of the women with a positive NIPT continued their pregnancy (Chitty et al., 2016; Griffin et al., 2017). Very recently, a spokesperson of the Dutch Society of Gynaecology stated in De Volkskrant, a Dutch national newspaper, that “the percentage of women that wishes screening does not appear to increase strongly [after the introduction of NIPT in The Netherlands]. Moreover, there does not seem to be an increase in the number of terminations” (Huisman and Walsum, 2017). Indeed, due to a plethora of reasons, there will always be parents that welcome a child with DS.
Regardless of prevalence, people with DS, like any other individual in society, deserve high quality clinical and scientific research aimed at understanding and possibly counteracting a disease they (may) suffer from, such as dementia. Therefore, DS+AD research was, is and remains an important and relevant field of study. In addition, studying the underlying mechanisms of AD in DS does not only benefit the DS population, but may also provide insights and understanding of the disease process in the general population (Wiseman et al., 2015).
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