Dementia In Down Syndrome Research Articles

Increased levels of plasma total tau in adult Down syndrome.

Down syndrome (DS) is the most prevalent chromosomal abnormality. Early-onset dementia with the pathology of Alzheimer’s disease (AD) frequently develops in DS. Reliable blood biomarkers are needed to support the diagnosis for dementia in DS, since positron emission tomography or cerebrospinal fluid sampling is burdensome, particularly for patients with DS. Plasma t-tau is one of the established biomarkers for the diagnosis of AD, suggesting the potential value of t-tau as a biomarker for dementia in DS. The aim of this study was to assess and compare plasma levels of t-tau in adults with DS and in an age-matched control population. In this study, plasma levels of t-tau in 21 patients with DS and 22 control participants were measured by an ultrasensitive immunoassay technology, the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma t-tau levels in the DS group (mean ± standard deviation (SD) = 0.643±0.493) compared to those in the control group (mean ± SD = 0.470±0.232): P = 0.0050. Moreover, age dependent correlation of plasma t-tau was only found in the DS group, and not in the control group. These findings suggest that elevated plasma t-tau levels reflect AD pathology and therefore have potential as an objective biomarker to detect dementia in adult DS.

86 - Oxidative Stress and mTOR Activation in Down Syndrome Brain: Roles in Aβ42 and Tau Neuropathology and Transition to Alzheimer Disease-Like Dementia

Down syndrome (DS), the most frequent chromosomal abnormality in humans, results from complete or partial trisomy of chromosome 21 (Chr21). Though there is intellectual disability in DS people from birth, at about 40-50 years of age conversion to Alzheimer disease (AD)-like neuropathology and dementia often occurs. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation and insulin signaling, among other functions, is implicated in several diseases, including AD. Numerous studies, many from our laboratory, linked activation of the mTOR pathway by, among other means, oxidative stress-associated Aβ42 to age-dependent pathology of AD and AD-like dementia in DS. Several Chr21 gene products are associated with oxidative stress, among which is amyloid precursor protein, the source of Aβ42. Specific genes involved in the formation of AD-related senile plaques (composed mostly of fibrillar Aβ), and neurofibrillary tangles (NFT, composed mostly of hyperphosphorylated tau protein), two main pathological hallmarks of AD, are mapped on Chr21. This presentation highlights our recent research on DS brain using oxidative stress and redox proteomics methods showing activation of mTOR signaling contributes to generation of neurotoxic and oxidative stress-associated Aβ-oligomers (and senile plaques) and the formation of NFT. Thus, a vicious cycle between oxidative stress-related, Aβ-associated mTOR activation and mTOR activation-mediated AD-like pathology and dementia in conversion of DS to DS with AD is present. Identification of potential new therapeutic targets associated with the mTOR pathway to modulate this conversion in DS to DS with AD and new insights into AD itself resulted from our studies and will be shown.

Clinical aspects and biomarkers of Alzheimer's disease in Down syndrome.

Alzheimer's disease (AD) may affect in excess of 90% of individuals with Down syndrome (DS) after age 60, due to duplication of the APP gene in trisomy of chromosome 21, with neuropathology that is comparable to Sporadic AD and Familial AD (FAD). Previous literature suggested some unique features in clinical presentation of dementia in DS (DSd), which might be due to diagnostic difficulties, or represent a real difference compared to SAD or FAD. We review current knowledge on clinical diagnosis and presentation of dementia in DS in comparison with FAD due to APP mutations and APP duplication. We suggest that the clinical presentation in DS (prominent memory decline and behavioral symptoms, and early development of myoclonus and seizures) are similar to the clinical features associated with APP mutations that is known to have an increased Aβ42/ Aβ40 ratio, and highlight the relative lack of vascular complications associated with cerebral amyloid angiopathy in DS in comparison with those rare individuals with FAD due to duplication APP. We consider the biomarker evidence associated with DS and DSd with reference to Aβ peptide levels and oxidative stress, and suggest future directions for research to explore the potential mechanisms associated with the clinical presentation of DSd.

MTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia.

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Aβ generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Aβ and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS.

An evidenced based checklist to support anti-dementia medication withdrawal in people with down syndrome (DS), intellectual disability (Id) and dementia

DS with aging is associated with greatly increased risk of developing dementia similar to Alzheimer's. Anti-dementia drug discontinuation is recommended when clinical benefit is not determined. In DS it is more complex as medication ill effects of stopping needs to be weighed in balance to extraneous processes such as environment changes, sensory impediments and physical ill health and natural progression of dementia.AimCan identified risk factors extracted from a comprehensive literature review be developed into an evidence based check list to support risk minimized person centered withdrawal of anti-dementia drugs when considered not to be efficacious in DS?MethodA detailed literature review using Medline, PsychInfo, Cinahl and Embase with relevant search terms in various permutations and combinations without any date limit enquiring current evidence base on anti-dementia medication withdrawal was conducted. The review also looked to extract the common risk factors in stopping medication. All risk factors were collated, reviewed by a focus group of experts, developed into a checklist.ResultsThirty abstracts were obtained following the search. Six papers were short-listed. No papers identified a structured approach to medication reduction. An 18-factor checklist was applied prospectively to 30 cases. The checklist was sensitive to identify change to guide clinical decision-making.ConclusionsCurrently, decision to peg medication withdrawal risk is arbitrary and clinical in dementia especially in DS dementia. The evidenced based developed checklist is useful to support and structure clinical decisions. It helps clinicians and patients to focus on promoting safety, reduce harm and guide treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Down syndrome: age-dependence of PiB binding in postmortem frontal cortex across the lifespan

Beta-amyloid (Aβ) deposition in brain accumulates as a function of age in people with Down syndrome (DS) with subsequent development into Alzheimer disease neuropathology, typically by 40 years of age. In vivo imaging using the Pittsburgh compound B (PiB) ligand has facilitated studies linking Aβ, cognition, and dementia in DS. However, there are no studies of PiB binding across the lifespan in DS. The current study describes in vitro 3H-PiB binding in the frontal cortex of autopsy cases with DS compared to non-DS controls. Tissue from 64 cases included controls (n = 25) and DS (n = 39). In DS, 3H-PiB binding was significantly associated with age. After age 40 years in DS, 3H-PiB binding rose dramatically along with increasing individual variability. 3H-PiB binding correlated with the amount of Aβ42. Using fixed frontal tissue and fluorescent 6-CN-PiB, neuritic and cored plaques along with extensive cerebral amyloid angiopathy showed 6-CN-PiB binding. These results suggest that cortical PiB binding as shown by positron emission tomography imaging reflects plaques and cerebral amyloid angiopathy in DS brain.

Cognitive decline and dementia in Down syndrome.

Alzheimer's disease is most likely universal in older individuals with Down syndrome, due to having three copies of the amyloid precursor protein gene, resulting in amyloid-beta plaque deposition. Down syndrome is an important population in which to consider clinical trials of treatments to prevent or delay the development of dementia. However, assessment of subtler cognitive changes is challenging due to the presence of intellectual disability. Recent research confirmed that older adults with Down syndrome often present with cognitive decline: more than 80% may experience dementia by age 65 years. Efforts have been made to improve and validate neuropsychological assessment and to describe the relationship with comorbidities such as epilepsy and haemorrhagic stroke. There have also been advances in biomarkers such as neuroimaging using amyloid PET. Clinical trials of treatments, particularly in the presymptomatic phase of Alzheimer's disease, are important to consider in individuals with Down syndrome given their high dementia burden, and may also serve as proof of concept for other forms of Alzheimer's disease. However, further work is required to improve outcome measures and better understand the biomarkers of progression of disorder and their relationship with symptom development during the presymptomatic period.

P.5.b.003 - Behavioural and psychological symptoms of dementia in Down syndrome: European development of the novel BPSD-DS evaluation scale

P.5.b.003 - Behavioural and psychological symptoms of dementia in Down syndrome: European development of the novel BPSD-DS evaluation scale

Are Gait Stereotypies a Marker for Neurodegeneration in Down Syndrome? A Prospective Observation.

Down syndrome (DS) is the most common genetic cause of intellectual disability. Besides systemic involvement, patients with DS may present with a wide range of neurological manifestations, which include dementia resembling Alzheimer’s disease, seizures, vascular disease and stroke, psychiatric comorbidities, and movement disorders.1–3 Abnormal movements in DS are diverse, and the clinical relevance of these neurological manifestations is misunderstood.4 In this article, we report a patient with DS that presented with movement disorders characterized by gait stereotypies as the first neurological manifestation, evolving to a severe neurodegenerative process and dementia in the following 3 years. We try to demonstrate on the basis of a single report that early movement disorders, particularly stereotypies and gait abnormalities, may predict neurodegeneration and dementia in DS.

The challenges of diagnosis and treatment of dementia in Down's syndrome.

People with Down syndrome (DS) are at high risk for developing dementia and early diagnosis is vital in enhancing quality of life. Our aim was to compare our practice to consensus recommendations on evaluation, diagnosis and pharmacological treatment of individuals with DS who develop dementia. We also aimed to establish the average time taken to make a diagnosis of dementia and to commence pharmacotherapy, and to assess tolerability to acetylcholinesterase inhibitors. Retrospective chart review in an exhaustive sample containing all current service users attending our service with DS and a diagnosis of dementia (n=20). The sample was 75% female and 70% had a moderate intellectual disability. The average age at diagnosis of dementia was 52.42 years old. The average time to diagnosis from first symptom was 1.13 years and the average time to commence pharmacotherapy was 0.23 years. A total of 17 patients commenced on acetylcholinesterase inhibitors, and of these seven discontinued medication due to side-effects or lack of efficacy. The results on anticholinesterases add to the limited pool of data on treatment of dementia in DS. There was an identified need to improve the rates of medical, vision and hearing assessments, and prospective screening. Deficiencies in screening and diagnosis may be addressed by implementing a standardised dementia assessment pathway to include prospective screening and longitudinal assessment using easily administered scales. We highlight the importance of improving the diagnostic process, as a vital window of opportunity to commence a comprehensive care plan may be lost.

Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP.

People with Down syndrome (DS) virtually all develop intellectual disability (ID) of varying degree of severity, and also have a high risk of early Alzheimer's disease (AD). ID prior to the onset of dementia, and its relationship to the onset of dementia in DS is a complex phenomenon influenced by many factors, and scarcely understood. Unraveling the causative factors and modulators of these processes remains a challenge, with potential to be informative for both ID and AD, for the development of early biomarkers and/or therapeutic approaches. We review the potential relative and inter-connected roles of the chromosome 21 gene for amyloid precursor protein (APP), in both pathological conditions. Rare non-DS people with duplication of APP (dupAPP) get familial early onset AD (FEOAD) with virtually 100% penetrance and prominent cerebrovascular pathology, but don't suffer from ID before dementia onset. All of these features appear to be radically different in DS. On the other hand, rare individuals with partial trisomy 21 (T21) (with APP, but not DS-critical region in trisomy) have been described having ID. Likewise, partial T21 DS (without APP trisomy) show a range of ID, but no AD pathology. We review the multi-faceted roles of APP that might affect cognitive functioning. Given the fact that both Aβ secretion and synaptic maturation/plasticity are dependent on neuronal activity, we explore how this conflicting inter-dependency might affect cognitive pathogenesis in a dynamic way in DS, throughout the lifespan of an individual.

Rapid assessment of cognitive function in down syndrome across intellectual level and dementia status.

Adults with Down syndrome (DS) are at risk of developing dementia and cognitive assessment is a fundamental part of the diagnostic process. Previously, we developed a Rapid Assessment for Developmental Disabilities (RADD), a brief, broadly focused direct test of cognition. In the current report, we assess whether the RADD is sensitive to dementia in DS and the degree to which it compares with other cognitive measures of dementia in this population. In a sample of 114 individuals with DS, with dementia diagnosed in 62%, the RADD was compared with the Dementia Questionnaire for Mentally Retarded Persons (DMR), the Bristol Activities of Daily Living Scale, Severe Impairment Battery (SIB), and the Brief Praxis Test (BPT). The RADD showed predicted effects across intellectual disability (ID) levels and dementia status (p < 0.001). Six-month test-retest reliability for the subset of individuals without dementia was high (r(41) = 0.95, p < 0.001). Criterion-referenced validity was demonstrated by correlations between RADD scores and ID levels based upon prior intelligence testing and clinical diagnoses (rs (114) = 0.67, p = 0.001) and with other measures of cognitive skills, such as the BPT, SIB, and DMR-Sum of Cognitive scores (range 0.84 through 0.92). Using receiver operating characteristic curves for groups varying in pre-morbid severity of ID, the RADD exhibited high sensitivity (0.87) and specificity (0.81) in discriminating among individuals with and without dementia, although sensitivity was somewhat lower (0.73) for the subsample of dementia cases diagnosed no more than 2 years prior to their RADD assessment. Taken together, findings indicated that the RADD, a relatively brief, easy-to-administer test for cognitive function assessment across ID levels and dementia status, would be a useful component of cognitive assessments for adults with DS, including assessments explicitly focused on dementia.

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

The majority of people with Down syndrome (DS) develop dementia due to Alzheimer's 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. 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. 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. 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. 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.

Dementia diagnostic criteria in Down syndrome.

Dementia is a common clinical presentation among older adults with Down syndrome. The presentation of dementia in Down syndrome differs compared with typical Alzheimer's disease. The performance of manualised dementia criteria in the International Classification of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) is uncertain in this population.We aimed to determine the concurrent validity and reliability of clinicians' diagnoses of dementia against ICD-10 and DSM-IV-TR diagnoses. Validity of clinical diagnoses were also explored by establishing the stability of diagnoses over time. We used clinical data from memory assessments of 85 people with Down syndrome, of whom 64 (75.3%) had a diagnosis of dementia. The cases of dementia were presented to expert raters who rated the case as dementia or no dementia using ICD-10 and DSM-IV-TR criteria and their own clinical judgement. We found that clinician's judgement corresponded best with clinically diagnosed cases of dementia, identifying 84.4% cases of clinically diagnosed dementia at the time of diagnosis. ICD-10 criteria identified 70.3% cases, and DSM-IV-TR criteria identified 56.3% cases at the time of clinically diagnosed dementia. Over time, the proportion of cases meeting ICD-10 or DSM-IV-TR diagnoses increased, suggesting that experienced clinicians used their clinical knowledge of dementia presentation in Down syndrome to diagnose the disorder at an earlier stage than would have been possible had they relied on the classic description contained in the diagnostic systems. Clinical diagnosis of dementia in Down syndrome is valid and reliable and can be used as the standard against which new criteria such as the DSM-5 are measured.

Upregulation of SET expression by BACE1 and its implications in Down syndrome.

Down syndrome (DS) is one of the most common genetic diseases. Patients with DS display growth delay and intellectual disabilities and develop Alzheimer's disease (AD) neuropathology after middle age, including neuritic plaques and neurofibrillary tangles. Beta-site amyloid β precursor protein (APP) cleaving enzyme 1 (BACE1), essential for Aβ production and neuritic plaque formation, is elevated in DS patients. However, its homolog, β-site APP cleaving enzyme 2 (BACE2), functions as θ-secretase and plays a differential role in plaque formation. In this study, by using Two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (2D SDS-PAGE) and LC-MS/MS proteomic profiling analysis, we found that the SET oncogene protein (SET) expression was associated with BACE1 but not BACE2. SET protein was increased in BACE1 overexpressing cells and was markedly reduced in the BACE1 knockout mice. We found that the overexpression of BACE1 or SET significantly inhibited cell proliferation. Moreover, knockdown of SET in BACE1 overexpression cells significantly rescued BACE1-induced cell growth suppression. Furthermore, both BACE1 and SET protein levels were increased in Down syndrome patients. It suggests that BACE1 overexpression-induced SET upregulation may contribute to growth delay and cognitive impairment in DS patients. Our work provides a new insight that BACE1 overexpression not only promotes neuritic plaque formation but may also potentiate neurodegeneration mediated by SET elevation in Alzheimer-associated dementia in DS.

Dementia in intellectual disability

Dementia is emerging as a significant condition in the population with intellectual disability. This review is aimed at clinicians working in the field. We revisit what is known on the subject and expand on this with results from recent research. The emphasis of this review is on the clinical research rather than laboratory or molecular research. Research has encompassed all aspects of dementia in intellectual disability, from epidemiology, assessment and diagnosis, through to management. There remains a lack of evidence concerning both pharmacological and nonpharmacological treatment of dementia in people with intellectual disability. Recent research has tended to focus on dementia in Down syndrome. More research is necessary in order to translate improvements in the understanding of the neuropathology of intellectual disability and dementia into effective treatments. There is also a need to investigate the optimum environment in which to provide holistic care for individuals affected.

Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome

It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.

Predicting dementia in Down syndrome: Study of a Portuguese cohort

Predicting dementia in Down syndrome: Study of a Portuguese cohort

Neurodevelopment and aging in Down syndrome

Down syndrome (DS) is the most common genetic form of intellectual disability and is due to trisomy of all or part of the 21st chromosome. Cognitive profiles in DS are diverse. Typically, morpho-syntax, verbal short term memory, and explicit long-term memory are impaired whereas visuospatial short term memory, associative learning and implicit long-term memory are relatively preserved. Impaired language communication in DS can affect testing of higher cortical functioning and has resulted in the development of the Arizona Cognitive Test Battery which supports a platform of non-verbal tests focusing on prefrontal, hippocampal and cerebellar dysfunction. In part due to triplication of the amyloid-precursor-protein gene, brain amyloid accumulates across the lifespan in DS. By age 40 years, the classical neuropathological changes of Alzheimer's disease (AD) are present although dementia is not invariable even at older ages. The clinical manifestations of dementia are similar to those seen in AD within the general population and include emotional change, gait dyspraxia, memory difficulties, incontinence and seizures. Seizures have been associated with precipitous cognitive decline in individuals with DS and dementia. In this sense, the prognosis for seizures in adults with DS is worse than that seen when children experience seizures. Other medical conditions that can confound a diagnosis of dementia in DS include hypothyroidism, sensory deficits in vision and hearing, and psychiatric co-morbidities. Co-morbid symptoms of autistic disorder seem to be more common in DS than would be anticipated based on prevalence data of the two conditions. Aside from a higher incidence of moya-moya disease in young people with DS, vascular complications of dementia appear to be rare. In summary, understanding the relationship of amyloid accumulation to development and aging in people with DS can inform the pathogenesis in AD within the general population.

Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome

It is known that individuals with Down syndrome develop Alzheimer’s disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer’s disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer’s disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer’s disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer’s disease in Down syndrome.