Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome

Dekker, Alain D.; Fortea, Juan; Blesa, Rafael; Deyn, Peter Paul De

doi:10.1016/j.dadm.2017.02.006

Cited by 36 publications

(31 citation statements)

References 65 publications

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“…Although lumbar puncture has been demonstrated as a safe procedure in DS population (Carmona-Iragui, Santos, et al, 2017), there are few studies that look into CSF biomarkers in DS (Carmona-Iragui, Balasa, et al, 2017;Dekker, Fortea, Blesa, & De, 2017;Fortea et al, 2018), and only one assessed their correlation with CAA neuroimaging biomarkers in DS (and also in sporadic early onset AD, ADAD, and healthy controls (Carmona-Iragui, Balasa, et al, 2017). In that study, CSF-Aß1-40 levels did not discriminate CAA neuroimaging features in any clinical group, suggesting that that amyloid vascular burden in CAA in ADAD and DS contains not just Aß1-40, but also Aß1-42.…”

Section: Csf Biomarkersmentioning

confidence: 99%

Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis

Carmona-Iragui

Videla

Lleó

et al. 2019

Developmental Neurobiology

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Down syndrome (DS) is the main genetic cause of intellectual disability worldwide. The overexpression of the Amyloid Precursor Protein, present in chromosome 21, leads to β‐amyloid deposition that results in Alzheimer disease (AD) and, in most cases, also to cerebral amyloid angiopathy (CAA) neuropathology. People with DS invariably develop the neuropathological hallmarks of AD at the age of 40, and they are at an ultra high risk for suffering AD‐related cognitive impairment thereafter. In the general population, cerebrovascular disease is a significant contributor to AD‐related cognitive impairment, while in DS remains understudied. This review describes the current knowledge on cerebrovascular disease in DS and reviews the potential biomarkers that could be useful in the future studies, focusing on CAA. We also discuss available evidence on sporadic AD or other genetically determined forms of AD. We highlight the urgent need of large biomarker‐characterized cohorts, including neuropathological correlations, to study the exact contribution of CAA and related vascular factors that play a role in cognition and occur with aging, their characterization and interrelationships. DS represents a unique context in which to perform these studies as this population is relatively protected from some conventional vascular risk factors and they develop significant CAA, DS represents a particular atheroma‐free model to study AD‐related vascular pathologies. Only deepening on these underlying mechanisms, new preventive and therapeutic strategies could be designed to improve the quality of life of this population and their caregivers and lead to new avenues of treatment also in the general AD population.

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Section: Csf Biomarkersmentioning

confidence: 99%

Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis

Carmona-Iragui

Videla

Lleó

et al. 2019

Developmental Neurobiology

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“…Neuropathological biomarkers of AD, including Aβ 40 and Aβ 42, have been detected in brain tissue and cerebrospinal fluid (CSF) decades before the onset of dementia in general (Blennow & Zetterberg, ) and DS population (Dekker, Fortea, Blesa, & De Deyn, ). The progressive accumulation of AD pathology in the DS population suggests that there is a preclinical phase to DS‐AD since there are at least two decades between the onset of AD pathology and dementia diagnosis in those with DS (Head et al, ; Prasher et al, ; Schupf et al, ; Wiseman et al, ).…”

Section: Exosomal Cargomentioning

confidence: 99%

“…Positron emission tomography (PET) imaging studies established that accumulation of Aβ occurs almost without exceptions in the DS brain in the 3rd to 5th decade (Annus et al, 2016;Cole et al, 2017;Handen et al, 2012;Hartley et al, 2015Hartley et al, , 2017Lao et al, 2017;Neale et al, 2018;Rafii et al, 2017;Wilcock, Schmitt, & Head, 2016). Increased levels of Aβ 42 have been reported in the CSF of adults with DS without dementia (Dekker et al, 2017;Fortea et al, 2018). Interestingly, findings from the Dominantly Inherited Alzheimer Network (DIAN), an international registry of individuals at risk for developing autosomal dominant AD, suggest that early high levels of Aβ in the CSF, followed by reduced CSF Aβ levels at more progressive disease stages successfully mark the onset of AD (Moulder et al, 2013).…”

Section: Exosome Cargo In Ad and Ds-admentioning

confidence: 99%

“…In addition to the pronounced Aβ deposition seen in subjects with DS, abundant NFTs and increased phospho-Tau levels also occur (Head et al, 2003;Hof et al, 1995;Kasai et al, 2017;Rafii, 2019). NFTs are first seen in the entorhinal cortex in the mid-30s, hippocampus in mid-40s, and neocortex in the mid-50s, but variability exists between individuals with DS (Davidson et al, 2018;Dekker et al, 2017;Hartley et al, 2015). In a neuropathological study of people with DS and of different ages, NFT pathology was observed in 4 cases below 36 years of age and in all 20 cases above that age, again suggesting individual variability in terms of onset (Wegiel, Wisniewski, Dziewiatkowski, Popovitch, & Tarnawski, 1996).…”

Section: Exosome Cargo In Ad and Ds-admentioning

confidence: 99%

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Exosome release and cargo in Down syndrome

Hamlett

LaRosa

Mufson

et al. 2019

Developmental Neurobiology

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Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically increased life expectancy, yet there are many etiologies of this disorder that are in need of further research. The advent of the ability to capture extracellular vesicles (EVs) in blood from specific cell types allows for the investigation of novel intracellular processes. Exosomes are one type of EVs that have demonstrated great potential in uncovering new biomarkers of neurodegeneration and disease, and also that appear to be intricately involved in the transsynaptic spread of pathogenic factors underlying Alzheimer's disease and other neurological diseases. Exosomes are nanosized vesicles, generated in endosomal multivesicular bodies (MVBs) and secreted by most cells in the body. Since exosomes are important mediators of intercellular communication and genetic exchange, they have emerged as a major research focus and have revealed novel biological sequelae involved in conditions afflicting the DS population. This review summarizes current knowledge on exosome biology in individuals with DS, both early in life and in aging individuals. Collectively these studies have demonstrated that complex multicellular processes underlying DS etiologies may include abnormal formation and secretion of extracellular vesicles such as exosomes.

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“…The (early) diagnosis of dementia in DS is fairly complex compared to the general population given the pre-existing intellectual disability (ID), behavior and co-morbidities [6,7]. Unlike the general population, a sensitive and specific cerebrospinal fluid biomarker profile for AD in DS is not available [8], and the clinical utility of positron emission tomography (PET) for amyloid is questionable [4,9]. Clinical diagnosis by physicians and (neuro)psychologists thus remains the gold standard [10].…”

Section: Introductionmentioning

confidence: 99%

The behavioral and psychological symptoms of dementia in Down syndrome (BPSD-DS) scale: Comprehensive assessment of psychopathology in Down syndrome

Dekker

Deyn

2019

European Neuropsychopharmacology

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People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

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Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome

Cited by 36 publications

References 65 publications

Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis

Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis

Exosome release and cargo in Down syndrome

The behavioral and psychological symptoms of dementia in Down syndrome (BPSD-DS) scale: Comprehensive assessment of psychopathology in Down syndrome

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