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.
Abstract Introduction Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as ...non-AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid-β (Aβ) peptides and phosphorylated-tau in neuronal exosomes may document preclinical AD. Methods AD neuropathogenic proteins Aβ1–42 , P-T181-tau, and P-S396-tau were quantified by enzyme-linked immunosorbent assays in extracts of neuronal exosomes purified from blood of individuals with DS and age-matched controls. Results Neuronal exosome levels of Aβ1–42 , P-T181-tau, and P-S396-tau were significantly elevated in individuals with DS compared with age-matched controls at all ages beginning in childhood. No significant gender differences were observed. Discussion These early increases in Aβ1–42 , P-T181-tau, and P-S396-tau in individuals with DS may provide a basis for early intervention as targeted treatments become available.
Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a ...biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 95% CI 0.73-0.87 and 0.92 95% CI 0.89-0.95 for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.
Epilepsy and Alzheimer's disease (AD) incidence increases with age. There are reciprocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent ...risk factor for developing epilepsy in old age, and abnormal AD biomarkers in PET and/or CSF are frequently found in late-onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes, including neuronal hyperexcitability and an early excitatory-inhibitory dysregulation, leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anatomopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies, suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy, share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology, such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epileptiform activity and electroclinical seizures in AD appears to accelerate the progression of cognitive decline, and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly patients without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with an altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASMs). There is also a potential role for ASMs to be used as disease-modifying drugs in AD.
Objective
The purpose of this study was to examine the Alzheimer's disease metabolite signature through magnetic resonance spectroscopy in adults with Down syndrome and its relation with Alzheimer's ...disease biomarkers and cortical thickness.
Methods
We included 118 adults with Down syndrome from the Down Alzheimer Barcelona Imaging Initiative and 71 euploid healthy controls from the Sant Pau Initiative on Neurodegeneration cohort. We measured the levels of myo‐inositol (a marker of neuroinflammation) and N‐acetyl‐aspartate (a marker of neuronal integrity) in the precuneus using magnetic resonance spectroscopy. We investigated the changes with age and along the disease continuum (asymptomatic, prodromal Alzheimer's disease, and Alzheimer's disease dementia stages). We assessed the relationship between these metabolites and Aβ42/Aβ40 ratio, phosphorylated tau‐181, neurofilament light (NfL), and YKL‐40 cerebrospinal fluid levels as well as amyloid positron emission tomography uptake using Spearman correlations controlling for multiple comparisons. Finally, we computed the relationship between cortical thickness and metabolite levels using Freesurfer.
Results
Asymptomatic adults with Down syndrome had a 27.5% increase in the levels of myo‐inositol, but equal levels of N‐acetyl‐aspartate compared to euploid healthy controls. With disease progression, myo‐inositol levels increased, whereas N‐acetyl‐aspartate levels decreased in symptomatic stages of the disease. Myo‐inositol was associated with amyloid, tau, and neurodegeneration markers, mainly at symptomatic stages of the disease, whereas N‐acetyl‐aspartate was related to neurodegeneration biomarkers in symptomatic stages. Both metabolites were significantly associated with cortical thinning, mainly in symptomatic participants.
Interpretation
Magnetic resonance spectroscopy detects Alzheimer's disease related inflammation and neurodegeneration, and could be a good noninvasive disease‐stage biomarker in Down syndrome. ANN NEUROL 2021;90:407–416
Objective
To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD).
Methods
In this cross‐sectional study, ...normal controls (n = 145) from the Alzheimer's Disease Neuroimaging Initiative underwent structural 3T magnetic resonance imaging (MRI) and lumbar puncture. CSF β‐amyloid1–42 (Aβ) and phospho‐tau181p (p‐tau) levels were measured by Luminex assays. Samples were dichotomized using published cutoffs (Aβ+/Aβ− and p‐tau+/ptau−). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction by analysis of covariance.
Results
We found a significant biomarker interaction between CSF Aβ and CSF p‐tau levels affecting brain structure. Cortical atrophy only occurs in subjects with both Aβ+ and p‐tau+. The stratified correlation analyses showed that the relationship between p‐tau and CTh is modified by Aβ status and the relationship between Aβ and CTh is modified by p‐tau status. p‐Tau–dependent thinning was found in different cortical regions in Aβ+ subjects but not in Aβ− subjects. Cortical thickening was related to decreasing CSF Aβ values in the absence of abnormal p‐tau, but no correlations were found in p‐tau+ subjects.
Interpretation
Our data suggest that interactions between biomarkers in AD result in a 2‐phase phenomenon of pathological cortical thickening associated with low CSF Aβ, followed by atrophy once CSF p‐tau becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy. Ann Neurol 2014;76:223–230
Diagnosis of Alzheimer's disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in ...this population.
We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimer's disease, or Alzheimer's disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23–58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-β (Aβ)1–40, Aβ1–42, total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimer's disease and between asymptomatic participants and those with Alzheimer's disease dementia.
Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimer's disease, 49 Alzheimer's disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve AUC between 0·53 95% CI 0·44–0·62 and 0·74 0·66–0·82) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82–0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimer's disease group and 0·95 (0·92–0·98) for the asymptomatic group versus the Alzheimer's disease dementia group. In CSF, except for Aβ1–40 concentrations (AUC 0·60, 95% CI 0·45–0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimer's disease comparison: AUC 0·92 (95% CI 0·85–0·99) for Aβ1–42, 0·81 (0·69–0·94) for t-tau, 0·80 (0·67–0·93) for p-tau, and 0·88 (0·79–0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimer's disease dementia comparison (AUC ≥0·90 for all except Aβ1–40 0·59, 0·45–0·72). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p<0·0001).
Plasma NfL and CSF biomarkers have good diagnostic performance to detect Alzheimer's disease in adults with Down syndrome. Our findings support the utility of plasma NfL for the early detection of Alzheimer's disease in Down syndrome in clinical practice and clinical trials.
Institute of Health Carlos III, Fundació La Marató de TV3, Fundació Bancaria Obra Social La Caixa, Fundació Catalana Síndrome de Down, and Fundació Víctor Grífols i Lucas.
Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD).
We included healthy control subjects (N = 254), mild cognitive impairment (N ...= 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum.
Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages.
These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification.
Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing ...in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.
OBJECTIVE:To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with ...suspected non-Alzheimer pathology (SNAP).
METHODS:We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau t-tau, phospho-tau p-tau), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging–Alzheimerʼs Association classificationstage 0, 1, 2, 3, and SNAP.
RESULTS:The median age in the whole cohort was 58.8 years (range 39.8–81.6). Participants in stages 2–3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2–3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42.
CONCLUSIONS:Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.
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