Cerebrospinal fluid (CSF) Aβ1-42 levels and the Aβ1-42/Aβ1-40 ratio are markers of amyloid pathology, but previous studies suggest that their levels might be influenced by additional ...pathophysiological processes.
To compare Aβ1-42 and the Aβ1-42/Aβ1-40 ratio in CSF in different neurodegenerative disorders and study their association with other biomarkers (tTau, pTau181, and NfL) and with cognitive and functional progression.
We included all participants from the Sant Pau Initiative on Neurodegeneration (SPIN) with CSF Aβ1-42 and Aβ1-42/Aβ1-40. Participants had diagnoses of Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal lobar degeneration-related syndromes, non-neurodegenerative conditions, or were cognitively normal. We classified participants as "positive" or "negative" according to each marker. We compared CSF levels of tTau, pTau181, and NfL between concordant and discordant groups through ANCOVA and assessed differences in cognitive (MMSE, FCSRT) and functional (GDS, CDR-SOB) progression using Cox regression and linear-mixed models.
In the 1791 participants, the agreement between Aβ1-42 and Aβ1-42/Aβ1-40 was 78.3%. The Aβ1-42/Aβ1-40 ratio showed a stronger correlation with tTau and pTau181 than Aβ1-42 and an agreement with tTau and pTau181 of 73.1% and 77.1%, respectively. Participants with a low Aβ1-42/Aβ1-40 ratio showed higher tTau and pTau181 and worse cognitive and functional prognosis, regardless of whether they were positive or negative for Aβ1-42. The results were consistent across stages, diagnostic categories, and use of different cutoffs.
Although Aβ1-42 and Aβ1-42/Aβ1-40 are considered markers of the same pathophysiological pathway, our findings provide evidence favoring the use of the Aβ1-42/Aβ1-40 ratio in clinical laboratories in the context of AD.
OBJECTIVETo characterize the cortical macrostructure and microstructure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS)–frontotemporal dementia (FTD) continuum.
...METHODSWe prospectively recruited 88 participants with a 3T MRI structural and diffusion-weighted imaging sequences31 with ALS, 20 with the behavioral variant of FTD (bvFTD), and 37 cognitively normal controls. Participants with ALS underwent a comprehensive cognitive and behavioral assessment and were dichotomized into ALS without cognitive or behavioral impairment (ALSno-cbi; n = 12) and ALS with cognitive or behavioral impairment (ALScbi; n = 19). We computed cortical thickness and cortical mean diffusivity using a surface-based approach and explored the cortical correlates of cognitive impairment with the Edinburgh Cognitive and Behavioral ALS Screen.
RESULTSThe ALSno-cbi and ALScbi groups showed different patterns of reduced cortical thickness and increased cortical mean diffusivity. In the ALSno-cbi group, cortical thinning was restricted mainly to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on frontoinsular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum. Participants with ALS with either cognitive or behavioral impairment showed increased cortical mean diffusivity in the prefrontal cortex in the absence of cortical thickness.
CONCLUSIONSCortical mean diffusivity might be a useful biomarker for the study of extramotor cortical neurodegeneration in the ALS-FTD clinical spectrum.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that the cortical microstructure correlates with cognitive impairment in the ALS-FTD continuum.
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.
Down syndrome (DS) is the most common worldwide cause of intellectual disability of genetic origin and the most common chromosomal disorder affecting live-born infants. In addition to intellectual ...disability, individuals with DS have other comorbidities and complex medical conditions. The increase in the life expectancy of patients with DS requires expanding the knowledge about their clinical characteristics and related laboratory parameters. Several studies exploring laboratory tests in DS patients exist, but their focus is limited to specific areas of metabolism. Therefore, our main goal was to describe the biochemical and hematological findings in a DS cohort and to compare the values to those of a control population. A total of 248 DS individuals and 84 control subjects were enrolled. DS individuals had a higher frequency of several clinical conditions compared to control individuals and presented with significant differences with respect to the controls in both biochemical and hematological parameters. We found age- and sex-related differences in several of the parameters. A good understanding of the differences in our cohort might be of aid in the clinical follow-up of adults with DS, especially considering that the lifespan of DS individuals may reach 60 years of age in developed countries.
BACKGROUND
Cortical microinfarcts (CMI) were attributed to cerebrovascular disease and cerebral amyloid angiopathy (CAA). CAA is frequent in Down syndrome (DS) while hypertension is rare, yet no ...studies have assessed CMI in DS.
METHODS
We included 195 adults with DS, 63 with symptomatic sporadic Alzheimer's disease (AD), and 106 controls with 3T magnetic resonance imaging. We assessed CMI prevalence in each group and CMI association with age, AD clinical continuum, vascular risk factors, vascular neuroimaging findings, amyloid/tau/neurodegeneration biomarkers, and cognition in DS.
RESULTS
CMI prevalence was 11.8% in DS, 4.7% in controls, and 17.5% in sporadic AD. In DS, CMI increased in prevalence with age and the AD clinical continuum, was clustered in the parietal lobes, and was associated with lacunes and cortico‐subcortical infarcts, but not hemorrhagic lesions.
DISCUSSION
In DS, CMI are posteriorly distributed and related to ischemic but not hemorrhagic findings suggesting they might be associated with a specific ischemic CAA phenotype.
Highlights
This is the first study to assess cortical microinfarcts (assessed with 3T magnetic resonance imaging) in adults with Down syndrome (DS).
We studied the prevalence of cortical microinfarcts in DS and its relationship with age, the Alzheimer's disease (AD) clinical continuum, vascular risk factors, vascular neuroimaging findings, amyloid/tau/neurodegeneration biomarkers, and cognition.
The prevalence of cortical microinfarcts was 11.8% in DS and increased with age and along the AD clinical continuum. Cortical microinfarcts were clustered in the parietal lobes, and were associated with lacunes and cortico‐subcortical infarcts, but not hemorrhagic lesions.
In DS, cortical microinfarcts are posteriorly distributed and related to ischemic but not hemorrhagic findings suggesting they might be associated with a specific ischemic phenotype of cerebral amyloid angiopathy.
Introduction
We aimed to define prodromal Alzheimer's disease (AD) and AD dementia using normative neuropsychological data in a large population‐based cohort of adults with Down syndrome (DS).
...Methods
Cross‐sectional study. DS participants were classified into asymptomatic, prodromal AD and AD dementia, based on neurologist's judgment blinded to neuropsychological data (Cambridge Cognitive Examination for Older Adults with Down's syndrome CAMCOG‐DS and modified Cued Recall Test mCRT). We compared the cutoffs derived from the normative data in young adults with DS to those from receiver‐operating characteristic curve (ROC) analysis.
Results
Diagnostic performance of the CAMCOG‐DS and modified Cued Recall Test (mCRT) in subjects with mild and moderate levels of intellectual disability (ID) was high, both for diagnosing prodromal AD and AD dementia (area under the curve AUC 0.73–0.83 and 0.90–1, respectively). The cutoffs derived from the normative data were similar to those derived from the ROC analyses.
Discussion
Diagnosing prodromal AD and AD dementia in DS with mild and moderate ID using population norms for neuropsychological tests is possible with high diagnostic accuracy.
Adults with Down syndrome are at an ultra-high risk of developing early-onset Alzheimer's disease. Episodic memory deficits are one of the earliest signs of the disease, but their association with ...regional brain atrophy in the population with Down syndrome has not been explored. We aimed to investigate the neuroanatomical correlates of episodic memory in adults with Down syndrome and symptomatic Alzheimer's disease.
Single-center, cross-sectional study. A total of 139 adults with Down syndrome (85 asymptomatic and 54 with symptomatic Alzheimer's disease) were included in the study (mean age 43.6 ± 10.9 years, 46% female). Episodic memory was assessed using the modified Cued Recall Test. Immediate (trial 1 free immediate recall, trial 3 free immediate recall, total free immediate recall score, and total immediate score) and delayed scores (free delayed recall score and total delayed score) were examined. Cortical thickness from magnetic resonance imaging was determined with surface-based morphometry using the FreeSurfer 6.0 software package. The clusters of reduced cortical thickness were compared between symptomatic and asymptomatic participants to create a cortical atrophy map. Then, the correlation between cortical thickness and the modified Cued Recall Test subscores were separately assessed in symptomatic and asymptomatic subjects, controlling for age, sex, and severity of intellectual disability.
Compared with asymptomatic participants, those with symptomatic Alzheimer's disease showed a pattern of cortical atrophy in posterior parieto-temporo-occipital cortices. In symptomatic subjects, trial 1 immediate free recall significantly correlated with cortical atrophy in lateral prefrontal regions. Trial 3 free immediate recall and total free immediate recall were associated with the most widespread cortical atrophy. Total immediate score was related to posterior cortical atrophy, including lateral parietal and temporal cortex, posterior cingulate cortex, precuneus, and medial temporal lobe areas. Delayed memory scores were associated with cortical atrophy in temporoparietal and medial temporal lobe regions. No significant relationships were observed between episodic memory measures and cortical atrophy in asymptomatic subjects.
Different episodic memory measures were associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer's disease. These results overlap with those described in sporadic Alzheimer's disease and further support the similarities between Down syndrome-associated Alzheimer's disease and that in the general population.
There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess ...response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment.
We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ
ratio, CSF Aβ
, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing.
In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ
(adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002).
These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
Background
Cortical microinfarcts (CMI) are emerging biomarkers of vascular damage associated with cognitive decline and are frequent in sporadic AD (sAD) patients. However, no study assessed CMI in ...Down syndrome (DS), a genetically determined form of AD. Therefore, we aimed to assess CMI’s frequency in adults with DS, sAD, and cognitively unimpaired euploid controls and its relationship with age, sex, clinical status, and APOE ε4 carriership.
Method
Cross‐sectional study. We included 175 participants with 3T‐MRI: 64 with DS (39 asymptomatic aDS, 11 prodromal AD pDS, and 14 AD‐dementia dDS), 62 with sAD (41 prodromal AD, 21 AD dementia), and 49 controls. A neuroradiologist blind to participants’ data visually analyzed the 3T‐MRI images following a validated protocol to detect CMI (Figure 1). We compared CMI’s prevalence in the different clinical groups along the AD continuum in DS and sAD, in APOE ε4 carriers vs. non‐carriers, and males vs. females using Chi‐square, Mann‐Whitney, or Kruskal‐Wallis tests when appropriate.
Result
CMI’s prevalence was 7.8% in DS (5.1% in aDS, 21.4% in pDS, and 0% in dDS p = 0.085), 17.7% in sAD (22.0% in prodromal AD and 9.5% in AD dementia p = 0.389), and 10.2% in controls (p = 0.207). CMI frequency increased with age in DS, sAD, and controls (Table 1). Regarding sex, CMI’s frequency was 10% in men and 5.9% in women with DS (p = 0.884), and 27.3% in men and 12.5% in women with sAD (p = 0.267). In controls, CMIs’ frequency was 10% in men and 10.3% in women (p = 1.000). Regarding APOEε4 carriership, CMI’s prevalence was 21.4% in APOEε4 carriers and 9.1% in non‐carriers in sAD (p = 0.428), 8.7% in carriers and 6.0% in non‐carriers in DS (p = 1.000), and 8.3% in carriers and 8.6% in non‐carriers controls (p = 1.000) (Table 2).
Conclusion
CMI’s prevalence increased with age, but was not different in DS, sporadic AD, and controls. Also, sex and APOEε4 carriership did not impact the prevalence of CMI in the three study groups.
Introduction
People with Down syndrome (DS) are at ultra‐high risk of developing Alzheimer’s disease (AD). A comprehensive health care approach is needed to enable an early diagnosis and an ...individualized follow up. The Alzheimer‐Down Unit developed a health plan which is offered to every adult with Down syndrome in Catalonia and which includes annual neurological and neuropsychological assessments together with clinical support and social counseling when needed. Within this plan, the “Domiciliary Alzheimer Visiting in Down syndrome” (DAVIS) pilot project adds domiciliary visits to bring closer this plan to those candidates who are not able to come to our site. In the present study, we analyze the preliminary results of this project.
Methods
Pilot observational cross‐sectional study. We contacted occupational centers /residences which included users with Down syndrome and we organized the visit of a neurologist and a neuropsychologist from our team. Candidates and their caregivers were informed about the health plan and those who accepted to participate were assessed. According to their cognitive status, they were classified into 3 groups: without cognitive impairment (aDS), prodromal AD (pDS) or AD dementia (dDS). Subsequently, a physically present or telephonic follow‐up visit, together with the option of collaborating with Primary Care, was offered. Participation in biomarkers research projects was also proposed.
Results
Between October 2018 and December 2019 we assessed 92 participants (mean age 42.5, 48.9% males) classified as aDS (77.1%), pDS (4.4%) or dDS (18.5%). The 67.4% and the 28.3% of the participants were recruited to continue with the physically present or telephonic follow‐up, respectively. A 10.9% of the participants agreed to collaborate on research projects.
Conclusions
The DAVIS pilot project facilitates the dissemination of our comprehensive health plan for adults with DS in Catalonia. Its clinical application allows the diagnosis of new cases of AD and brings closer research to the adult population with DS. The DAVIS pilot project emphasizes the need of social and health care improvements for adults with DS; however, an extended DAVIS project will generate solid data to influence on health policy and, potentially, to improve the people with DS and their caregivers quality of life.
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