Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloid-β deposition, by their fifth decade of life. In the current study, we examined the association ...between brain amyloid-β deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P < 0.0001) between age and neocortical Pittsburgh compound B retention. This robust association makes it difficult to discriminate normative age-related decline in cognitive functioning from any potential effects of amyloid-β deposition. When controlling for chronological age in addition to mental age, there were no significant differences between the adults with Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloid-β deposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloid-β deposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloid-β deposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.
INTRODUCTION
Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer's disease (AD). Understanding AD biomarker trajectories is necessary for DS‐specific ...clinical interventions and interpretation of drug‐related changes in the disease trajectory.
METHODS
A total of 177 adults with DS from the Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS) underwent positron emission tomography (PET) and MR imaging. Amyloid‐beta (Aβ) trajectories were modeled to provide individual‐level estimates of Aβ‐positive (A+) chronicity, which were compared against longitudinal tau change.
RESULTS
Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I‐III was observed 0–2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe.
DISCUSSION
These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age.
Highlights
Longitudinal amyloid trajectories reveal rapid Aβ accumulation in Down syndrome
NFT stage tau was strongly associated with A+ chronicity
Early longitudinal tau increases were observed 2.5–5 years after reaching A+
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The present study provided an investigation of associations between leisure activity and early Alzheimer’s disease neuropathology (i.e., brain β‐amyloid) and episodic memory in a sample of 65 adults ...with Down syndrome (aged 30–53 years), at baseline and follow‐up, approximately three years apart. Findings indicated that leisure activity at baseline was not associated with brain β‐amyloid at baseline or change in brain β‐amyloid from baseline to follow‐up. Greater cognitively stimulating leisure activity at baseline was associated with better episodic memory at baseline, and greater social leisure activity at baseline was associated with less decline in episodic memory from baseline to follow‐up. High (as opposed to low) levels of social and overall leisure activity at baseline moderated the association between increase in brain β‐amyloid and decline in episodic memory, from baseline to follow‐up. Findings suggest that cognitively stimulating and social leisure activity could protect against the effect of Alzheimer’s disease neuropathology on episodic memory in adults with Down syndrome.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Background: We estimated the prevalence and incidence of amyloid-β deposition (A), small-vessel disease (V), and neurodegeneration (N) biomarker positivity in community-dwelling cognitively ...normal individuals (CN). We determined the longitudinal association between the respective biomarker indices with progression to all-cause mild cognitive impairment (MCI) and its amnestic and nonamnestic subtypes.
Methods: CN participants, recruited by advertising, underwent brain C-11Pittsburgh Compound-B (PiB)-positron emission tomography (PET), magnetic resonance imaging, and F-18fluoro-2-deoxy-glucose (FDG)-PET, and were designated as having high or low amyloid-β (A+/A−), greater or lower white matter hyperintensities burden (V+/V−) and diminished or normal cortical glucose metabolism (N+/N−). MCI was adjudicated using clinical assessments. We examined the association between A, V, and N biomarker positivity at study baseline and endpoint, with progression to MCI using linear regression, Cox proportional hazards and Kaplan–Meier analyses adjusted for age and APOE-ε4 carrier status.
Results: In 98 CN individuals (average age 74 years, 65% female), A+, V+, and N+ prevalence was 26%, 33%, and 8%, respectively. At study endpoint (median: 5.5 years), an A+, but not a V+ or N+ scan, was associated with higher odds of all-cause MCI (Chi-square = 3.9, p = .048, odds ratio, 95% confidence interval = 2.6 1.01–6.8). Baseline A+, V+, or N+ were not associated with all-cause MCI, however, baseline A+ (p = .018) and A+N+ (p = .049), and endpoint A+N+ (p = .025) were associated with time to progression to amnestic, not nonamnestic, MCI.
Conclusion: Longitudinal assessments clarify the association between amyloid-β and progression to all-cause MCI in CN individuals. The association between biomarker positivity indices of amyloid-β and neurodegeneration, and amnestic MCI reflects the underlying pathology involved in the progression to prodromal Alzheimer’s disease.
6-(fluoro-
F)-3-(1H-pyrrolo2,3-cpyridin-1-yl)isoquinolin-5-amine (
FMK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to ...test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of
FMK6240 in target regions.
We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal
FMK6240 SUVs and SUV ratios (SUVRs) (mean ± SD, 2.25 ± 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with
FMK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 ± 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-β-negative and tau-negative, 58.50 ± 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed
testing and Pearson correlation testing were used to determine the difference between groups and associations between changes in region uptake, respectively.
Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-β status, cross-sectionally and over time.
FMK6240 uptake significantly differed between CUY and CU adults in the putamen or pallidum (affecting ∼75% of the region) and in the Braak II region (affecting ∼35%). Changes in meningeal and putamen or pallidum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated.
Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and stable over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible,
FMK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related
FMK6240 signal, and in vivo studies should further explore its impact on tracer quantification.
•We developed a method for measuring the cardiac-induced cerebral pulsatility map.•Subsets of pulsatility voxels and brain volumes are significantly associated.•The brain volumes are mediators ...between the pulsatility and cognitive measures.
Changes of cardiac-induced regional pulsatility can be associated with specific regions of brain volumetric changes, and these are related with cognitive alterations. Thus, mapping of cardiac pulsatility over the entire brain can be helpful to assess these relationships. A total of 108 subjects (age: 66.5 ± 8.4 years, 68 females, 52 healthy controls, 11 subjective cognitive decline, 17 impaired without complaints, 19 MCI and 9 AD) participated. The pulsatility map was obtained directly from resting-state functional MRI time-series data at 3T. Regional brain volumes were segmented from anatomical MRI. Multidomain neuropsychological battery was performed to test memory, language, attention and visuospatial construction. The Montreal Cognitive Assessment (MoCA) was also administered. The sparse partial least square (SPLS) method, which is desirable for better interpreting high-dimensional variables, was applied for the relationship between the entire brain voxels of pulsatility and 45 segmented brain volumes. A multiple holdout SPLS framework was used to optimize sparsity for assessing the pulsatility-volume relationship model and to test the reliability by fitting the models to 9 different splits of the data. We found statistically significant associations between subsets of pulsatility voxels and subsets of segmented brain volumes by rejecting the omnibus null hypothesis (any of 9 splits has p < 0.0056 (=0.05/9) with the Bonferroni correction). The pulsatility was positively associated with the lateral ventricle, choroid plexus, inferior lateral ventricle, and 3rd ventricle and negatively associated with hippocampus, ventral DC, and thalamus volumes for the first pulsatility-volume relationship. The pulsatility had an additional negative relationship with the amygdala and brain stem volumes for the second pulsatility-volume relationship. The spatial distribution of correlated pulsatility was observed in major feeding arteries to the brain regions, ventricles, and sagittal sinus. The indirect mediating pathways through the volumetric changes were statistically significant between the pulsatility and multiple cognitive measures (p < 0.01). Thus, the cerebral pulsatility, along with volumetric measurements, could be a potential marker for better understanding of pathophysiology and monitoring disease progression in age-related neurodegenerative disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Introduction In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology. Methods ...PET imaging with carbon 11–labeled Pittsburgh compound B examined the pattern of amyloid-β deposition in 68 nondemented adults with DS (30–53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellar gray matter as the reference region. Results Multiple linear regression revealed slight but highly significant (corrected P < .05) positive correlations between SUVR and age. The striatum showed the strongest correlation, followed by precuneus, parietal cortex, anterior cingulate, frontal cortex, and temporal cortex. Conclusion There is an age-related amyloid-β deposition in the DS population, but as a pattern of elevated cortical retention becomes apparent, the correlation of SUVR with age ceases to be significant. Factors unrelated to aging may drive an increase in deposition during early Alzheimer's disease pathogenesis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. ...Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.
Methods
We describe the development of a multi‐center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid‐based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16‐month intervals), as well as genetic modifiers of AD risk and progression.
Results
Approximately 400 individuals will be enrolled in the study (more than 370 to date). The methodological approach from the administrative, clinical, neuroimaging, omics, neuropathology, and statistical cores is provided.
Discussion
This represents the largest U.S.‐based, multi‐site, biomarker initiative of AD in DS. Findings can inform other multidisciplinary networks studying AD in the general population.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD).
The temporal ordering and spatial association between ...amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD.
Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent 11CPiB, 18FFDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest.
Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume.
In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.
The focus of Alzheimer’s disease (AD) neuroimaging research has shifted towards an investigation of the earliest stages of AD pathogenesis, which manifests in every young adult with Down syndrome ...(DS; trisomy 21) resulting from a deterministic genetic predisposition to amyloid precursor protein overproduction. Due to morphological differences in brain structure in the DS population, special consideration must be given to processing pipelines and the use of normative atlases developed for the non-DS population. Further, the use of typical MRI to MRI template spatial normalization is less desirable in this cohort due to a greater presence of motion artefacts in MRI images. The diffuse nature of PiB uptake and comparatively lower spatial resolution of the PET image permits the purposing of this modality as a template for spatial normalization, which can substantially improve the robustness of this procedure in the cases of MRI images with motion. The aim of this work was to establish standardized methods for spatial normalization and tissue type segmentation using DS specific templates in order to perform voxel-wise analyses. A total of 72 adults with DS underwent
11
CPiB PET to assess brain amyloid burden and volumetric MRI imaging. A DS specific PiB template for spatial normalization and a set of DS specific prior probability templates were created with two-pass methods. With implementation of this DS specific PiB template, no participants were excluded due to poor spatial normalization, thus maximizing the sample size for PiB analyses in standardized space. In addition, difference images between prior probability templates created from the general population and the DS population reflected known morphological differences, particularly in the frontal cortex. In conclusion, DS specific templates that account for unique challenges improve spatial normalization and tissue type segmentation, and provide a framework for reliable voxel-wise analysis of AD biomarkers in this atypical population.
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