Introduction
Adults with Down syndrome (DS) are at high risk for early onset Alzheimer's disease (AD), characterized by a progressive decline in multiple cognitive domains including language, which ...can impact social interactions, behavior, and quality of life. This cross‐sectional study examined the relationship between language skills and dementia.
Methods
A total of 168 adults with DS (mean age = 51.4 years) received neuropsychological assessments, including Vineland Communication Domain, McCarthy Verbal Fluency, and Boston Naming Test, and were categorized in one of three clinical groups: cognitively stable (CS, 57.8%); mild cognitive impairment (MCI‐DS, 22.6%); and probable/definite dementia (AD‐DS, 19.6%). Logistic regression was used to determine how well language measures predict group status.
Results
Vineland Communication, particularly receptive language, was a significant predictor of MCI‐DS. Semantic verbal fluency was the strongest predictor of AD‐DS.
Discussion
Assessment of language skills can aid in the identification of dementia in adults with DS. Clinically, indications of emerging language problems should warrant further evaluation and monitoring.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Down syndrome (DS) is associated with a higher risk of dementia. We hypothesize that amyloid beta (Aβ) in specific brain regions differentiates mild cognitive impairment in DS (MCI‐DS) ...and test these hypotheses using cross‐sectional and longitudinal data.
Methods
18F‐AV‐45 (florbetapir) positron emission tomography (PET) data were collected to analyze amyloid burden in 58 participants clinically classified as cognitively stable (CS) or MCI‐DS and 12 longitudinal CS participants.
Results
The study confirmed our hypotheses of increased amyloid in inferior parietal, lateral occipital, and superior frontal regions as the main effects differentiating MCI‐DS from the CS groups. The largest annualized amyloid increases in longitudinal CS data were in the rostral middle frontal, superior frontal, superior/middle temporal, and posterior cingulate cortices.
Discussion
This study helps us to understand amyloid in the MCI‐DS transitional state between cognitively stable aging and frank dementia in DS. The spatial distribution of Aβ may be a reliable indicator of MCI‐DS in DS.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD)‐associated neuropathology by the age of 40, with risk for dementia increasing from the early 50s. White ...matter (WM) pathology has been reported in sporadic AD, including early demyelination, microglial activation, loss of oligodendrocytes and reactive astrocytes but has not been extensively studied in the at‐risk DS population.
Methods
Fifty‐six adults with DS (35 cognitively stable adults, 11 with mild cognitive impairment, 10 with dementia) underwent diffusion‐weighted magnetic resonance imaging (MRI), amyloid imaging, and had assessments of cognition and functional abilities using tasks appropriate for persons with intellectual disability.
Results
Early changes in late‐myelinating and relative sparing of early‐myelinating pathways, consistent with the retrogenesis model proposed for sporadic AD, were associated with AD‐related cognitive deficits and with regional amyloid deposition.
Discussion
Our findings suggest that quantification of WM changes in DS could provide a promising and clinically relevant biomarker for AD clinical onset and progression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Down syndrome (DS) is associated with elevated risk for Alzheimer's disease (AD) due to amyloid beta (Aβ) lifelong accumulation. We hypothesized that the spatial distribution of brain Aβ ...predicts future dementia conversion in individuals with DS.
Methods
We acquired 18F‐florbetapir positron emission tomography scans from 19 nondemented individuals with DS at baseline and monitored them for 4 years, with five individuals transitioning to dementia. Machine learning classification using an independent test set determined features on 18F‐florbetapir standardized uptake value ratio maps that predicted transition.
Results
In addition to “AD signature” regions including the inferior parietal cortex, temporal lobes, and the cingulum, we found that Aβ cortical binding in the prefrontal and superior frontal cortices distinguished subjects who transitioned to dementia. Classification did well in predicting transitioners.
Discussion
Our study suggests that specific regional profiles of brain amyloid in older adults with DS may predict cognitive decline and are informative in evaluating the risk for dementia.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
An increase in global deposition of amyloid is known to be related to declines in a variety of cognitive domains among people with Down syndrome (DS). Less known is the correspondence ...between increased regional amyloid load and declines in specific functions. Since a decline in frontal lobe functions (e.g., attention, inhibitory control, shifting, motivation) is considered by many to be a key early indicator of AD dementia in adults with DS, the current study aims to identify regional amyloid changes that are associated with executive function (EF) decline in both pre‐symptomatic and symptomatic adults with DS.
Method
Longitudinal data from participants of the Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome (ADDS) consortium, at all stages of AD (pre‐clinical, prodromal, and clinical dementia), were examined. Forty‐two participants received amyloid PET and MRI scans and extensive neuropsychological testing of select cognitive functions at two time points, approximately 16 months apart. Changes in amyloid accumulation in the anterior and posterior cingulate, frontal lobe, superior temporal lobe, and parietal lobe were hypothesized to be related to performance on three measures of EF: Rapid Assessment of Developmental Disabilities (RADD) Digit Span Forward and Stroop Cats and Dogs Naming and Switching. PET data were co‐registered with T1‐weighted MRIs, converted to SUVR units using the cerebellum cortex reference region, and spatially normalized using a DS MRI template in MNI space. We modeled relationships between amyloid SUVR and EF using multiple regression in SPM12 with covariates accounting for time difference between the scans and neurocognitive assessment acquisition and sex.
Results
Consistent with our hypothesis, we found clear associations between increased amyloid deposition and decline in EF in people with DS in approximately the same regions as found in neurotypical populations without AD (Figure 1). Frontal lobe amyloid deposition disrupts dorsal and ventral attention network processes.
Conclusions
We found amyloid deposition in specific functional networks correspond to EF decline in a population with lifelong amyloid production and cognitive impairments. These findings bring us one step closer to validating biomarkers of early AD in DS.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
By age 40, virtually all people with Down syndrome (DS) have sufficient beta‐amyloid and tau pathologies present to meet the criteria for pathological Alzheimer's disease (AD). Determining ...the timing and location of neurobiological changes caused by AD is critically important for effective intervention within this high‐risk population and more broadly in the general population, but little is known about the brain changes associated with clinical onset of AD in DS. Previous studies in sporadic AD suggest that functional connectivity of the default mode network (DMN) and medial temporal lobe (MTL) is vulnerable to AD pathology‐related impairment.
Method
Seventy‐five individuals with DS (mean age 49.9±6.6, 36% women) from a subset of the Alzheimer’s Biomarkers Consortium ‐ Down Syndrome study underwent MRI, including an MPRAGE scan and a resting state functional scan. Participants completed a battery of neuropsychological tests and were assigned a consensus diagnosis for the presence or absence of mild cognitive impairment (MCI‐DS) or AD dementia. Forty‐eight participants were classified as cognitively stable (CS) (mean age 48±6.1, 42% women), 16 participants had MCI‐DS (mean age 50.8±4.2, 19% women), and 11 participants had dementia (mean age 57.2±6.6, 36% women).
Result
Participants with dementia had lower functional connectivity between the posterior DMN and the MTL relative to the CS and MCI‐DS groups. MCI‐DS participants had greater functional connectivity within the MTL relative to the CS group. Functional connectivity differences in these networks tracked with memory performance as well.
Conclusion
Changes in DMN and MTL functional connectivity are related to the progression of clinical symptoms of AD‐DS and may reflect synaptic changes stemming from AD pathology.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Down syndrome (DS) is associated with early development of Alzheimer’s disease pathology. Both the severity of tau pathology and the increase of neurofilament light chain (NfL) protein are ...correlated with cognitive decline in the neurotypical populations. Here, we assessed whether tau accumulation in the hippocampus and entorhinal cortex and plasma NfL concentrations were associated with memory performance in adults with DS.
Method
We used 18F‐AV‐1451 (FTP) positron emission tomography (PET) to assess tau accumulation in 44 participants enrolled in the multi‐site Alzheimer’s Disease in Down syndrome (ADDS) study (age 50.72 + 6.21). FTP‐PET scans were partial volume‐corrected, and weighted standardized uptake value ratio (SUVR) were calculated for each of the following regions of interests (ROIs): entorhinal cortex, hippocampus, and the precentral gyrus (control). Participants' plasma NfL concentration (in pg/mL) was measured on a single plex plate using the ultra‐sensitive single molecule array (Simoa) technology platform HD‐X. Memory performance was measured with the modified Cued Recall Test. We evaluated the relationship between FTP SUVRs, NfL, and memory performance using linear regression analysis. Sex and site were used as covariates.
Result
Increased FTP SUVR in the hippocampus and entorhinal cortex were associated with lower scores on free recall (hippocampus: r2 = 0.53, p <0.001; entorhinal: r2 = 0.35, p <0.001) and total recall (hippocampus: r2 = 0.46, p <0.001; entorhinal: r2 = 0.29, p <0.01). As expected, no association between FTP SUVRs and memory performance was found in the precentral gyrus. Additionally, higher plasma NfL concentrations were associated with lower free recall (r2 = 0.35, p <0.001) and total recall (r2 = 0.29, p <0.01). Further, increased levels of plasma NfL were associated with increased FTP SUVRs in the hippocampus (r2 = 0.38, p <0.001), entorhinal cortex (r2 = 0.28, p<0.01), and precentral gyrus (r2 = 0.19, p<0.05).
Conclusion
Increased levels of both in‐vivo tau in medial temporal ROIs and NfL in plasma were associated with worse memory performance, consistent with observations in the neurotypical population. Future work will investigate the impact of tau accumulation and NfL concentration on longitudinal cognitive decline in older adults with DS.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Down syndrome (DS) is associated with early development of Alzheimer’s disease pathology. Both the severity of tau pathology and the increase of neurofilament light chain (NfL) protein are ...correlated with cognitive decline in the neurotypical populations. Here, we assessed whether tau accumulation in the hippocampus and entorhinal cortex and plasma NfL concentrations were associated with memory performance in adults with DS.
Method
We used 18F‐AV‐1451 (FTP) positron emission tomography (PET) to assess tau accumulation in 44 participants enrolled in the multi‐site Alzheimer’s Disease in Down syndrome (ADDS) study (age 50.72 + 6.21). FTP‐PET scans were partial volume‐corrected, and weighted standardized uptake value ratio (SUVR) were calculated for each of the following regions of interests (ROIs): entorhinal cortex, hippocampus, and the precentral gyrus (control). Participants' plasma NfL concentration (in pg/mL) was measured on a single plex plate using the ultra‐sensitive single molecule array (Simoa) technology platform HD‐X. Memory performance was measured with the modified Cued Recall Test. We evaluated the relationship between FTP SUVRs, NfL, and memory performance using linear regression analysis. Sex and site were used as covariates.
Result
Increased FTP SUVR in the hippocampus and entorhinal cortex were associated with lower scores on free recall (hippocampus: r2 = 0.53, p <0.001; entorhinal: r2 = 0.35, p <0.001) and total recall (hippocampus: r2 = 0.46, p <0.001; entorhinal: r2 = 0.29, p <0.01). As expected, no association between FTP SUVRs and memory performance was found in the precentral gyrus. Additionally, higher plasma NfL concentrations were associated with lower free recall (r2 = 0.35, p <0.001) and total recall (r2 = 0.29, p <0.01). Further, increased levels of plasma NfL were associated with increased FTP SUVRs in the hippocampus (r2 = 0.38, p <0.001), entorhinal cortex (r2 = 0.28, p<0.01), and precentral gyrus (r2 = 0.19, p<0.05).
Conclusion
Increased levels of both in‐vivo tau in medial temporal ROIs and NfL in plasma were associated with worse memory performance, consistent with observations in the neurotypical population. Future work will investigate the impact of tau accumulation and NfL concentration on longitudinal cognitive decline in older adults with DS.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Trisomy 21 causes Down syndrome (DS) and is a recognized cause of Alzheimer’s disease (AD). The triplication of the amyloid precursor protein gene leads to an overexpression of ...amyloid‐beta (Aβ), which accumulates into extracellular plaques, followed by intracellular neurofibrillary tau tangles (Lott & Head, 2019). However, variability in the age of AD onset in DS spans 25+ years (Iulita et al., 2022). As the DS field moves to AD clinical trials, it is important to identify factors related to this variability, such as premorbid severity of intellectual disability (ID). We compared the age‐trajectory of the AD biomarkers Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type (full, mosaic, translocation) and APOE status
Method
Analyses involved 361 adults with DS (M = 45.22 years, SD = 9.92) from the Alzheimer’s Biomarkers Consortium‐Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was recorded. PET was acquired using 11C PiB for Aβ, and 18F AV‐1451 for tau in 162 participants. Aβ was quantified using the centiloid method and tau was quantified as SUVR (reference: cerebellar cortex) in a composite region determined as the volume‐weighted average of select FreeSurfer 5.3, T1 MR‐based components.
Results
General linear models controlling for site, age, trisomy type and APOE status indicated no significant effect of premorbid ID level by age on the cognitive outcomes (Figure 1a‐e). There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET (Figure 2a‐b). There was not a significant difference in age of those with mild cognitive impairment‐DS (MCI‐DS) or dementia by premorbid ID level (Figure 3).
Conclusion
This study adds to the characterization of the time course of AD pathology and clinical symptomology in DS. Findings provide robust evidence of a similar time course in AD trajectory across severity of ID, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials. Premorbid IQ may have little effect on AD biomarkers in DS in contrast to findings in neurotypical populations.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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