Publications by authors named "Elizabeth Head"

193 Publications

Postmortem Neocortical H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer's Disease.

Front Aging Neurosci 2021 13;13:728739. Epub 2021 Aug 13.

Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States.

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer's disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and -terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43-63 years and 17 late-onset AD cases aged 62-99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS.
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http://dx.doi.org/10.3389/fnagi.2021.728739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416541PMC
August 2021

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study.

Lancet Neurol 2021 08;20(8):605-614

Sant Pau Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain; Horizon 21 Consortium, Paris, France. Electronic address:

Background: Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.

Methods: We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses.

Findings: Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6-9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76-0·91) in the prodromal group and 0·94 (0·90-0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01-1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4-5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9-18·5) per year in the asymptomatic progressors group, and 16·0% (8·4-24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3-34·1).

Interpretation: Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials.

Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.
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http://dx.doi.org/10.1016/S1474-4422(21)00129-0DOI Listing
August 2021

Opportunities, barriers, and recommendations in down syndrome research.

Transl Sci Rare Dis 2021 15;5(3-4):99-129. Epub 2021 Apr 15.

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

Background: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community.

Objective: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan.

Methods: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS.

Results: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade.

Conclusions: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.
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http://dx.doi.org/10.3233/trd-200090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279178PMC
April 2021

Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer's disease.

Nat Genet 2021 08 8;53(8):1143-1155. Epub 2021 Jul 8.

Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, CA, USA.

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell types at a subset of AD risk loci defined by genome-wide association studies, demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, such as SREBF1, and their regulatory targets. Finally, we introduce single-nucleus consensus weighted gene coexpression analysis, a coexpression network analysis strategy robust to sparse single-cell data, and perform a systems-level analysis of the AD transcriptome.
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http://dx.doi.org/10.1038/s41588-021-00894-zDOI Listing
August 2021

APOE ε4 Association With Cognition and Alzheimer Disease Biomarkers in Down Syndrome-Implications for Clinical Trials and Treatments for All.

JAMA Neurol 2021 Aug;78(8):913-915

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri.

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http://dx.doi.org/10.1001/jamaneurol.2021.1649DOI Listing
August 2021

Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.

Alzheimers Dement (Amst) 2021 2;13(1):e12184. Epub 2021 May 2.

Institute of Psychiatry, Psychology, and Neuroscience Department of Forensic and Neurodevelopmental Sciences King's College London London UK.

Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages.

Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria.

Results: There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests.

Discussion: We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS.
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http://dx.doi.org/10.1002/dad2.12184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088591PMC
May 2021

Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain.

J Neurosci 2021 Jun 5;41(23):5124-5133. Epub 2021 May 5.

Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, California 92697

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain ( = 30, male and female). We find that tacrolimus reduces hippocampal ( = 0.001) and parahippocampal ( = 0.002) neurite density index, as well as protects against an age-associated increase in the parahippocampal ( = 0.007) orientation dispersion index. Tacrolimus also protects against an age-related decrease in fractional anisotropy in the prefrontal cortex ( < 0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administered at middle age. Hyperactive calcineurin signaling causes neuroinflammation and other neurobiological changes often associated with pathologic aging and Alzheimer's disease (AD). Controlling the expression of calcineurin before gross cognitive deficits are observable might serve as a promising avenue for preventing AD pathology. In this study, we show that the administration of the calcineurin inhibitor, tacrolimus, over 1 year prevents age- and AD-associated microstructural changes in the hippocampus, parahippocampal cortex, and prefrontal cortex of the middle-aged beagle brain, with no noticeable adverse effects. Tacrolimus is already approved by the Food and Drug Administration for use in humans to prevent solid organ transplant rejection, and our results bolster the promise of this drug to prevent AD and aging-related pathology.
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http://dx.doi.org/10.1523/JNEUROSCI.0361-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197636PMC
June 2021

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study.

J Clin Med 2021 Apr 28;10(9). Epub 2021 Apr 28.

Department of Psychiatry, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ, Aβ), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.
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http://dx.doi.org/10.3390/jcm10091907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124643PMC
April 2021

Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome.

J Alzheimers Dis 2021 ;79(2):671-681

University of North Texas Health Science Center, Institute for Translational Research and Department of Pharmacology and Neuroscience, Fort Worth, TX, USA.

Background: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.

Objective: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.

Methods: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.

Results: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.

Conclusion: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.
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http://dx.doi.org/10.3233/JAD-201167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273927PMC
September 2021

Longitudinal assessment of dementia measures in Down syndrome.

Alzheimers Dement (Amst) 2020 14;12(1):e12075. Epub 2020 Nov 14.

Department of Neurology University of Kentucky Lexington Kentucky USA.

Introduction: Early detection of dementia symptoms is critical in Down syndrome (DS) but complicated by clinical assessment barriers. The current study aimed to characterize cognitive and behavioral impairment using longitudinal trajectories comparing several measures of cognitive and behavioral functioning.

Methods: Measures included global cognitive status (Severe Impairment Battery [SIB]), motor praxis (Brief Praxis Test [BPT]), and clinical dementia informant ratings (Dementia Questionnaire for People with Learning Disabilities [DLD]). One-year reliability was assessed using a two-way mixed effect, consistency, single measurement intraclass correlation among non-demented participants. Longitudinal assessment of SIB, BPT, and DLD was completed using linear mixed effect models.

Results: One-year reliability (n = 52; 21 male) was moderate for DLD (0.69 to 0.75) and good for SIB (0.87) and BPT (0.80). Longitudinal analysis (n = 72) revealed significant age by diagnosis interactions for SIB ((2, 115.02) = 6.06, = .003), BPT ((2, 85.59) = 4.56, = .013), and DLD ((2, 103.56) = 4.48, = .014). SIB progression (PR) had a faster decline in performance versus no-dementia (ND) (t(159) = -2.87; = .013). Dementia had a faster decline in BPT performance versus ND (t(112) = -2.46; = .041). PR showed quickly progressing scores compared to ND (t(128) = -2.86; = .014).

Discussion: Current measures demonstrated moderate to good reliability. Longitudinal analysis revealed that SIB, BPT, and DLD changed with age depending on diagnostic progression; no change rates were dependent on baseline cognition, indicating usefulness across a variety of severity levels in DS.
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http://dx.doi.org/10.1002/dad2.12075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666427PMC
November 2020

The AT(N) framework for Alzheimer's disease in adults with Down syndrome.

Alzheimers Dement (Amst) 2020 27;12(1):e12062. Epub 2020 Oct 27.

Institute for Translational Research and Department of Pharmacology and Neuroscience University of North Texas Health Science Center Fort Worth Texas USA.

The National Institute on Aging in conjunction with the Alzheimer's Association (NIA-AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which to select and enrich samples for clinical trials. This new framework is highly flexible and allows the addition of newly confirmed AD biomarkers into the existing AT(N) groups. As biomarkers for other pathological processes are validated, they can also be added to the AT(N) classification scheme, which will allow for better characterization and staging of AD in DS. These biological classifications can then be merged with clinical staging for an examination of factors that impact the biological and clinical progression of the disease. Here, we leverage previously published guidelines for the AT(N) framework to generate such a plan for AD among adults with DS.
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http://dx.doi.org/10.1002/dad2.12062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588820PMC
October 2020

Distribution of microglial phenotypes as a function of age and Alzheimer's disease neuropathology in the brains of people with Down syndrome.

Alzheimers Dement (Amst) 2020 14;12(1):e12113. Epub 2020 Oct 14.

Department of Pathology and Laboratory Medicine University of California, Irvine Irvine California USA.

Introduction: Microglial cells play an important role in the development of Alzheimer's disease (AD). People with Down syndrome (DS) inevitably develop AD neuropathology (DSAD) by 40 years of age. We characterized the distribution of different microglial phenotypes in the brains of people with DS and DSAD.

Methods: Autopsy tissue from the posterior cingulate cortex (PCC) from people with DS, DSAD, and neurotypical controls was immunostained with the microglial marker Iba1 to assess five microglia morphological types.

Results: Individuals with DS have more hypertrophic microglial cells in their white matter. In the gray matter, individuals with DSAD had significantly fewer ramified microglia and more dystrophic microglia than controls and the younger individuals with DS. The DSAD group also exhibited more rod-shaped and amoeboid cells than the AD group.

Discussion: Individuals with DS and DSAD show a microglial phenotype that distinguishes them from non-DS controls.
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http://dx.doi.org/10.1002/dad2.12113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560512PMC
October 2020

Alzheimer-Related Cerebrovascular Disease in Down Syndrome.

Ann Neurol 2020 12 9;88(6):1165-1177. Epub 2020 Oct 9.

Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY.

Objective: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.

Methods: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status.

Results: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct.

Interpretation: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.
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http://dx.doi.org/10.1002/ana.25905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729262PMC
December 2020

Feasibility of dual-task gait to estimate Alzheimer's related cognitive decline in Down syndrome.

Alzheimers Dement (Amst) 2020 25;12(1):e12092. Epub 2020 Aug 25.

Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA.

Introduction: The striatum and frontal lobes have been shown to have early Alzheimer's disease (AD) neuropathology and are critical for motor and cognitive function. We hypothesized gait would be associated with early-stage dementia in Down syndrome (DS), a cohort at risk for AD.

Methods: Twenty-eight participants with DS were enrolled in the study. Participants walked at their self-selected pace and while completing a dual task (counting, obstacle, or counting+obstacle).

Results: All participants were able to complete the self-paced condition and 78.57-96.42% completed the dual-task conditions. There was a trend for greater dual-task effects on gait velocity based on dementia diagnosis. Gait velocity had stronger associations with clinical dementia assessments than age or diagnosis.

Discussion: A dual-task gait paradigm is feasible to conduct with adults with DS and is associated with age and cognitive impairment. Dual-task gait may serve as an indicator of early stage dementia in DS.
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http://dx.doi.org/10.1002/dad2.12092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447907PMC
August 2020

Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention.

Prog Neurobiol 2021 01 11;196:101892. Epub 2020 Aug 11.

Department of Biochemical Sciences "A. Rossi Fanelli", Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy. Electronic address:

A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor. In contrast, PERK prolonged activation leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), in which aging confers a high risk of Alzheimer disease (AD). By investigating human DS frontal cortices, we found early and sustained PERK activation associated with the induction of eIF2α and ATF4 downstream signals. We also observed that the Nrf2 response is uncoupled from PERK and its antioxidant effects are repressed in a mechanism implicating the transcription repressor Bach1. The pharmacological inhibition of PERK in DS mice reduced eIF2α-related translational repression and promoted Nrf2 nuclear translocation, favoring the rescue of Nrf2/Bach1 imbalance. The further analysis of peripheral cells from living DS individuals provided strong support of the pathological link between PERK and trisomy 21. Our results suggest that failure to regulate the PERK pathway is a peculiar characteristic of DS pathology and it may represent an essential step to promote cellular dysfunction, which actively contributes in the brain to the early development of AD.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101892DOI Listing
January 2021

The Alzheimer's Biomarker Consortium-Down Syndrome: Rationale and methodology.

Alzheimers Dement (Amst) 2020 3;12(1):e12065. Epub 2020 Aug 3.

Irvine School of Medicine Department of Pediatrics University of California Orange California USA.

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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http://dx.doi.org/10.1002/dad2.12065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396809PMC
August 2020

Proteomic profiles for Alzheimer's disease and mild cognitive impairment among adults with Down syndrome spanning serum and plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study.

Alzheimers Dement (Amst) 2020 30;12(1):e12039. Epub 2020 Jun 30.

Department of Pharmacology and Neuroscience Institute for Translational Research University of North Texas Health Science Center Fort Worth Texas USA.

Introduction: Previously generated serum and plasma proteomic profiles were examined among adults with Down syndrome (DS) to determine whether these profiles could discriminate those with mild cognitive impairment (MCI-DS) and Alzheimer's disease (DS-AD) from those cognitively stable (CS).

Methods: Data were analyzed on n = 305 (n = 225 CS; n = 44 MCI-DS; n = 36 DS-AD) enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS).

Results: Distinguishing MCI-DS from CS, the serum profile produced an area under the curve (AUC) = 0.95 (sensitivity [SN] = 0.91; specificity [SP] = 0.99) and an AUC = 0.98 (SN = 0.96; SP = 0.97) for plasma when using an optimized cut-off score. Distinguishing DS-AD from CS, the serum profile produced an AUC = 0.93 (SN = 0.81; SP = 0.99) and an AUC = 0.95 (SN = 0.86; SP = 1.0) for plasma when using an optimized cut-off score. AUC remained unchanged to slightly improved when age and sex were included. Eotaxin3, interleukin (IL)-10, C-reactive protein, IL-18, serum amyloid A , and FABP3 correlated fractions at r> = 0.90.

Discussion: Proteomic profiles showed excellent detection accuracy for MCI-DS and DS-AD.
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http://dx.doi.org/10.1002/dad2.12039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327223PMC
June 2020

Biomarkers in Down syndrome can help us understand Alzheimer's disease.

Lancet 2020 06;395(10242):1951-1953

Department of Neurology, Washington University, St Louis, MO, USA.

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http://dx.doi.org/10.1016/S0140-6736(20)30916-8DOI Listing
June 2020

Further understanding the connection between Alzheimer's disease and Down syndrome.

Alzheimers Dement 2020 07 16;16(7):1065-1077. Epub 2020 Jun 16.

Alzheimer's Therapeutics Research Institute and Department of Neurology, University of Southern California, Los Angeles, California, USA.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.
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http://dx.doi.org/10.1002/alz.12112DOI Listing
July 2020

Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.

Alzheimers Dement (Amst) 2020 5;12(1):e12028. Epub 2020 Apr 5.

Taub Institute for Research in Alzheimer's Disease and the Aging Brain Columbia University New York New York USA.

Introduction: Disruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).

Methods: We examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS-AD), 43 who met criteria for mild cognitive impairment (DS-MCI), and 211 who were cognitively unaffected and stable (CS).

Results: We measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate-corrected < 0.05. From the DE features, a nine-feature classifier model classified the CS and DS-AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two-feature model classified the DS-MCI and DS-AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism.

Discussion: Our results reveal metabolic alterations in DS-AD that are similar to those seen in LOAD. The pattern of results in this cross-sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non-demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS-AD.
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http://dx.doi.org/10.1002/dad2.12028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131985PMC
April 2020

APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease.

Neurobiol Dis 2020 06 12;139:104834. Epub 2020 Mar 12.

Magnetic Resonance Research Center, Yale University, New Haven, CT, United States of America; Quantitative Neuroscience with Magnetic Resonance Core Center, Yale University, New Haven, CT, United States of America; Department of Diagnostic Radiology, Yale University, New Haven, CT, United States of America; Department of Biomedical Engineering, Yale University, New Haven, CT, United States of America.

The ε4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid beta (Aβ) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit Aβ retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in the mice that express human APOE4 gene and overexpress Aβ (the E4FAD mice). Another goal of the study was to identify the potential pharmacogenetic differences in response to rapamycin between the E4FAD and E3FAD mice, the mice with human APOE ε3 allele. We used multi-modal MRI to measure in vivo cerebral blood flow (CBF), neurotransmitter levels, white matter integrity, water content, cerebrovascular reactivity (CVR) and somatosensory response; used behavioral assessments to determine cognitive function; used biochemistry assays to determine Aβ retention and blood-brain barrier (BBB) functions; and used metabolomics to identify brain metabolic changes. We found that in the E4FAD mice, rapamycin normalized bodyweight, restored CBF (especially in female), BBB activity for Aβ transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice. As the multi-modal MRI methods used in the study are readily to be used in humans and rapamycin is FDA-approved, our results may pave a way for future clinical testing of the pharmacogenetic responses in humans with different APOE alleles, and potentially using rapamycin to prevent AD for asymptomatic APOE4 carriers.
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http://dx.doi.org/10.1016/j.nbd.2020.104834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486698PMC
June 2020

Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome.

Neurobiol Dis 2020 04 24;137:104772. Epub 2020 Jan 24.

Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy. Electronic address:

Dysregulation of insulin signaling pathway with reduced downstream neuronal survival and plasticity mechanisms is a fundamental abnormality observed in Alzheimer's disease (AD) brain. This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the uncoupling of insulin receptor (IR) from its direct substrate (IRS1). Considering that Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration, i.e., brain insulin resistance, in DS and whether it would contribute to early onset AD in DS population. Changes of levels and activation of main brain proteins belonging to the insulin signaling pathway (i.e., IR, IRS1, PTEN, GSK3β, PKCζ, AS160, GLUT4) were evaluated. Furthermore, we analyzed whether changes of these proteins were associated with alterations of: (i) proteins regulating brain energy metabolism; (ii) APP cleavage; and (ii) regulation of synaptic plasticity mechanisms in post-mortem brain samples collected from people with DS before and after the development of AD pathology (DSAD) compared with their age-matched controls. We found that DS cases were characterized by key markers of brain insulin resistance (reduced IR and increased IRS1 inhibition) early in life. Furthermore, downstream from IRS1, an overall uncoupling among the proteins of insulin signaling was observed. Dysregulated brain insulin signaling was associated with reduced hexokinase II (HKII) levels and proteins associated with mitochondrial complexes levels as well as with reduced levels of syntaxin in DS cases. Tellingly, these alterations precede the development of AD neuropathology and clinical presentations in DS. We propose that markers of brain insulin resistance rise earlier with age in DS compared with the general population and may contribute to the cognitive impairment associated with the early development of AD in DS.
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http://dx.doi.org/10.1016/j.nbd.2020.104772DOI Listing
April 2020

Brain-Blood Partition Coefficient and Cerebral Blood Flow in Canines Using Calibrated Short TR Recovery (CaSTRR) Correction Method.

Front Neurosci 2019 5;13:1189. Epub 2019 Nov 5.

F. Joseph Halcomb III, Department of Biomedical Engineering, University of Kentucky, Lexington, KY, United States.

The brain-blood partition coefficient (BBPC) is necessary for quantifying cerebral blood flow (CBF) when using tracer based techniques like arterial spin labeling (ASL). A recent improvement to traditional MRI measurements of BBPC, called calibrated short TR recovery (CaSTRR), has demonstrated a significant reduction in acquisition time for BBPC maps in mice. In this study CaSTRR is applied to a cohort of healthy canines ( = 17, age = 5.0 - 8.0 years) using a protocol suited for application in humans at 3T. The imaging protocol included CaSTRR for BBPC maps, pseudo-continuous ASL for CBF maps, and high resolution anatomical images. The standard CaSTRR method of normalizing BBPC to gadolinium-doped deuterium oxide phantoms was also compared to normalization using hematocrit (Hct) as a proxy value for blood water content. The results show that CaSTRR is able to produce high quality BBPC maps with a 4 min acquisition time. The BBPC maps demonstrate significantly higher BBPC in gray matter (0.83 ± 0.05 mL/g) than in white matter (0.78 ± 0.04 mL/g, = 0.006). Maps of CBF acquired with pCASL demonstrate a negative correlation between gray matter perfusion and age ( = 0.003). Voxel-wise correction for BBPC is also shown to improve contrast to noise ratio between gray and white matter in CBF maps. A novel aspect of the study was to show that that BBPC measurements can be calculated based on the known Hct of the blood sample placed in scanner. We found a strong correlation ( = 0.81 in gray matter, = 0.59 in white matter) established between BBPC maps normalized to the doped phantoms and BBPC maps normalized using Hct. This obviates the need for doped water phantoms which simplifies both the acquisition protocol and the post-processing methods. Together this suggests that CaSTRR represents a feasible, rapid method to account for BBPC variability when quantifying CBF. As canines have been used widely for aging and Alzheimer's disease studies, the CaSTRR method established in the animals may further improve CBF measurements and advance our understanding of cerebrovascular changes in aging and neurodegeneration.
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http://dx.doi.org/10.3389/fnins.2019.01189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848028PMC
November 2019

Alzheimer's disease in aging Down syndrome.

Dev Neurobiol 2019 07;79(7):611-612

Department of Epidemiology, Department of Neurology, Columbia University Medical Center, Sergievsky Center, Taub Institute, New York, New York.

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http://dx.doi.org/10.1002/dneu.22717DOI Listing
July 2019

Assessing general cognitive and adaptive abilities in adults with Down syndrome: a systematic review.

J Neurodev Disord 2019 08 30;11(1):20. Epub 2019 Aug 30.

Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, London, SE5 8AF, UK.

Background: Measures of general cognitive and adaptive ability in adults with Down syndrome (DS) used by previous studies vary substantially. This review summarises the different ability measures used previously, focusing on tests of intelligence quotient (IQ) and adaptive behaviour (AB), and where possible examines floor effects and differences between DS subpopulations. We aimed to use information regarding existing measures to provide recommendations for individual researchers and the DS research community.

Results: Nineteen studies reporting IQ test data met inclusion for this review, with 17 different IQ tests used. Twelve of these IQ tests were used in only one study while five were used in two different studies. Eleven studies reporting AB test data met inclusion for this review, with seven different AB tests used. The only AB scales to be used by more than one study were the Vineland Adaptive Behaviour Scale (VABS; used by three studies) and the Vineland Adaptive Behavior Scale 2nd Edition (VABS-II; used by two studies). A variety of additional factors were identified which make comparison of test scores between studies problematic, including different score types provided between studies (e.g. raw scores compared to age-equivalent scores) and different participant inclusion criteria (e.g. whether individuals with cognitive decline were excluded). Floor effects were common for IQ tests (particularly for standardised test scores). Data exists to suggest that floor effects may be minimised by the use of raw test scores rather than standardised test scores. Raw scores may, therefore, be particularly useful in longitudinal studies to track change in cognitive ability over time.

Conclusions: Studies assessing general ability in adults with DS are likely to benefit from the use of both IQ and AB scales. The DS research community may benefit from the development of reporting standards for IQ and AB data, and from the sharing of raw study data enabling further in-depth investigation of issues highlighted by this review.
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http://dx.doi.org/10.1186/s11689-019-9279-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716931PMC
August 2019

Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease.

Dev Neurobiol 2019 07 26;79(7):622-638. Epub 2019 Aug 26.

Department of Neurology, The University of California, Irvine, Irvine, California.

Down syndrome (DS) is a well-known neurodevelopmental disorder most commonly caused by trisomy of chromosome 21. Because individuals with DS almost universally develop heavy amyloid burden and Alzheimer's disease (AD), biomarker discovery in this population may be extremely fruitful. Moreover, any AD biomarker in DS that does not directly involve amyloid pathology may be of high value for understanding broader mechanisms of AD generalizable to the neurotypical population. In this retrospective biomarker discovery study, we examined banked peripheral plasma samples from 78 individuals with DS who met clinical criteria for AD at the time of the blood draw (DS-AD) and 68 individuals with DS who did not (DS-NAD). We measured the relative abundance of approximately 5,000 putative features in the plasma using untargeted mass spectrometry (MS). We found significantly higher levels of a peak putatively annotated as lactic acid in the DS-AD group (q = .014), a finding confirmed using targeted MS (q = .011). Because lactate is the terminal product of glycolysis and subsequent lactic acid fermentation, we performed additional targeted MS focusing on central carbon metabolism which revealed significantly increased levels of pyruvic (q = .03) and methyladipic (q = .03) acids in addition to significantly lower levels of uridine (q = .007) in the DS-AD group. These data suggest that AD in DS is accompanied by a shift from aerobic respiration toward the less efficient fermentative metabolism and that bioenergetically derived metabolites observable in peripheral blood may be useful for detecting this shift.
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http://dx.doi.org/10.1002/dneu.22716DOI Listing
July 2019

Neuropathological correlates of amyloid PET imaging in Down syndrome.

Dev Neurobiol 2019 07 17;79(7):750-766. Epub 2019 Aug 17.

Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.

Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12-30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid-based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.
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http://dx.doi.org/10.1002/dneu.22713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892598PMC
July 2019

Paving the Way for Therapy: The Second International Conference of the Trisomy 21 Research Society.

Mol Syndromol 2019 Jan 30;9(6):279-286. Epub 2018 Oct 30.

University of California-Irvine, Irvine, CA, USA.

In the last decade, a number of important research advances in different fields have allowed Down syndrome (DS) research to flourish, creating a time of both unparalleled opportunity and considerable challenge. Building a scientific framework that distills mechanisms involved in the developmental intellectual disability of DS as well as the early-onset component of Alzheimer disease and the several other comorbidities associated with the condition is a challenge that scientists are now tackling using novel technologies and multidisciplinary approaches. The Trisomy 21 Research Society (T21RS) was founded in 2014 to address these evolving needs and challenges. In June of 2017, the T21RS held its 2nd International Conference in Chicago, USA. With more than 200 scientists, advocates, people with DS, and family members in attendance, the meeting served as a forum for the discussion of the latest research and clinical advances as well as the most compelling needs of people with DS and their families.
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http://dx.doi.org/10.1159/000494231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381890PMC
January 2019

Dementia in Down syndrome: unique insights for Alzheimer disease research.

Nat Rev Neurol 2019 03;15(3):135-147

Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. Amyloid-β accumulates in the brain across the lifespan of people with DS, which provides a unique opportunity to understand the temporal progression of AD and the epigenetic factors that contribute to the age of dementia onset. This age dependency in the development of AD in DS can inform research into the presentation of AD in the general population, in whom a longitudinal perspective of the disease is not often available. Comparison of the risk profiles, biomarker profiles and genetic profiles of adults with DS with those of individuals with AD in the general population can help to determine common and distinct pathways as well as mechanisms underlying increased risk of dementia. This Review evaluates the similarities and differences between the pathological cascades and genetics underpinning DS and AD with the aim of providing a platform for common exploration of these disorders.
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http://dx.doi.org/10.1038/s41582-018-0132-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061428PMC
March 2019

Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.

Alzheimers Dement 2019 02 13;15(2):292-312. Epub 2018 Dec 13.

Department of Psychology, University of Glasgow, Glasgow, Scotland, UK.

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
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http://dx.doi.org/10.1016/j.jalz.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368893PMC
February 2019
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