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INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. HIGHLIGHTS: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education.
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INTRODUCTION: Well-chosen biomarkers have the potential to increase the efficiency of clinical trials and drug discovery and should show good precision as well as clinical validity. METHODS: We suggest measures that operationalize these criteria and describe a general approach that can be used for inference-based comparisons of biomarker performance. The methods are applied to measures obtained from structural magnetic resonance imaging (MRI) from individuals with mild dementia (n = 70) or mild cognitive impairment (MCI; n = 303) enrolled in the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Ventricular volume and hippocampal volume showed the best precision in detecting change over time in both individuals with MCI and with dementia. Differences in clinical validity varied by group. DISCUSSION: The methodology presented provides a standardized framework for comparison of biomarkers across modalities and across different methods used to generate similar measures and will help in the search for the most promising biomarkers. HIGHLIGHTS: A framework for comparison of biomarkers on pre-defined criteria is presented. Criteria for comparison include precision in capturing change and clinical validity. Ventricular volume has high precision in change for both dementia and mild cognitive impairment (MCI) trials. Imaging measures' performance in clinical validity varies more for dementia than for MCI.
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The goal of the Biostatistics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been to ensure that sound study designs and statistical methods are used to meet the overall goals of ADNI. We have supported the creation of a well-validated and well-curated longitudinal database of clinical and biomarker information on ADNI participants and helped to make this accessible and usable for researchers. We have developed a statistical methodology for characterizing the trajectories of clinical and biomarker change for ADNI participants across the spectrum from cognitively normal to dementia, including multivariate patterns and evidence for heterogeneity in cognitive aging. We have applied these methods and adapted them to improve clinical trial design. ADNI-4 will offer us a chance to help extend these efforts to a more diverse cohort with an even richer panel of biomarker data to support better knowledge of and treatment for Alzheimer's disease and related dementias. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) Biostatistics Core provides study design and analytic support to ADNI investigators. Core members develop and apply novel statistical methodology to work with ADNI data and support clinical trial design. The Core contributes to the standardization, validation, and harmonization of biomarker data. The Core serves as a resource to the wider research community to address questions related to the data and study as a whole.
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Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.
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Enfermedad de Alzheimer , Hispánicos o Latinos , Cuerpos de Lewy , Población Blanca , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/etnología , Femenino , Masculino , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Cuerpos de Lewy/patología , Angiopatía Amiloide Cerebral/patología , Angiopatía Amiloide Cerebral/etnología , alfa-Sinucleína/metabolismo , Encéfalo/patología , Enfermedades de los Pequeños Vasos Cerebrales/patología , Enfermedades de los Pequeños Vasos Cerebrales/etnología , Arterioloesclerosis/patologíaRESUMEN
The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides , Neuroimagen/métodos , Biomarcadores , Progresión de la Enfermedad , Proteínas tau , Disfunción Cognitiva/diagnóstico por imagenRESUMEN
INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Proteína C9orf72/genética , Pruebas Genéticas , Estudios Longitudinales , Mutación , Presenilina-1/genética , Presenilina-2/genéticaRESUMEN
INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Reproducibilidad de los Resultados , Lóbulo Temporal/patología , Imagen por Resonancia Magnética/métodos , Atrofia/patología , BiomarcadoresRESUMEN
Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Radiocirugia , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapiaRESUMEN
INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. METHODS: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. HIGHLIGHTS: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Sustancia Blanca , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/complicaciones , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Imagen por Resonancia Magnética , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/complicaciones , Proteínas Amiloidogénicas , AmiloideRESUMEN
INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3 , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Estudios Longitudinales , Biomarcadores/líquido cefalorraquídeo , Neurogranina/líquido cefalorraquídeoRESUMEN
Despite the increasing demographic diversity of the United States' aging population, there remain significant gaps in post-mortem research investigating the ethnoracial heterogeneity in the neuropathological landscape of Alzheimer Disease (AD). Most autopsy-based studies have focused on cohorts of non-Hispanic White decedents (NHWD), with few studies including Hispanic decedents (HD). We aimed to characterize the neuropathologic landscape of AD in NHWD (n = 185) and HD (n = 92) evaluated in research programs across three institutions: University of California San Diego, University of California Davis, and Columbia University. Only persons with a neuropathologic diagnosis of intermediate/high AD determined by NIA Reagan and/or NIA-AA criteria were included. A frequency-balanced random sample without replacement was drawn from the NHWD group using a 2:1 age and sex matching scheme with HD. Four brain areas were evaluated: posterior hippocampus, frontal, temporal, and parietal cortices. Sections were stained with antibodies against Aß (4G8) and phosphorylated tau (AT8). We compared the distribution and semi-quantitative densities for neurofibrillary tangles (NFTs), neuropil threads, core, diffuse, and neuritic plaques. All evaluations were conducted by an expert blinded to demographics and group status. Wilcoxon's two-sample test revealed higher levels of neuritic plaques in the frontal cortex (p = 0.02) and neuropil threads (p = 0.02) in HD, and higher levels of cored plaques in the temporal cortex in NHWD (p = 0.02). Results from ordinal logistic regression controlling for age, sex, and site of origin were similar. In other evaluated brain regions, semi-quantitative scores of plaques, tangles, and threads did not differ statistically between groups. Our results demonstrate HD may be disproportionately burdened by AD-related pathologies in select anatomic regions, particularly tau deposits. Further research is warranted to understand the contributions of demographic, genetic, and environmental factors to heterogeneous pathological presentations.
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Enfermedad de Alzheimer , Humanos , Anciano , Placa Amiloide , Blanco , Neuropatología , Ovillos NeurofibrilaresRESUMEN
INTRODUCTION: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). METHODS: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). RESULTS: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. DISCUSSION: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.
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Enfermedad de Alzheimer , Humanos , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Estudios Longitudinales , Recolección de DatosRESUMEN
OBJECTIVE: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. METHODS: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]). RESULTS: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. CONCLUSIONS: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Apolipoproteínas E/genética , Estudios Longitudinales , Apolipoproteína E4/genética , Recolección de DatosRESUMEN
INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022. METHODS: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (â¼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials. RESULTS AND DISCUSSION: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Participación de la Comunidad , Participación de los Interesados , Neuroimagen/métodos , Biomarcadores , Disfunción Cognitiva/diagnóstico por imagen , Péptidos beta-AmiloidesRESUMEN
Alzheimer's disease is marked by brain damage from tau and amyloid aggregates, particularly to the hippocampus and the default network. A new study in PLOS Biology shows sex differences in the patterns of damage and in their association with risk and protective factors.
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Enfermedad de Alzheimer , Lesiones Encefálicas , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/etiología , Proteínas tau/metabolismo , Caracteres Sexuales , Alelos , Encéfalo/metabolismo , Apolipoproteínas E , Factores de RiesgoRESUMEN
In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 µm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p<0.05) with 70.6% down-regulated in NBDG-low cells. Hierarchical clustering of DETs showed distinct segregation of NBDG-low from NBDG-med and NBDG-high groups with marked transcription expression alterations in the NBDG-low group consistent with cancer survival. In conclusion, A unique subpopulation of cells with low glucose uptake (NBDG-low) in B-ALL was discovered. These cells, despite their quiescence characteristics, once transplanted in mice, showed potent leukemia initiating capacity. Although NBDG-med cells also initiated leukemia, gene expression profiling revealed a distinct signature that clearly distinguishes NBDG-low cells from NBDG-med and the rest of the leukemia populations. These results suggest that NBDG-low cells may represent quiescent LSCs. These cells can be activated in the appropriate environment in vivo, showing leukemia initiating capacity. Our study provides insight into the biologic mechanisms of B-ALL initiation and survival.
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The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-ß42, amyloid-ß40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the â¼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-ß42, amyloid-ß40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.
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Enfermedad de Alzheimer , Amiloidosis , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Imagen por Resonancia Magnética/métodos , BiomarcadoresRESUMEN
INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. METHODS: We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion. RESULTS: Disease progression studies supported pivotal roles for regional amyloid beta (Aß) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aß status. Plasma Aß, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity. DISCUSSION: ADNI has had a profound impact in improving clinical trials for AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Biomarcadores , Progresión de la Enfermedad , Humanos , Neuroimagen/métodos , Proteínas tauRESUMEN
Stress is a significant part of daily life, and systemic social inequities, such as racism and discrimination, are well-established contributors of chronic stress for African Americans. Added exposure to the stress of caregiving may exacerbate adverse health outcomes. This secondary analysis describes subjective and objective stress in African American family caregivers, and relationships of subjective and objective stress to health outcomes. Baseline data from 142 African American dementia family caregivers from the "Great Village" study were described using means and frequencies; regression models and Pearson's correlation were used to examine associations between demographics, social determinants of health, and health outcomes. Mixed models were used to examine change and change variation in cortisol. Most caregivers had moderate degrees of stress. Stress was associated with sleep disruption and depressive symptoms, and discrimination appeared to be an independent contributor to depressive symptoms. This work provides a foundation for interpreting subjective and objective indicators of stress to tailor existing multicomponent interventions.
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Negro o Afroamericano , Demencia , Cuidadores , Humanos , Hidrocortisona , Estrés PsicológicoRESUMEN
Several models have been developed to predict the effects of folic acid fortification programs on prevention of neural tube defects (NTDs), but each relies on different assumptions and data inputs. We identified and reviewed 7 models that predict the effects of folic acid intake or status on NTD risk. We applied 4 of these models [the original and a modified version of the Lives Saved Tool (LiST) and models developed by Arth et al. and Wald et al.] to predict the effect of folic acid fortification of wheat flour on reduction of NTDs using national survey data from Cameroon. The estimated percentage of NTDs averted due to fortified wheat flour (5.0 µg folic acid/g flour) varied by predictive model, with a 21-31% reduction in LiST to 83% in Arth's model, and 15% in Wald's model. As the simulated fortification level was increased from 1.0 to 7.0 µg folic acid/g flour, the pattern of change in estimated numbers of NTDs averted differed due to different model assumptions: the number of NTDs averted increased and then reached a plateau in the modified LiST model (as would be expected in real-world conditions), increased sharply in Arth's model, and increased continuously in Wald's model. This wide variation in predicted effects, and implausible results in some cases, undermines the models' utility for users of model outputs. Concurrent collection of dietary and biomarker data, including plasma and RBC folate concentrations, and NTD outcomes, is necessary to validate these models and monitor change in folic acid intake, folate-related biomarkers, and reduced NTD risk due to fortification. In the meantime, models based on erythrocyte folate concentration are recommended, based on biological plausibility and consistency with empirical evidence. Where erythrocyte folate data are unavailable, sensitivity analyses (using several models) could be conducted to examine the range of possible outcomes.