Faculty Bibliography
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76
Impact of Dendritic Spine Loss on Excitability of Hippocampal CA1 Pyramidal Neurons: A Computational Study of Early Alzheimer Disease
Synaptic spine loss is an early pathophysiologic hallmark of Alzheimer disease (AD) that precedes overt loss of dendritic architecture and frank neurodegeneration. While spine loss signifies a decreased engagement of postsynaptic neurons by presynaptic targets, the degree to which loss of spines and their passive components impacts the excitability of postsynaptic neurons and responses to surviving synaptic inputs is unclear. Using passive multicompartmental models of CA1 pyramidal neurons (PNs), implicated in early AD, we find that spine loss alone drives a boosting of remaining inputs to their proximal and distal dendrites, targeted by CA3 and entorhinal cortex (EC), respectively. This boosting effect is higher in distal versus proximal dendrites and can be mediated by spine loss restricted to the distal compartment, enough to impact synaptic input integration, somatodendritic backpropagation, and plateau potential generation. This has particular relevance to very early stages of AD in which pathophysiology extends from EC to CA1.
PMCID:12344546
PMID: 40799150
ISSN: 1098-1063
CID: 5907262
Associations Between Hippocampal Transverse Relaxation Time and Amyloid PET in Cognitively Normal Aging Adults
BACKGROUND:Identifying early neuropathological changes in Alzheimer's disease (AD) is important for improving treatment efficacy. Among quantitative MRI measures, transverse relaxation time (T2) has been shown to reflect tissue microstructure relevant in aging and neurodegeneration; however, findings regarding T2 changes in both normal aging and AD have been inconsistent. The association between T2 and amyloid-beta (Aβ) accumulation, a hallmark of AD pathology, is also unclear, particularly in cognitively normal individuals who may be in preclinical stages of the disease. PURPOSE/OBJECTIVE:To investigate longitudinal hippocampal T2 changes in a cognitively normal cohort of older adults and their association with global Aβ accumulation. STUDY TYPE/METHODS:Retrospective, longitudinal. SUBJECTS/METHODS:56 cognitively normal adults between 55 and 90 years of age (17 males and 39 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:3 Tesla; multi-echo spin echo sequence for T2 mapping; 18F-florbetaben positron emission tomography for Aβ measurement. ASSESSMENT/RESULTS:Bilateral hippocampal T2 and volume were extracted to relate to Aβ PET measurements. To understand variations in AD risk, participants were separated into Aβ-high and Aβ-low subgroups using a predetermined threshold. STATISTICAL TESTS/METHODS:Linear mixed-effect models and general linear models were used. A p-value < 0.025 was considered significant to account for bilateral comparisons. RESULTS:Older age was associated with increased T2 in the bilateral hippocampus (left: β = 0.30, right: β = 0.25) and smaller hippocampal volume on the left (β = -0.12). In the Aβ-low subgroup, both longitudinal T2 increase rates (β = 0.65) in the left hippocampus and bilateral cross-sectional T2 (left: β = 0.64, right: β = 0.46) were positively correlated with Aβ PET, independent of hippocampal volume. DATA CONCLUSION/CONCLUSIONS:This study provided in vivo evidence linking hippocampal T2 to Aβ accumulation in cognitively normal aging individuals, suggesting that quantitative T2 may be sensitive to microstructural changes accompanying early Aβ pathology, such as neuroinflammation, demyelination, and reduced tissue integrity. EVIDENCE LEVEL/METHODS:3. TECHNICAL EFFICACY/UNASSIGNED:Stage 2.
PMID: 40844208
ISSN: 1522-2586
CID: 5909362
Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease
BACKGROUND:Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS:We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS:Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.
PMCID:12273372
PMID: 40676597
ISSN: 1474-760x
CID: 5897492
Tablet-Based Assessment of Picture Naming in Prodromal Alzheimer's Disease: An Accessible and Effective Tool for Distinguishing Mild Cognitive Impairment from Normal Aging
Effective mild cognitive impairment (MCI) screening requires accessible testing. This study compared two tests for distinguishing MCI patients from controls: Rapid Automatized Naming (RAN) for naming speed and Low Contrast Letter Acuity (LCLA) for sensitivity to low contrast letters. Two RAN tasks were used: the Mobile Universal Lexicon Evaluation System (MULES, picture naming) and Staggered Uneven Number test (SUN, number naming). Both RAN tasks were administered on a tablet and in a paper/pencil format. The tablet format was administered using the Mobile Integrated Cognitive Kit (MICK) application. LCLA was tested at 2.5% and 1.25% contrast. Sixty-four participants (31 MCI, 34 controls; mean age 73.2 ± 6.8 years) were included. MCI patients were slower than controls for paper/pencil (75.0 vs. 53.6 sec, p < 0.001), and tablet MULES (69.0 sec vs. 50.2 sec, p = 0.01). The paper/pencil SUN showed no significant difference (MCI: 59.5 sec vs. controls: 59.9 sec, p = 0.07), nor did tablet SUN (MCI: 59.3 sec vs. controls: 55.7 sec, p = 0.36). MCI patients had worse performance on LCLA testing at 2.5% contrast (33 letters vs. 36, p = 0.04*) and 1.25% (0 letters vs. 14. letters, p < 0.001). Receiver operating characteristic (ROC) analysis showed similar performance of paper/pencil and tablet MULES in distinguishing MCI from controls (AUC = 0.77), outperforming both SUN (AUC = 0.63 paper, 0.59 tablet) and LCLA (2.5% contrast: AUC = 0.65, 1.25% contrast: AUC = 0.72). The MULES, in both formats, may be a valuable screening tool for MCI.
PMID: 40499520
ISSN: 1421-9824
CID: 5868792
The association between measures of sleepiness and subjective cognitive decline symptoms in a diverse population of cognitively normal older adults
Subjective cognitive decline (SCD) is associated with preclinical Alzheimer's disease (AD). Suboptimal sleep is also a risk factor for cognitive decline, but with unclear relationship to SCD. We conducted a retrospective cross-sectional study in a biracial research cohort of 148 cognitively normal older adults who underwent quantification of SCD (Cognitive Change Index; CCI), sleepiness (Epworth Sleepiness Scale; ESS), depression (Geriatric Depression Scale; GDS), and amyloid/tau PET. ESS score was associated with total, amnestic, and non-amnestic CCI scores, after adjustment for GDS, amyloid/tau burden, and race. This supports future longitudinal work on how sleepiness impacts SCD outcomes.
PMID: 40170406
ISSN: 1875-8908
CID: 5819022
-Penalized Multinomial Regression: Estimation, Inference, and Prediction, With an Application to Risk Factor Identification for Different Dementia Subtypes
High-dimensional multinomial regression models are very useful in practice but have received less research attention than logistic regression models, especially from the perspective of statistical inference. In this work, we analyze the estimation and prediction error of the contrast-based
PMID: 39532663
ISSN: 1097-0258
CID: 5751462
Evaluating Large Language Models in extracting cognitive exam dates and scores
Ensuring reliability of Large Language Models (LLMs) in clinical tasks is crucial. Our study assesses two state-of-the-art LLMs (ChatGPT and LlaMA-2) for extracting clinical information, focusing on cognitive tests like MMSE and CDR. Our data consisted of 135,307 clinical notes (Jan 12th, 2010 to May 24th, 2023) mentioning MMSE, CDR, or MoCA. After applying inclusion criteria 34,465 notes remained, of which 765 underwent ChatGPT (GPT-4) and LlaMA-2, and 22 experts reviewed the responses. ChatGPT successfully extracted MMSE and CDR instances with dates from 742 notes. We used 20 notes for fine-tuning and training the reviewers. The remaining 722 were assigned to reviewers, with 309 each assigned to two reviewers simultaneously. Inter-rater-agreement (Fleiss' Kappa), precision, recall, true/false negative rates, and accuracy were calculated. Our study follows TRIPOD reporting guidelines for model validation. For MMSE information extraction, ChatGPT (vs. LlaMA-2) achieved accuracy of 83% (vs. 66.4%), sensitivity of 89.7% (vs. 69.9%), true-negative rates of 96% (vs 60.0%), and precision of 82.7% (vs 62.2%). For CDR the results were lower overall, with accuracy of 87.1% (vs. 74.5%), sensitivity of 84.3% (vs. 39.7%), true-negative rates of 99.8% (98.4%), and precision of 48.3% (vs. 16.1%). We qualitatively evaluated the MMSE errors of ChatGPT and LlaMA-2 on double-reviewed notes. LlaMA-2 errors included 27 cases of total hallucination, 19 cases of reporting other scores instead of MMSE, 25 missed scores, and 23 cases of reporting only the wrong date. In comparison, ChatGPT's errors included only 3 cases of total hallucination, 17 cases of wrong test reported instead of MMSE, and 19 cases of reporting a wrong date. In this diagnostic/prognostic study of ChatGPT and LlaMA-2 for extracting cognitive exam dates and scores from clinical notes, ChatGPT exhibited high accuracy, with better performance compared to LlaMA-2. The use of LLMs could benefit dementia research and clinical care, by identifying eligible patients for treatments initialization or clinical trial enrollments. Rigorous evaluation of LLMs is crucial to understanding their capabilities and limitations.
PMCID:11634005
PMID: 39661652
ISSN: 2767-3170
CID: 5762692
Vascular Aging in the Choroid Plexus: A 7T Ultrasmall Superparamagnetic Iron Oxide (USPIO)-MRI Study
BACKGROUND:The choroid plexus (ChP), a densely vascularized structure, has drawn increasing attention for its involvement in brain homeostasis and waste clearance. While the volumetric changes have been explored in many imaging studies, few studies have investigated the vascular degeneration associated with aging in the ChP. PURPOSE/OBJECTIVE:To investigate the sub-structural characteristics of the ChP, particularly the vascular compartment using high-resolution 7T imaging enhanced with Ferumoxytol, an ultrasmall super-paramagnetic iron oxide, which greatly increase the susceptibility contrast for vessels. STUDY TYPE/METHODS:Prospective. SUBJECTS/METHODS:Forty-nine subjects without neurological disorders (age: 21-80 years; 42 ± 17 years; 20 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:7-T with 2D and 3D T2* GRE, 3D MPRAGE T1, 2D TSE T2, and 2D FLAIR. ASSESSMENT/RESULTS:ratio) and susceptibility change (Δχ) induced by Ferumoxytol were analyzed on 3D GRE-derived susceptibility-weighted imaging and quantitative susceptibility mapping, respectively. STATISTICAL TESTS/METHODS:Independent t-test, Mann-Whitney U test, and Chi-square test were utilized for group comparisons. The relationship between age and ChP's vascular alterations was examined using Pearson's correlation. Intra-class coefficient was calculated for inter-observer agreement. A P value <0.05 was considered statistically significant. RESULTS:2D GRE images demonstrated superior contrast and accurate delineation of ChP substructures (ICC = 0.86). Older subjects exhibited a significantly smaller vascular density (16.5 ± 4.34%) and lower Δχ (22.10 ± 12.82 ppb) compared to younger subjects (24.85 ± 6.84% and 34.64 ± 12.69 ppb). Vascular density and mean Δχ within the ChP negatively correlated with age (r = -0.48, and r = -0.45). DATA CONCLUSION/CONCLUSIONS:Ferumoxytol-enhanced 7T images can demonstrate ChP alterations in elderly with decreased vascular density and expansion of nonvascular compartment. EVIDENCE LEVEL/METHODS:1 TECHNICAL EFFICACY: Stage 2.
PMID: 38587279
ISSN: 1522-2586
CID: 5646032
The relationship between anxiety and levels of Alzheimer's disease plasma biomarkers
Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.
PMID: 39604275
ISSN: 1875-8908
CID: 5759182
Alzheimer Disease-Related Biomarkers in Patients on Maintenance Hemodialysis
PMCID:11440795
PMID: 39350957
ISSN: 2590-0595
CID: 5703332
