Faculty Bibliography
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577
Body mass index and blood volume influence plasma biomarkers and positron emission tomography classification in preclinical Alzheimer's disease
INTRODUCTION/BACKGROUND:Blood-based biomarkers (BBMs) are promising tools for Alzheimer's disease (AD) diagnosis, but their accuracy may be affected by body mass index (BMI) and blood volume (BV) through dilution. We investigated how BMI and BV influence BBM concentrations and PET prediction. METHODS:, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and BBM-based PET predictions. RESULTS:and NfL, independent of brain amyloid burden. BMI-stratified thresholds improved amyloid PET prediction, with higher BBM thresholds and area under the curve (AUC) values seen in normal weight compared to overweight or obese participants. Drastic BMI/BV declines due to weight loss increased BBM variability and systematic PET misclassification. DISCUSSION/CONCLUSIONS:Adjusting for BMI/BV in BBM-based diagnostics appears to improve accuracy and reliable detection of AD pathology, especially in preclinical stages. HIGHLIGHTS/CONCLUSIONS:Body mass index (BMI) and blood volume (BV) significantly influenced plasma BBM concentrations in cognitively unimpaired (CU) individuals. Blood-based biomarkers (BBMs) associated more strongly with BV than with BMI. Dilution effects were independent of brain amyloid burden. BMI-stratified BBM thresholds improved amyloid positron emission tomography (PET) classification accuracy. Declines in BMI/BV resulted in PET prediction bias and systematic errors.
PMCID:12514939
PMID: 41074913
ISSN: 1552-5279
CID: 5952532
Celebrating neuropathology's contributions to Alzheimer's Disease Research Centers [Historical Article]
Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical-pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease-modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. HIGHLIGHTS: We celebrate 40 years of NIA-funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease-modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.
PMCID:12519528
PMID: 41085158
ISSN: 1552-5279
CID: 5954632
Hippocampal subfields in aging: Sex-specific trajectories in structure and hemodynamics
Sex differences in hippocampal aging have been increasingly recognized, with females showing greater vulnerability to neurodegeneration, particularly after menopause. However, the underlying neurobiological mechanisms remain unclear, especially at the level of hippocampal subfields. Leveraging high-resolution T1-, T2-weighted, and multi-delay arterial spin labeling MRI from 650 adults in the Human Connectome Project-Aging dataset, we examined sex-specific alterations in hippocampal subfield volume, arterial transit time (ATT), and cerebral blood flow (CBF) across the adult lifespan. All hippocampal subfields showed age-related atrophy and ATT prolongation. An age × sex interaction effect on ATT was observed in CA1 and CA2, indicating that age-related increases in ATT were more pronounced in females than in males in these subfields. Moreover, females exhibited more pronounced hippocampal subfields CBF reductions with aging and atrophy, while males showed relatively preserved CBF, with an increase in subiculum perfusion. Furthermore, CA1 showed the lowest perfusion and the strongest association with atrophy among hippocampal subfields. To investigate the potential impact of menopausal hormonal changes on sex-specific patterns, we explored the hypothalamic structure and hemodynamic alterations during aging and their effects on the hippocampus, given that hypothalamus regulates gonadal hormone secretion through the hypothalamic-pituitary-gonadal axis. We found significant hypothalamic atrophy during aging in both sexes, accompanied by ATT prolongation exclusively in females, which was associated with hippocampal atrophy and impaired hemodynamics. Our study highlights the intricate interplay between hippocampal structure and vascular function, revealing sex- and subfield-specific aging trajectories. These findings provide a normative quantitative imaging reference to age-related neurodegenerative diseases such as Alzheimer's Disease.
PMID: 40544898
ISSN: 1095-9572
CID: 5902832
Reducing ARIA risk in Alzheimer's disease: Real-world impact of APOE genotype-guided slow titration with aducanumab and lecanemab
We evaluated whether apolipoprotein E (APOE) genotype-guided slow titration of monoclonal antibodies reduced amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease. We retrospectively analyzed ARIA incidence in 25 patients on aducanumab and 19 patients on lecanemab on a genotype-informed protocol in a private practice setting. ARIA-E and ARIA-H each occurred in 4% of the aducanumab group and 5% of the lecanemab group. Plaque clearance was achieved in 50% of evaluable aducanumab patients and 26.3% of lecanemab patients. Compared to clinical trial ARIA rates, our results suggest that individualized, genotype-informed titration improves safety although plaque clearance rates were less robust.
PMID: 40801838
ISSN: 1875-8908
CID: 5907372
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
CT, I-123-Ioflupane SPECT, and Integrated FDG PET-MRI of a Patient With Fahr Disease
Fahr disease is a rare neurodegenerative syndrome characterized by abnormal symmetric calcium deposition in the white matter, cerebral cortex, deep gray, and cerebellar nuclei. The characteristic CT pattern is well known, but descriptions of molecular imaging in Fahr disease remain sparse. We present the characteristic imaging patterns of Fahr disease by CT, I-123-Ioflupane SPECT, and integrated FDG PET/MRI in a single patient.
PMID: 40392166
ISSN: 1536-0229
CID: 5852972
Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease
Almost all individuals with Down Syndrome (DS) develop Alzheimer's disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD pathophysiology from asymptomatic to dementia stages and compared the proteomic biomarker changes in DS to those observed in LOAD and ADAD. Although many proteomic alterations were shared across DS, LOAD, and ADAD, DS demonstrated more severe changes in immune-related proteins, extracellular matrix pathways, and plasma proteins likely related to blood-brain barrier dysfunction compared to LOAD. These changes were present in young adults with DS prior to the onset of Aβ or tau pathology, suggesting they are associated with trisomy 21 and may serve as risk factors for DSAD. DSAD showed an earlier increase in markers of axonal and white matter pathology and earlier changes in markers potentially associated with cerebral amyloid angiopathy compared to ADAD. The unique features of DSAD may have important implications for treatment strategies in this population.
PMCID:12214755
PMID: 40595720
ISSN: 2041-1723
CID: 5887882
Febrile Seizures and Sudden Death Risk: A Case-Control Analysis
BACKGROUND:Febrile seizures occur in 3%-4% of US children aged six months to five years and are considered benign. However, sudden unexplained death in childhood is associated with 10 times increase in febrile seizures. We assessed the characteristics of children with febrile seizure and sudden death to identify factors that confer increased sudden death risk. METHODS:We conducted a case-control analysis of children with febrile seizure and subsequent sudden death versus living controls from December 2021 to June 2023 through an ∼10-minute anonymous online survey. We enrolled parents of children, living or deceased, whose child had experienced a febrile seizure from age six months to six years. Subjects were excluded if the child had an afebrile seizure or parents had not witnessed a febrile seizure. Demographic characteristics, parasomnias, and febrile seizure features were analyzed. RESULTS:A total of 381 completed surveys were received; 53 (14%) cases of febrile seizure with sudden death and 328 (86%) living controls. Cases reported febrile seizure onset >2 months earlier (P = 0.013) and reported developmental concerns (odds ratio [OR] = 2.32, 95% confidence interval [CI] [1.14, 4.71], P = 0.03), less frequent night awakenings (OR = 0.34, 95% CI [0.18, 0.65], P = 0.001), and less restless sleep (OR = 0.37, 95% CI [0.16, 0.85], P = 0.02). Cases were also less likely to drool (OR = 0.442, 95% CI [0.218, 0.900], P = 0.032) or be unresponsive for more than one minute (OR = 0.45, 95% CI [0.238, 0.854], P = 0.021). CONCLUSIONS:We report novel associations of febrile seizure and sudden death related to age, development, sleep, and observed ictal features. Anonymous survey methodology cannot exclude ascertainment bias and any related potential effect on results. Our findings suggest that impaired arousal mechanisms may increase risk of death in subjects with febrile seizure.
PMID: 40602049
ISSN: 1873-5150
CID: 5888072
The history of Down syndrome-associated Alzheimer's disease; past, present, and future [Historical Article]
The landscape of Down syndrome-associated Alzheimer's disease (DSAD) research reflects decades of scientific endeavor and collaborative effort, charting a remarkable journey from initial observations to the elucidation of complex genetic and molecular mechanisms. This perspective article chronicles key milestones and breakthroughs, paying homage to the pioneering scientists and advancements that have shaped the field. A thorough review of historical and contemporary literature offers a comprehensive narrative, highlighting the evolution of knowledge surrounding DSAD, from early recognition to the characterization of clinical presentation and natural history. The unique challenges and ethical considerations associated with DSAD populations are also examined, underscoring the importance of tailoring research and clinical approaches. By reflecting on the field's trajectory, this work celebrates past achievements while emphasizing the critical need for sustained research efforts. As part of a special issue, this article provides a foundation for appreciating the challenges and opportunities that lie ahead in advancing DSAD understanding and care. HIGHLIGHTS: This article provides a comprehensive overview of Down syndrome-associated Alzheimer's disease (DSAD) history, from early descriptions to its recognition as a genetic form of AD. It reflects on historical challenges faced by individuals with intellectual disabilities in achieving inclusion in scientific research. This historical perspective highlights the critical contributions of individuals with DS in advancing understanding of AD natural history. It explores pivotal milestones and efforts that have driven progress in DSAD research. Finally, it provides context to understand challenges and opportunities in DSAD research and its future directions.
PMCID:12138279
PMID: 40469048
ISSN: 1552-5279
CID: 5862592
X-chromosome-wide association study for Alzheimer's disease
Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-
PMID: 39633006
ISSN: 1476-5578
CID: 5804132
