Faculty Bibliography
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Total Results:
574
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
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
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
SARS-CoV-2 infection of human cortical cells is influenced by the interaction between aneuploidy and biological sex: insights from a Down syndrome in vitro model
Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e.g., TMPRSS2) or indirectly influence the SARS-CoV-2 entry into central nervous system (CNS) cells. The anti-viral immune response may also be altered in cells with trisomy-21 (T21) due to triplication of genes encoding for several interferon receptor subunits and interferon-stimulated genes (ISGs). Here, we demonstrate that human cells derived from fetal cortical specimens and maintained in primary cultures are susceptible to infection with a molecular clone of vesicular stomatitis virus engineered to express the Spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and to authentic SARS-CoV-2. The level of SARS-CoV-2 infectivity in cultures originated from different cortical specimens varied, seemingly depending on ploidy and chromosomal sex of the cells. We confirmed the presence of ACE2 and TMPRSS2 in cultures and found that XY T21 group had the highest TMPRSS2 mRNA levels, which was associated with increased infectivity in XY-compared to XX T21 cultures. The XX T21 cultures exhibited elevated expression of several ISGs (MX1, STAT1, and STAT2) which was associated with lower infectivity. The comparisons of postmortem aged brain specimens revealed reduced ACE2, TMPRSS2, but elevated STAT2 protein levels in individuals with DS and Alzheimer's disease (DS-AD) compared to control and Alzheimer's disease (AD) group. Collectively, these results suggest multifactorial regulation of SARS-CoV-2 infectivity in cortical cells that involves ploidy, chromosomal sex, and the expression of genes implicated in regulation of virus entry and anti-viral response as contributing factors.
PMCID:12125050
PMID: 40445428
ISSN: 1432-0533
CID: 5854522
The interactome of tau phosphorylated at T217 in Alzheimer's disease human brain tissue
Hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated. The emerging studies suggest that phosphorylation of specific residues may alter the role of tau. The role of specific pTau species can be explored through protein interactome studies. The aim of this study was to analyse the interactome of tau phosphorylated at T217 (pT217), which biomarker studies suggest is one of the earliest accumulating tau species in AD. pT217 interactors were identified in fresh-frozen human brain tissue from 10 cases of advanced AD using affinity purification-mass spectrometry. The cases included a balanced cohort of APOE ε3/ε3 and ε4/ε4 genotypes (n = 5 each) to explore how apolipoprotein E altered phosphorylated tau interactions. The results were compared to our previous interactome dataset that profiled the interactors of PHF1-enriched tau to determine if individual pTau species have different interactomes. 23 proteins were identified as bona fide pT217 interactors, including known pTau interactor SQSTM1. pT217 enriched tau was phosphorylated at fewer residues compared to PHF1-enriched tau, suggesting an earlier stage of pathology development. Notable pT217 interactors included five subunits of the CTLH E3 ubiquitin ligase (WDR26, ARMC8, GID8, RANBP9, MAEA), which has not previously been linked to AD. In APOE ε3/ε3 cases pT217 significantly interacted with 46 proteins compared to 28 in APOE ε4/ε4 cases, but these proteins were significantly overlapped. CTLH E3 ubiquitin ligase subunits significantly interacted with phosphorylated tau in both APOE genotypes. pT217 interactions with SQSTM1, WDR26 and RANBP9 were validated using co-immunoprecipitation and immunofluorescent microscopy of post-mortem human brain tissue, which showed colocalisation of both protein interactors with tau pathology. Our results report the interactome of pT217 in human Alzheimer's disease brain tissue for the first time and highlight the CTLH E3 ubiquitin ligase complex as a significant novel interactor of pT217 tau.
PMCID:12049313
PMID: 40317322
ISSN: 1432-0533
CID: 5834712
Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids
Fibrillary aggregation of α-synuclein in Lewy body inclusions and nigrostriatal dopaminergic neuron degeneration define Parkinson's disease neuropathology. Mutations in GBA1, encoding glucocerebrosidase, are the most frequent genetic risk factor for Parkinson's disease. However, the lack of reliable experimental models able to reproduce key neuropathological signatures has hampered the clarification of the link between mutant glucocerebrosidase and Parkinson's disease pathology. Here, we describe an innovative protocol for the generation of human induced pluripotent stem cell-derived midbrain organoids containing dopaminergic neurons with nigral identity that reproduce characteristics of advanced maturation. When applied to patients with GBA1-related Parkinson's disease, this method enabled the differentiation of midbrain organoids recapitulating dopaminergic neuron loss and fundamental features of Lewy body pathology observed in human brains, including the generation of α-synuclein fibrillary aggregates with seeding activity that also propagate pathology in healthy control organoids. Still, we observed that the retention of mutant glucocerebrosidase in the endoplasmic reticulum and increased levels of its substrate glucosylceramide are determinants of α-synuclein aggregation into Lewy body-like inclusions. Consistently, the reduction of glucocerebrosidase activity accelerated α-synuclein pathology by promoting fibrillary α-synuclein deposition. Finally, we demonstrated the efficacy of ambroxol and GZ667161 - two modulators of the glucocerebrosidase pathway in clinical development for the treatment of GBA1-related Parkinson's disease - in reducing α-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant pre-clinical platform for investigational drug screening.
PMID: 39570889
ISSN: 1460-2156
CID: 5758782
