Browsing by Author "Jones, David T."

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    Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)
    (Wiley, 2023) Cho, Hanna; Mundada, Nidhi S.; Apostolova, Liana G.; Carrillo, Maria C.; Shankar, Ranjani; Amuiri, Alinda N.; Zeltzer, Ehud; Windon, Charles C.; Soleimani-Meigooni, David N.; Tanner, Jeremy A.; Heath, Courtney Lawhn; Lesman-Segev, Orit H.; Aisen, Paul; Eloyan, Ani; Lee, Hye Sun; Hammers, Dustin B.; Kirby, Kala; Dage, Jeffrey L.; Fagan, Anne; Foroud, Tatiana; Grinberg, Lea T.; Jack, Clifford R.; Kramer, Joel; Kukull, Walter A.; Murray, Melissa E.; Nudelman, Kelly; Toga, Arthur; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily J.; Salloway, Stephen; Sha, Sharon; Turner, Raymond Scott; Wingo, Thomas S.; Wolk, David A.; Koeppe, Robert; Iaccarino, Leonardo; Dickerson, Bradford C.; La Joie, Renaud; Rabinovici, Gil D.; LEADS Consortium; Neurology, School of Medicine
    Introduction: We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). Methods: We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification. Results: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. Discussion: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. Highlights: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.
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    Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort
    (Wiley, 2023) Polsinelli, Angelina J.; Wonderlin, Ryan J.; Hammers, Dustin B.; Pena Garcia, Alex; Eloyan, Anii; Taurone, Alexander; Thangarajah, Maryanne; Beckett, Laurel; Gao, Sujuan; Wang, Sophia; Kirby, Kala; Logan, Paige E.; Aisen, Paul; Dage, Jeffrey L.; Foroud, Tatiana; Griffin, Percy; Iaccarino, Leonardo; Kramer, Joel H.; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Nudelman, Kelly; Soleimani-Meigooni, David N.; Rumbaugh, Malia; Toga, Arthur W.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario F.; Womack, Kyle; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    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. Keywords: early-onset Alzheimer's disease; early-onset dementia; mild cognitive impairment; neuropharmacology; neuropsychiatric symptoms; psychotropic medications.
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    Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study
    (Wiley, 2023) Dage, Jeffrey L.; Eloyan, Ani; Thangarajah, Maryanne; Hammers, Dustin B.; Fagan, Anne M.; Gray, Julia D.; Schindler, Suzanne E.; Snoddy, Casey; Nudelman, Kelly N. H.; Faber, Kelley M.; Foroud, Tatiana; Aisen, Paul; Griffin, Percy; Grinberg, Lea T.; Iaccarino, Leonardo; Kirby, Kala; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur W.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Beckett, Laurel A.; Day, Gregory S.; Graff-Radford, Neill R.; Duara, Ranjan; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Womack, Kyle B.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    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 Aβ1-40, Aβ1-42, 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 Aβ42/40, 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, Aβ42/40, 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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    Classification of Intrinsically Disordered Regions and Proteins
    (American Chemical Society, 2014-07-09) van der Lee, Robin; Buljan, Marija; Lang, Benjamin; Weatheritt, Robert J.; Daughdrill, Gary W.; Dunker, A. Keith; Fuxreiter, Monika; Gough, Julian; Gsponer, Joerg; Jones, David T.; Kim, Philip M.; Kriwacki, Richard W.; Oldfield, Christopher J.; Pappu, Rohit V.; Tompa, Peter; Uversky, Vladimir N.; Wright, Peter E.; Babu, M. Madan; Department of Biochemistry & Molecular Biology, IU School of Medicine
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    Influence of amyloid and diagnostic syndrome on non-traditional memory scores in early-onset Alzheimer's disease
    (Wiley, 2023) Bushnell, Justin; Hammers, Dustin B.; Aisen, Paul; Dage, Jeffrey L.; Eloyan, Ani; Foroud, Tatiana; Grinberg, Lea T.; Iaccarino, Leonardo; Jack, Clifford R., Jr.; Kirby, Kala; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Nudelman, Kelly; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; Clark, David G.; LEADS Consortium; Neurology, School of Medicine
    Introduction: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. Methods: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. Results: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time. Discussion: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. Highlights: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.
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    Learning slopes in early-onset Alzheimer's disease
    (Wiley, 2023) Hammers, Dustin B.; Nemes, Sára; Diedrich, Taylor; Eloyan, Ani; Kirby, Kala; Aisen, Paul; Kramer, Joel; Nudelman, Kelly; Foroud, Tatiana; Rumbaugh, Malia; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steve; Sha, Sharon J.; Turner, Raymond Scott; Weintraub, Sandra; Wingo, Thomas S.; Wolk, David A.; Wong, Bonnie; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    Objective: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity. METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined. RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses. CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. Highlights: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.
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    Longitudinal Clinical, Neuropsychological, and Neuroimaging Characterization of a Kindred with a 12-Octapeptide Repeat Insertion in PRNP: The Next Generation
    (Taylor & Francis, 2020-08) Townley, Ryan A.; Polsinelli, Angelina J.; Fields, Julie A.; Machulda, Mary M.; Jones, David T.; Graff-Radford, Jonathan; Kantarci, Kejal M.; Lowe, Val J.; Rademakers, Rosa V.; Baker, Matt C.; Kumar, Neeraj; Boeve, Bradley F.; Neurology, School of Medicine
    Background: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method: Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. Conclusions and relevance: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.
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    New Insights into Atypical Alzheimer’s Disease in the Era of Biomarkers
    (Elsevier, 2021) Graff-Radford, Jonathan; Yong, Keir X.X.; Apostolova, Liana G.; Bouwman, Femke H.; Carrillo, Maria; Dickerson, Bradford C.; Rabinovici, Gil D.; Schott, Jonathan M.; Jones, David T.; Murray, Melissa E.; Neurology, School of Medicine
    Most patients with Alzheimer's disease present with amnestic problems; however, a substantial proportion, over-represented in young-onset cases, have atypical phenotypes including predominant visual, language, executive, behavioural, or motor dysfunction. In the past, these individuals often received a late diagnosis; however, availability of CSF and PET biomarkers of Alzheimer's disease pathologies and incorporation of atypical forms of Alzheimer's disease into new diagnostic criteria increasingly allows them to be more confidently diagnosed early in their illness. This early diagnosis in turn allows patients to be offered tailored information, appropriate care and support, and individualised treatment plans. These advances will provide improved access to clinical trials, which often exclude atypical phenotypes. Research into atypical Alzheimer's disease has revealed previously unrecognised neuropathological heterogeneity across the Alzheimer's disease spectrum. Neuroimaging, genetic, biomarker, and basic science studies are providing key insights into the factors that might drive selective vulnerability of differing brain networks, with potential mechanistic implications for understanding typical late-onset Alzheimer's disease.
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    Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort
    (Wiley, 2023) Nudelman, Kelly N. H.; Jackson, Trever; Rumbaugh, Malia; Eloyan, Ani; Abreu, Marco; Dage, Jeffrey L.; Snoddy, Casey; Faber, Kelley M.; Foroud, Tatiana; Hammers, Dustin B.; DIAN/DIAN-TU Clinical/Genetics Committee; Taurone, Alexander; Thangarajah, Maryanne; Aisen, Paul; Beckett, Laurel; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; Murray, Melissa E.; Toga, Arthur W.; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon J.; Turner, R. Scott; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Medical and Molecular Genetics, School of Medicine
    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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    Profiling baseline performance on the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort near the midpoint of data collection
    (Wiley, 2023) Hammers, Dustin B.; Eloyan, Ani; Taurone, Alexander; Thangarajah, Maryanne; Beckett, Laurel; Gao, Sujuan; Kirby, Kala; Aisen, Paul; Dage, Jeffrey L.; Foroud, Tatiana; Griffin, Percy; Grinberg, Lea T.; Jack, Clifford R., Jr.; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; Mundada, Nidhi S.; La Joie, Renaud; Soleimani-Meigooni, David N.; Iaccarino, Leonardo; Murray, Melissa E.; Nudelman, Kelly; Polsinelli, Angelina J.; Rumbaugh, Malia; Toga, Arthur; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario F.; Womack, Kyle; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon J.; Turner, Raymond Scott; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    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.