Browsing by Author "Raman, Rema"
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Item Alzheimer’s disease progression by geographical region in a clinical trial setting(BioMed Central, 2015-06-25) Henley, David B.; Dowsett, Sherie A.; Chen, Yun-Fei; Liu-Seifert, Hong; Grill, Joshua D.; Doody, Rachelle S.; Aisen, Paul; Raman, Rema; Miller, David S.; Hake, Ann M.; Cummings, Jeffrey; Department of Medicine, IU School of MedicineINTRODUCTION: To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer's disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology. METHODS: Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). RESULTS: Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. CONCLUSIONS: These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm.Item Alzheimer’s disease research progress in the Mediterranean region: the Alzheimer’s Association International Conference Satellite Symposium(Wiley, 2022) Sexton, Claire; Solis, Michele; Aharon-Peretz, Judith; Alexopoulos, Panagiotis; Apostolova, Liana; Bayen, Eléonore; Birkenhager, Betty; Cappa, Stefano; Constantinidou, Fofi; Fortea, Juan; Gerritsen, Debby L.; Hassanin, Hany I.; Ibanez, Agustin; Ioannidis, Panagiotis; Karageorgiou, Elissaios; Korczyn, Amos; Leroi, Iracema; Lichtwarck, Bjorn; Logroscino, Giancarlo; Lynch, Chris; Mecocci, Patrizia; Molinuevo, Jose Luis; Papatriantafyllou, John; Papegeorgiou, Sokratis; Politis, Antonis; Raman, Rema; Ritchie, Karen; Sanchez-Juan, Pascual; Sano, Mary; Scarmeas, Nikolas; Spiru, Luiza; Stathi, Afroditi; Tsolaki, Magda; Yener, Görsev; Zaganas, Ioannis; Zygouris, Stelios; Carrillo, Maria; Neurology, School of MedicineAs research and services in the Mediterranean region continue to increase, so do opportunities for global collaboration. To support such collaborations, the Alzheimer's Association was due to hold its seventh Alzheimer's Association International Conference Satellite Symposium in Athens, Greece in 2021. Due to the COVID-19 pandemic, the meeting was held virtually, which enabled attendees from around the world to hear about research efforts in Greece and the surrounding Mediterranean countries. Research updates spanned understanding the biology of, treatments for, and care of people with Alzheimer's disease (AD_ and other dementias. Researchers in the Mediterranean region have outlined the local epidemiology of AD and dementia, and have identified regional populations that may expedite genetic studies. Development of biomarkers is expected to aid early and accurate diagnosis. Numerous efforts have been made to develop culturally specific interventions to both reduce risk of dementia, and to improve quality of life for people living with dementia.Item Anxiety in late life depression is associated with poorer performance across multiple cognitive domains(Cambridge University Press, 2024) Kryza-Lacombe, Maria; Kassel, Michelle T.; Insel, Philip S.; Rhodes, Emma; Bickford, David; Burns, Emily; Butters, Meryl A.; Tosun, Duygu; Aisen, Paul; Raman, Rema; Saykin, Andrew J.; Toga, Arthur W.; Jack, Clifford R., Jr.; Weiner, Michael W.; Nelson, Craig; Radiology and Imaging Sciences, School of MedicineObjective: Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains. Method: Older adults with major depressive disorder (N = 228, ages 65-91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning. Results: Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity. Conclusions: Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.Item Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy(Wiley, 2025) Wolk, David A.; Nelson, Peter T.; Apostolova, Liana; Arfanakis, Konstantinos; Boyle, Patricia A.; Carlsson, Cynthia M.; Corriveau-Lecavalier, Nick; Dacks, Penny; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Dugger, Brittany N.; Edelmayer, Rebecca; Fardo, David W.; Grothe, Michel J.; Hohman, Timothy J.; Irwin, David J.; Jicha, Gregory A.; Jones, David T.; Kawas, Claudia H.; Lee, Edward B.; Lincoln, Karen; Maestre, Gladys E.; Mormino, Elizabeth C.; Onyike, Chiadi U.; Petersen, Ronald C.; Rabinovici, Gil D.; Rademakers, Rosa; Raman, Rema; Rascovsky, Katya; Rissman, Robert A.; Rogalski, Emily; Scheltens, Philip; Sperling, Reisa A.; Yang, Hyun-Sik; Yu, Lei; Zetterberg, Henrik; Schneider, Julie A.; Neurology, School of MedicineLimbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE-NC) is a common co-pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.Item Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes(American Academy of Neurology, 2014-01-07) McAllister, Thomas W.; Ford, James C.; Flashman, Laura A.; Maerlender, Arthur; Greenwald, Richard M.; Beckwith, Jonathan G.; Bolander, Richard P.; Tosteson, Tor D.; Turco, John H.; Raman, Rema; Jain, Sonia; Department of Psychiatry, IU School of MedicineOBJECTIVE: To determine whether exposure to repetitive head impacts over a single season affects white matter diffusion measures in collegiate contact sport athletes. METHODS: A prospective cohort study at a Division I NCAA athletic program of 80 nonconcussed varsity football and ice hockey players who wore instrumented helmets that recorded the acceleration-time history of the head following impact, and 79 non-contact sport athletes. Assessment occurred preseason and shortly after the season with diffusion tensor imaging and neurocognitive measures. RESULTS: There was a significant (p = 0.011) athlete-group difference for mean diffusivity (MD) in the corpus callosum. Postseason fractional anisotropy (FA) differed (p = 0.001) in the amygdala (0.238 vs 0.233). Measures of head impact exposure correlated with white matter diffusivity measures in several brain regions, including the corpus callosum, amygdala, cerebellar white matter, hippocampus, and thalamus. The magnitude of change in corpus callosum MD postseason was associated with poorer performance on a measure of verbal learning and memory. CONCLUSION: This study suggests a relationship between head impact exposure, white matter diffusion measures, and cognition over the course of a single season, even in the absence of diagnosed concussion, in a cohort of college athletes. Further work is needed to assess whether such effects are short term or persistent.Item Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial(American Medical Association, 2021) Sperling, Reisa; Henley, David; Aisen, Paul S.; Raman, Rema; Donohue, Michael C.; Ernstrom, Karin; Rafii, Michael S.; Streffer, Johannes; Shi, Yingqi; Karcher, Keith; Raghavan, Nandini; Tymofyeyev, Yevgen; Bogert, Jennifer; Brashear, H. Robert; Novak, Gerald; Thipphawong, John; Saad, Ziad S.; Kolb, Hartmuth; Rofael, Hany; Sanga, Panna; Romano, Gary; Psychiatry, School of MedicineImportance: Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Design, setting, and participants: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Main outcomes and measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Conclusions and relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment.Item Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach(Springer Nature, 2025-02-06) Putcha, Deepti; Katsumi, Yuta; Touroutoglou, Alexandra; Eloyan, Ani; Taurone, Alexander; Thangarajah, Maryanne; Aisen, Paul; Dage, Jeffrey L.; Foroud, Tatiana; Jack, Clifford R., Jr.; Kramer, Joel H.; Nudelman, Kelly N. H.; Raman, Rema; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Grant, Ian M.; Honig, Lawrence S.; Johnson, Erik C. B.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon; Turner, R. Scott; Wingo, Thomas S.; Wolk, David A.; Womack, Kyle; Carrillo, Maria C.; Rabinovici, Gil D.; Dickerson, Bradford C.; Apostolova, Liana G.; Hammers, Dustin B.; LEADS Consortium; Neurology, School of MedicineBackground: The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort. Methods: Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of "predominant" impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes. Results: We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia. Conclusion: A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.Item Immediate Reactions to Alzheimer Biomarker Disclosure in Cognitively Unimpaired Individuals in a Global Truncated Randomized Trial(Wolters Kluwer, 2024) Grill, Joshua D.; Raman, Rema; Ernstrom, Karin; Wang, Shunran; Donohue, Michael C.; Aisen, Paul S.; Karlawish, Jason; Henley, David; Romano, Gary; Novak, Gerald; Brashear, H. Robert; Sperling, Reisa A.; Psychiatry, School of MedicineBackground and objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals. Methods: The EARLY trial was a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted in 143 centers across 14 countries from November 2015 to December 2018 after being stopped prematurely because of treatment-related hepatotoxicity. Participants age 60-85 years deemed cognitively unimpaired were disclosed an elevated or not elevated brain amyloid result by a certified clinician. Among 3,686 participants, 2,066 underwent amyloid imaging, 1,394 underwent CSF biomarker assessment, and 226 underwent both. Among biomarker-tested participants with at least one change score on an outcome of interest, 680 with elevated and 2,698 with not elevated amyloid were included in this analysis. We compared the Geriatric Depression Scale (GDS), the State-Trait Anxiety Scale (STAI), and the Columbia Suicide Severity Rating Scale (CSSRS) before disclosure between amyloid groups. After disclosure, we assessed for differences in the Impact of Events Scale (IES, collected 24-72 hours after disclosure), a measure of intrusive thoughts. Additional scales included the Concerns for AD scale. Results: Among 3378 included participants, the mean (SD) age was 69.0 (5.3); most were female (60%) and White race (84%). No differences were observed before disclosure between participants with elevated and not elevated amyloid for the GDS, STAI, or CSSRS. Participants with elevated amyloid demonstrated higher Concerns for AD scores compared with participants with not elevated amyloid before disclosure. Participants with elevated amyloid demonstrated higher IES scores (9.6 [10.8] vs 5.1 [8.0]) after disclosure and increased Concerns about AD. Patterns of reactions (elevated vs not elevated) were similar for biomarker modalities, although scores were lower among those undergoing CSF compared with PET testing. Although score differences were apparent comparing geographical regions, patterns of group differences were similar. Discussion: Although sample bias must be considered, these results suggest that amyloid disclosure resulted in increased perceived risk and mild distress in those learning an elevated result. Although this study did not assess psychological safety, observed associations intrusive thoughts and distress could be important considerations in the future clinical practice.Item The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression(IOS Press, 2021) Rhodes, Emma; Insel, Philip S.; Butters, Meryl A.; Morin, Ruth; Bickford, David; Tosun, Duygu; Gessert, Devon; Rosen, Howie J.; Aisen, Paul; Raman, Rema; Landau, Susan; Saykin, Andrew; Toga, Arthur; Jack, Clifford R.; Weiner, Michael W.; Nelson, Craig; Mackin, R. Scott; Alzheimer’s Disease Neuroimaging Initiative; ADNI Depression Project; Radiology and Imaging Sciences, School of MedicineBackground: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test -B (p = 0.032), and APOEɛ4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer's disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.Item Late Life Depression is Associated with Reduced Cortical Amyloid Burden: Findings from the ADNI Depression Project(Elsevier, 2021) Mackin, R. Scott; Insel, Philip S.; Landau, Susan; Bickford, David; Morin, Ruth; Rhodes, Emma; Tosun, Duygu; Rosen, Howie J.; Butters, Meryl; Aisen, Paul; Raman, Rema; Saykin, Andrew; Toga, Arthur; Jack, Clifford, Jr.; Koeppe, Robert; Weiner, Michael W.; Nelson, Craig; Alzheimer’s Disease Neuroimaging Initiative & the ADNI Depression Project; Radiology and Imaging Sciences, School of MedicineBackground: We evaluated the role of cortical amyloid deposition as a factor contributing to memory dysfunction and increased risk of dementia associated with late-life depression (LLD). Methods: A total of 119 older adult participants with a current diagnosis of major depression (LLD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) Depression Project study and 119 nondepressed (ND) cognitively unimpaired participants matched on age, sex, and APOE genotype were obtained from the ADNI database. Results: Thirty-three percent of LLD participants met ADNI criteria for mild cognitive impairment. Compared with ND individuals, the LLD group exhibited less global amyloid beta (Aβ) accumulation (p = .05). The proportion of amyloid positivity in the LLD group was 19.3% compared with 31.1% for the ND participants (p = .02). Among LLD participants, global Aβ was not associated with lifetime number of depressive episodes, lifetime length of depression, length of lifetime selective serotonin reuptake inhibitor use, or lifetime length of untreated depression (p > .21 for all). Global Aβ was associated with worse memory performance (p = .05). Similar results were found in secondary analyses restricting comparisons to the cognitively unimpaired LLD participants as well as when comparing the LLD group with an ND group that included participants with mild cognitive impairment. Conclusions: Contrary to expectation, the LLD group showed less Aβ deposition than the ND group and Aβ deposition was not associated with depression history characteristics. Aβ was associated with memory, but this relationship did not differ between LLD and ND. Our results suggest that memory deficits and accelerated cognitive decline reported in previous studies of LLD are not due to greater cortical Aβ accumulation.