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Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Chow, Tiffany W. | Chakravarty, M. Mallar | Caravaggio, Fernando | Gerretsen, Philip | Brown, Eric E. | Iwata, Yusuke | Mulsant, Benoit H. | Graff-Guerrero, Ariel

Article Type: Correction

DOI: 10.3233/JAD-159007

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1189-1190, 2016

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Chakravarty, M. Mallar | Caravaggio, Fernando | Takeuchi, Hiroyoshi | Gerretsen, Philip | Iwata, Yusuke | Patel, Raihaan | Mulsant, Benoit H. | Graff-Guerrero, Ariel

Article Type: Research Article

Abstract: Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimer’s Disease Neuroimaging …Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (p  = 0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non-converters over the 2-year period (p  = 0.003, p  = 0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia. Show more

Keywords: Dementia, depression, hippocampus, mild cognitive impairment

DOI: 10.3233/JAD-150679

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 743-754, 2016

Authors: Leh, Sandra E. | Kälin, Andrea M. | Schroeder, Clemens | Park, Min Tae M. | Chakravarty, M. Mallar | Freund, Patrick | Gietl, Anton F. | Riese, Florian | Kollias, Spyros | Hock, Christoph | Michels, Lars

Article Type: Research Article

Abstract: Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer’s disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n  = 16) to healthy subjects (CS, n  = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate “classical” cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, …insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD. Show more

Keywords: Alzheimer’s disease, cortical thickness, hippocampus, mild cognitive impairment, shape analysis, striatum, thalamus, volumetry

DOI: 10.3233/JAD-150080

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 237-249, 2016

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Chow, Tiffany W. | Chakravarty, M. Mallar | Caravaggio, Fernando | Gerretsen, Philip | Brown, Eric E. | Iwata, Yusuke | Mulsant, Benoit H. | Graff-Guerrero, Ariel | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Mounting evidence associates a lifetime history of major depression (LMD) with an increased risk for Alzheimer's disease (AD). Studies have shown that major depression (MD) is strongly linked to pathophysiological markers of AD, such as cortical amyloid-β (Aβ) burden. However, no imaging studies have shown in vivo whether an LMD is linked to increased Aβ accumulation in patients with mild cognitive impairment (MCI) in four cortical regions that have been highly associated with increased Aβ deposition in previous literature: frontal, cingulate, parietal, and temporal. Drawing from the ADNI database, we found that patients with amnestic MCI (aMCI) and an LMD …(n = 39) had significantly higher 18 F-Florbetapir standardized uptake value ratios, a surrogate measure of Aβ deposition, mainly in the bilateral frontal cortex, compared to patients with aMCI without an LMD (n = 39) (p = 0.02). This difference was not explained by current depressive symptoms, vascular risk factors, or the use of different PET scanners. The results were reliable employing two independent methods for analysis: region-of-interest and voxel-based analyses. Increased Aβ in the bilateral frontal lobes may be a biomarker of depressive symptomology in aMCI patients. Further studies should test whether higher Aβ predicts future conversion into AD in this population. Show more

Keywords: Alzheimer's disease, amyloid-β, major depression, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-142931

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 907-919, 2015

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Caravaggio, Fernando | Shinagawa, Shunichiro | Iwata, Yusuke | Gerretsen, Philip | Kim, Julia | Takeuchi, Hiroyoshi | Patel, Raihaan | Chakravarty, M. Mallar | Strafella, Antonio | Graff-Guerrero, Ariel | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Short Communication

Abstract: The clinical and structural trajectories of suspected non-Alzheimer’ pathology (SNAP) remain elusive due to its heterogeneous etiology. Baseline and longitudinal clinical (global cognition, daily functioning, symptoms of dementia, and learning memory) and hippocampal volume trajectories over two years were compared between patients with amnestic mild cognitive impairment (aMCI) with SNAP with reduced hippocampal volumes (SNAP+HIPPO) and aMCI patients with SNAP without reduced hippocampal volumes. SNAP+HIPPO showed overall worse baseline cognitive functions. Longitudinally, SNAP+HIPPO showed faster deterioration of clinical symptoms of dementia. Having both hippocampal atrophy and cortical hypometabolism without amyloid pathology may exacerbate symptoms of dementia in aMCI.

Keywords: Functional decline, hippocampus, mild cognitive impairment, suspected non-Alzheimer’s pathology

DOI: 10.3233/JAD-170098

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 341-347, 2017

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Caravaggio, Fernando | Iwata, Yusuke | Gerretsen, Philip | Kim, Julia | Takeuchi, Hiroyoshi | Shinagawa, Shunichiro | Patel, Raihaan | Chakravarty, M. Mallar | Graff-Guerrero, Ariel | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Suspected non-Alzheimer’s disease pathology (SNAP) characterizes individuals showing neurodegeneration (e.g., hypometabolism) without amyloid-β (Aβ). Findings from previous studies regarding clinical and structural trajectories of SNAP are inconsistent. Using data from the Alzheimer’s Disease Neuroimaging Initiative, patients with amnestic mild cognitive impairment (MCI) were categorized into four groups: amyloid positive with hypometabolism (Aβ+ND+), amyloid only (Aβ+ND–), neither amyloid nor hypometabolism (Aβ–ND–), and SNAP (Aβ–ND+). Aβ+ND+(n  = 33), Aβ+ND–(n  = 32), and Aβ–ND–(n  = 36) were matched to SNAP for age, gender, apolipoprotein E4 (apoE4) genotype, and scores on the Montreal Cognitive Assessment. Elderly controls (n  = 40) were also matched to SNAP for age, gender, …and apoE4 genotype. Longitudinal changes were compared across groups in terms of hippocampal volume, clinical symptoms, daily functioning, and cognitive functioning over a 2-year period. At baseline, no difference in cognition and functioning was observed between SNAP and Aβ+groups. SNAP showed worse clinical symptoms and impaired functioning at baseline compared to Aβ–ND–and controls. Two years of follow-up showed no differences in hippocampal volume changes between SNAP and any of the comparison groups. SNAP showed worse functional deterioration in comparison to Aβ–ND–and controls. However, Aβ+ND+ showed more severe changes in clinical symptoms in comparison to SNAP. Thus, patients with MCI and SNAP showed 1) more severe functional deterioration compared to Aβ–ND–and controls, 2) no differences with Aβ+ND–, and 3) less cognitive deterioration than Aβ+ND+. Future studies should investigate what causes SNAP, which is different from typical AD pathology and biomarker cascades. Show more

Keywords: Functional decline, hippocampus, mild cognitive impairment, suspected non-Alzheimer’s pathology

DOI: 10.3233/JAD-170201

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 747-762, 2017

Authors: Lozano, Andres M. | Fosdick, Lisa | Chakravarty, M. Mallar | Leoutsakos, Jeannie-Marie | Munro, Cynthia | Oh, Esther | Drake, Kristen E. | Lyman, Christopher H. | Rosenberg, Paul B. | Anderson, William S. | Tang-Wai, David F. | Pendergrass, Jo Cara | Salloway, Stephen | Asaad, Wael F. | Ponce, Francisco A. | Burke, Anna | Sabbagh, Marwan | Wolk, David A. | Baltuch, Gordon | Okun, Michael S. | Foote, Kelly D. | McAndrews, Mary Pat | Giacobbe, Peter | Targum, Steven D. | Lyketsos, Constantine G. | Smith, Gwenn S.

Article Type: Research Article

Abstract: Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD). Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Results: Surgery and electrical stimulation were safe and well tolerated. There …were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n  = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n  = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation. Show more

Keywords: Keywords: Alzheimer’s disease, dementia, deep brain stimulation, fornix

DOI: 10.3233/JAD-160017

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 777-787, 2016

Authors: Leoutsakos, Jeannie-Marie S. | Yan, Haijuan | Anderson, William S. | Asaad, Wael F. | Baltuch, Gordon | Burke, Anna | Chakravarty, M. Mallar | Drake, Kristen E. | Foote, Kelly D. | Fosdick, Lisa | Giacobbe, Peter | Mari, Zoltan | McAndrews, Mary Pat | Munro, Cynthia A. | Oh, Esther S. | Okun, Michael S. | Pendergrass, Jo Cara | Ponce, Francisco A. | Rosenberg, Paul B. | Sabbagh, Marwan N. | Salloway, Stephen | Tang-Wai, David F. | Targum, Steven D. | Wolk, David | Lozano, Andres M. | Smith, Gwenn S. | Lyketsos, Constantine G.

Article Type: Research Article

Abstract: Background: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. Objective: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f …treatment of mild AD after two years. Methods: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. Results: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. Conclusion: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, dementia, delayed start, fornix, treatment

DOI: 10.3233/JAD-180121

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 597-606, 2018