Tau in Late-Life Depression: A Systematic Review and Meta-Analysis
Authors: Brown, Eric E. | Iwata, Yusuke | Chung, Jun Ku | Gerretsen, Philip | Graff-Guerrero, Ariel
Article Type: Research Article
Abstract: A lifetime history of major depressive disorder (MDD) increases the risk of developing Alzheimer’s disease, of which neurofibrillary tangles due to abnormal tau proteins are a hallmark. We systematically reviewed the literature on tau in MDD and identified 49 relevant articles spanning a number of modalities, including cerebrospinal fluid (CSF) analysis, positron emission tomography, and clinicopathological correlation. We compared CSF total and phosphorylated tau proteins in MDD and controls using a meta-analytic approach. We found no difference in total or phosphorylated tau in MDD. We also found no difference in a comparison of a subgroup excluding studies with significant age …differences. Positron emission tomography studies lacked specificity. Clinicopathological studies failed to associate neurofibrillary tangles with MDD. The available data on tau in MDD is limited. The involvement of tau in a subset of MDD cannot be ruled out and requires prospective exploration. Show more
Keywords: Alzheimer’s disease, depression, depressive disorder, tau proteins
DOI: 10.3233/JAD-160401
Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 615-633, 2016
Psychosis in Frontotemporal Dementia
Authors: Shinagawa, Shunichiro | Nakajima, Shinichiro | Plitman, Eric | Graff-Guerrero, Ariel | Mimura, Masaru | Nakayama, Kazuhiko | Miller, Bruce L.
Article Type: Research Article
Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder, associated with a progressive decline in behavior caused by focal degeneration of the frontal lobes. Psychosis was an underestimated symptom of FTD, however, recent genetic research has revealed a high prevalence of psychosis in certain genetic groups. The primary objective of this work is to review the literature on psychosis in FTD and to propose directions for future research, with reference to findings on psychosis in schizophrenia. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included “frontotemporal dementia”, “psychosis”, “schizophreni* ”, “psychotic symptoms”, “hallucinations”, and “delusions”, and it identified 122 …articles. Results revealed: 1) prevalence is approximately 10%, 2) TDP-43 type B and FUS pathologies might have relatively high frequency of psychosis, 3) psychosis in FTD is higher with genetic mutations of C9ORF72 and GRN, 4) imaging researches did not achieve conclusive results, and 5) no treatment for psychosis in FTD is currently available. A limitation of this systematic review is that it includes a small number of studies specifically examining psychosis in FTD. It is suggested that a possible overlap exists between FTD and schizophrenia. This potential overlap indicates a vulnerability to psychosis due to brain systems and pathways shared by these disorders. Show more
Keywords: Frontotemporal dementia, gene mutation, neuropathology, psychosis, schizophrenia
DOI: 10.3233/JAD-140312
Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 485-499, 2014
Non-Pharmacological Management for Patients with Frontotemporal Dementia: A Systematic Review
Authors: Shinagawa, Shunichiro | Nakajima, Shinichiro | Plitman, Eric | Graff-Guerrero, Ariel | Mimura, Masaru | Nakayama, Kazuhiko | Miller, Bruce L.
Article Type: Research Article
Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by changes in behavior and language caused by focal degeneration of the frontal and anterior temporal lobes. The behavioral symptoms are distressing to patients and their caregivers. Non-pharmacological management is important as no disease-specific pharmacological treatment for FTD is currently available. The primary objective is to review the literature on non-pharmacological management for FTD and to propose directions for future research, with reference to findings. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included “frontotemporal dementia”, and words related to non-pharmacological management, and it identified a total of 858 …articles. Results revealed that very few randomized controlled trials exist on non-pharmacological management interventions for FTD. These interventions have been proposed by literature based on clinical experience. A small number of studies have supported behavioral management techniques that exploit disease-specific behaviors and preserved functions in patients with FTD, along with the management of caregivers' distress. These limitations warrant well-designed large-scale research to examine effects of non-pharmacological interventions on behavioral symptoms of FTD. Show more
Keywords: Behavioral management, caregiver support, environmental strategies, non-pharmacological interventions in frontotemporal dementia
DOI: 10.3233/JAD-142109
Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 283-293, 2015
Baseline Predictors of Antipsychotic Treatment Continuation and Response at Week 8 in Patients with Alzheimer’s Disease with Psychosis or Aggressive Symptoms: An Analysis of the CATIE-AD Study
Authors: Nagata, Tomoyuki | Nakajima, Shinichiro | Shinagawa, Shunichiro | Plitman, Eric | Nakayama, Kazuhiko | Graff-Guerrero, Ariel | Mimura, Masaru
Article Type: Research Article
Abstract: Background/Objective: The aim of the present study was to investigate predictors of atypical antipsychotic (AAP) treatment continuation and response by week 8 in patients with Alzheimer’s disease (AD) who have psychotic/aggressive symptoms using the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD) dataset. Methods: Clinical data was utilized from 421 AD outpatients with psychotic/aggressive symptoms who needed interventional treatment. Logistic regression analyses were performed to examine which baseline sociodemographic and clinical characteristics contributed to treatment ‘continuation’ and ‘response’, the latter of which was evaluated by the Clinical Global Impression of Change (CGI-C), Neuropsychiatric Inventory (NPI), and Brief Psychiatric Scale (BPRS). …Results: The treatment continuation rate was 48.7%, and CGI-C, NPI, and BPRS response rate by the last observation carried forward method were 42.7%, 48.6%, and 37.5%, respectively. No significant predictor was identified for treatment continuation in the Caucasian patients (n = 331), while better treatment response was predicted by a lower Mini-Mental State Examination score, treatment with risperidone (versus olanzapine and quetiapine), history of diabetes mellitus, healthier physical status, and more severe initial psychotic symptoms. Conclusions: Comparatively high intolerability from AAPs in the short term was confirmed. We found that baseline clinical predictors to treatment response in Caucasian AD patients with psychotic/aggressive symptoms include treatment with risperidone (versus quetiapine and olanzapine), diabetes mellitus, global physical status, cognitive impairment, and psychotic symptoms. Going forward, these findings may help to determine treatment strategies or care plans. Show more
Keywords: Aggression, Alzheimer’s disease, atypical antipsychotic, neuropsychiatric symptom, psychosis
DOI: 10.3233/JAD-170412
Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 263-272, 2017
Depressive Symptoms and Small Hippocampal Volume Accelerate the Progression to Dementia from Mild Cognitive Impairment
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
Lifetime History of Depression Predicts Increased Amyloid-β Accumulation in Patients with Mild Cognitive Impairment
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
Hippocampal and Clinical Trajectories of Mild Cognitive Impairment with Suspected Non-Alzheimer’s Disease Pathology
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
Effect of Education on Alzheimer’s Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer’s Disease: A Cross-Sectional Study
Authors: Wada, Masataka | Noda, Yoshihiro | Shinagawa, Shunichiro | Chung, Jun Ku | Sawada, Kyosuke | Ogyu, Kamiyu | Tarumi, Ryosuke | Tsugawa, Sakiko | Miyazaki, Takahiro | Yamagata, Bun | Graff-Guerrero, Ariel | Mimura, Masaru | Nakajima, Shinichiro | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Background: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. Objective: The aim of this study is to investigate the relationships among duration of education and Alzheimer’s disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD. Methods: We reanalyzed a part of the datasets of the Alzheimer’s Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy …controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n = 825), brain metabolism (n = 1,304), and brain volumes (n = 1,606) among three groups using data for 18 F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. Results: Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. Conclusions: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI. Show more
Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative (ADNI), brain reserve, brain volume, cognitive reserve, education, mild cognitive impairment
DOI: 10.3233/JAD-171168
Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 861-869, 2018
The Effects of Cortical Hypometabolism and Hippocampal Atrophy on Clinical Trajectories in Mild Cognitive Impairment with Suspected Non-Alzheimer’s Pathology: A Brief Report
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
Lifetime History of Depression Predicts Increased Amyloid-β Accumulation in Patients with Mild Cognitive Impairment
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