Your search for: 'author:("Fischer, Corinne E.")' has returned 20 results. (0.031s) Save search

Authors: Garcia-Segura, Monica Emili | Fischer, Corinne E. | Schweizer, Tom A. | Munoz, David G.

Article Type: Research Article

Abstract: Background: Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer’s disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4 ) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. Objective: To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. Methods: Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD 3 were classified as …High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ɛ 4 & ɛ 4 and ɛ 4/ɛ 4 groups depending on ɛ 4 copy number within APOE . Presence of AMB was assessed using NPI-Q. Results and Conclusion: AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOE ɛ 4 alleles as compared to No ɛ 4 & ɛ 4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes. Show more

Keywords: Aberrant motor behavior, Alzheimer’s disease, APOE gene, cerebral amyloid angiopathy, Lewy bodies, neuropathology, neuropsychiatric symptoms

DOI: 10.3233/JAD-190643

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1077-1087, 2019

Authors: Kim, Julia | Schweizer, Tom A. | Fischer, Corinne E. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The pathophysiology behind psychosis in patients with Alzheimer’s disease (AD) remains unknown. Recently, vascular risk factors have been recognized as important modifiers of the clinical presentation of AD. Objective: The purpose of our study is to investigate the mechanism through which vascular risk factors mediate psychosis and whether or not it involves cerebrovascular lesions. Methods: Data was provided by the National Alzheimer’s Coordinating Centre. The Uniform Data Set was used to collect information on subject-reported history of vascular risk factors, clinician-reported state of cognitive performance, and presence of psychosis based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). The Neuropathology Data …Set was used to evaluate the presence of vascular lesions and the severity of AD pathology. Subjects with high probability of AD based on the NIA/AA Reagan criteria were included in the analysis. Results: We identified 1,459 patients with high probability of AD and corresponding NPI-Q scores. We confirmed the association between hypertension and diabetes on psychosis, specifically in delusions and the co-occurrence of delusions and hallucinations. Furthermore, the presence of white matter rarefaction based on pathological evaluation was associated with hallucinations. A history of vascular risk factors was positively associated with vascular lesions. However, vascular lesions in the presence of vascular risk factors did not increase the likelihood of psychosis. Furthermore, vascular lesions were not associated with greater cognitive or functional impairments in this group with severe AD pathology. Conclusion: Vascular risk factors and vascular lesions are independently associated with psychosis in patients with severe AD. However, vascular lesions are not the mechanism through which vascular risk factors mediate psychosis. Show more

Keywords: Cerebrovascular diseases, delusions, dementia, hallucinations, infarction, neuropathology, pathology, risk factors, vascular

DOI: 10.3233/JAD-160506

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 381-389, 2017

Authors: Sennik, Simrin | Schweizer, Tom A. | Fischer, Corinne E. | Munoz, David G.

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms are common manifestations of Alzheimer’s disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. Objective: To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(–)] of agitation/aggression (A) in autopsy-confirmed AD. Methods: Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control …group or corrections for multiple comparisons. Results: 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p  = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits. Conclusions: Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions. Show more

Keywords: Alzheimer’s disease, agitation, aggression, neuropathology, (p)-TDP-43, traumatic brain injury, vascular lesions, vascular risk factors

DOI: 10.3233/JAD-160780

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1519-1528, 2017

Authors: Atayde, Adrienne L. | Fischer, Corinne E. | Schweizer, Tom A. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The relationship between sleep, neuropathology, and clinical manifestations of Alzheimer’s disease (AD) remains controversial. Objective: To determine whether nighttime behaviors (NTB) are associated with the development of AD histopathology or cognitive decline. Methods: We compared NTB prevalence in subjects with or without AD lesions, and with or without progressive cognitive decline. Subjects with either absent or severe plaques and tangles were identified from the National Alzheimer’s Disease Coordinating Center data sets and classified as cognitively declining if the standard deviation from their individual mean Mini-Mental Status Examination score was ≥2, and stable if <2 regardless of their initial score. …NTB was assessed using the Neuropsychiatric Inventory Questionnaire Quick Version (NPI-Q). Results: NTB was significantly greater in decliners than stable subjects in the group with severe histopathology as determined by frequent plaques (p  = 0.003) or high Braak stage (p  =��0.002). A similar significant trend was observed in subjects with absent plaques (p  = 0.019) or tangles (p  = 0.006). The prevalence of NTB was comparable between stable AD and non-AD subjects. NTB severity scores showed a similar pattern. Conclusion: The development of NTB as assessed by NPI-Q in subjects with or without AD lesions occurred concurrently with cognitive decline. Among cognitively stable subjects, the presence of AD histopathology did not alter NTB prevalence. Thus, NTB disruptions at the gross granularity level assessed by NPI-Q were much more closely related to cognitive decline than the formation of pathological lesions. Factors other than AD histopathology may mediate the association between NTB and cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid plaque, cognitive decline, neurofibrillary tangles, sleep

DOI: 10.3233/JAD-190907

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 839-850, 2020

Authors: Atayde, Adrienne L. | Fischer, Corinne E. | Schweizer, Tom A. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The temporal relationship between sleep, Alzheimer’s disease (AD), and cognitive impairment remains to be further elucidated. Objective: First, we aim to determine whether the Neuropsychiatric Inventory–Questionnaire (NPI-Q) assessed nighttime behaviors prior to cognitive decline influence the rate of cognitive deterioration in pathologically confirmed AD, and second, to assess the possible interactions with APOE allele and cerebral amyloid angiopathy (CAA). Methods: The rate of cognitive decline between cognitively asymptomatic participants from the National Alzheimer Coordinating Center who eventually received a neuropathologic diagnosis of AD with (+NTB) or without (−NTB) nighttime behaviors were compared using independent samples t -test. Participants were …stratified by APOE carrier and CAA status. Demographic and patient characteristics were assessed using descriptive statistics, and the independent samples t -test was used for continuous variables and chi-square test for categorical variables. The significance level was set at p ≤0.05. Results: The rate of cognitive decline was greater in +NTB (n  = 74; 3.30 points/year) than −NTB (n  = 330; 2.45 points/year) (p  = 0.016), even if there was no difference in cognitive status at onset. This difference was restricted to APOE ɛ4 carriers (p  = 0.049) and positive CAA participants (p  = 0.020). Significance was not reached in non-carriers (p  = 0.186) and negative CAA (p  = 0.364). APOE and CAA were not differentially distributed between the NTB groups. Conclusion: NPI-Q assessed nighttime behaviors, a surrogate for sleep disturbances, are associated with more rapidly deteriorating cognition in patients with AD neuropathology who are also carriers of APOE ɛ4 or show CAA. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, cerebral amyloid angiopathy, cognitive decline, neuropsychiatric symptoms, sleep

DOI: 10.3233/JAD-215276

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1137-1147, 2022

Authors: Hird, Megan A. | Egeto, Peter | Fischer, Corinne E. | Naglie, Gary | Schweizer, Tom A.

Article Type: Research Article

Abstract: Background: Many individuals with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are at an increased risk of driving impairment. There is a need for tools with sufficient validity to help clinicians assess driving ability. Objective: Provide a systematic review and meta-analysis of the primary driving assessment methods (on-road, cognitive, driving simulation assessments) in patients with MCI and AD. Methods: We investigated (1) the predictive utility of cognitive tests and domains, and (2) the areas and degree of driving impairment in patients with MCI and AD. Effect sizes were derived and analyzed in a random effects model. Results: Thirty-two articles …(including 1,293 AD patients, 92 MCI patients, 2,040 healthy older controls) met inclusion criteria. Driving outcomes included: On-road test scores, pass/fail classifications, errors; caregiver reports; real world crash involvement; and driving simulator collisions/risky behavior. Executive function (ES [95% CI]; 0.61 [0.41, 0.81]), attention (0.55 [0.33, 0.77]), visuospatial function (0.50 [0.34, 0.65]), and global cognition (0.61 [0.39, 0.83]) emerged as significant predictors of driving performance. Trail Making Test Part B (TMT-B, 0.61 [0.28, 0.94]), TMT-A (0.65 [0.08, 1.21]), and Maze test (0.88 [0.60, 1.15]) emerged as the best single predictors of driving performance. Patients with very mild AD (CDR = 0.5) mild AD (CDR = 1) were more likely to fail an on-road test than healthy control drivers (CDR = 0), with failure rates of 13.6%, 33.3% and 1.6%, respectively. Conclusion: The driving ability of patients with MCI and AD appears to be related to degree of cognitive impairment. Across studies, there are inconsistent cognitive predictors and reported driving outcomes in MCI and AD patients. Future large-scale studies should investigate the driving performance and associated neural networks of subgroups of AD (very mild, mild, moderate) and MCI (amnestic, non-amnestic, single-domain, multiple-domain). Show more

Keywords: KeywordsAlzheimer’s disease, automobile driving, cognition, mild cognitive impairment

DOI: 10.3233/JAD-160276

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 713-729, 2016

Authors: Hird, Megan A. | Vesely, Kristin A. | Fischer, Corinne E. | Graham, Simon J. | Naglie, Gary | Schweizer, Tom A.

Article Type: Short Communication

Abstract: The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n  = 11) and amnestic multiple-domain MCI (md-MCI, n  = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when …evaluating driving safety. Show more

Keywords: Automobile driving, cognition, computer simulation patient outcome assessment, mild cognitive impairment

DOI: 10.3233/JAD-160995

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 447-452, 2017

Authors: Fischer, Corinne E. | Churchill, Nathan | Leggieri, Melissa | Vuong, Veronica | Tau, Michael | Fornazzari, Luis R. | Thaut, Michael H. | Schweizer, Tom A.

Article Type: Research Article

Abstract: Background: Repeated exposure to long-known music has been shown to have a beneficial effect on cognitive performance in patients with AD. However, the brain mechanisms underlying improvement in cognitive performance are not yet clear. Objective: In this pilot study we propose to examine the effect of repeated long-known music exposure on imaging indices and corresponding changes in cognitive function in patients with early-stage cognitive decline. Methods: Participants with early-stage cognitive decline were assigned to three weeks of daily long-known music listening, lasting one hour in duration. A cognitive battery was administered, and brain activity was measured before and after intervention. …Paired-measures tests evaluated the longitudinal changes in brain structure, function, and cognition associated with the intervention. Results: Fourteen participants completed the music-based intervention, including 6 musicians and 8 non-musicians. Post-baseline there was a reduction in brain activity in key nodes of a music-related network, including the bilateral basal ganglia and right inferior frontal gyrus, and declines in fronto-temporal functional connectivity and radial diffusivity of dorsal white matter. Musician status also significantly modified longitudinal changes in functional and structural brain measures. There was also a significant improvement in the memory subdomain of the Montreal Cognitive Assessment. Conclusion: These preliminary results suggest that neuroplastic mechanisms may mediate improvements in cognitive functioning associated with exposure to long-known music listening and that these mechanisms may be different in musicians compared to non-musicians. Show more

Keywords: Alzheimer’s disease, cognitive reserve, functional MRI, imaging, MRI, music

DOI: 10.3233/JAD-210610

Citation: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 819-833, 2021

Authors: Showraki, Alireza | Murari, Geetanjali | Ismail, Zahinoor | Barfett, Joseph J. | Fornazzari, Luis | Munoz, David G. | Schweizer, Tom A. | Fischer, Corinne E.

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Objective: The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI. Methods: For this systematic review, four databases, PubMed (1946–2018), Cochrane (2005–2018), EMBASE (1947–2018), and PsycINFO (1806–2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria were defined as 1) at least one AD …CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded. Results: In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology. Conclusion: Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized “objective” approach for the evaluation of NPS. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, biomarkers, cerebrospinal fluid, neuropsychiatry, systematic review

DOI: 10.3233/JAD-190365

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 477-501, 2019

Authors: Fischer, Corinne E. | Qian, Winnie | Schweizer, Tom A. | Millikin, Colleen P. | Ismail, Zahinoor | Smith, Eric E. | Lix, Lisa M. | Shelton, Paul | Munoz, David G.

Article Type: Research Article

Abstract: Background: The neuropathological correlates of psychosis in Alzheimer’s disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association. Objective: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD. Method: We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to …the NPI-Q, were analyzed separately. Results: 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis. Method: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD. Show more

Keywords: Alzheimer’s disease, arteriosclerotic leukoencephalopathy, delusion, hallucination, neuropathology, psychosis, vascular pathology

DOI: 10.3233/JAD-150606

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 283-295, 2016

Authors: Golas, Angela C. | Salwierz, Patrick | Rajji, Tarek K. | Bowie, Christopher R. | Butters, Meryl A. | Fischer, Corinne E. | Flint, Alastair J. | Herrmann, Nathan | Mah, Linda | Mulsant, Benoit H. | Pollock, Bruce G. | Taghdiri, Foad | Wang, Wei | Tartaglia, M. Carmela

Article Type: Short Communication

Abstract: Major depressive disorder (MDD) is a risk factor for Alzheimer’s disease (AD). Cerebrovascular disease (CVD) is implicated in MDD and AD. Our study compared participants with AD positive and negative cerebrospinal fluid (CSF) biomarkers on neuropsychological performance, remitted MDD status, and CVD burden. Next, we compared AD-CSF biomarkers and white matter hyperintensities (WMH) burden among three groups: mild cognitive impairment (MCI) (n  = 12), MCI with remitted MDD (MDD+MCI) (n  = 12), and remitted MDD alone (MDD) (n  = 7). Few participants (18%) with MCI+MDD exhibited AD(+) biomarkers. Nearly all participants had moderate-severe WMH. WMH may contribute to cognitive impairment or depression in …MCI patients with AD(-) biomarkers. Show more

Keywords: Alzheimer’s disease, cerebrovascular disease, major depressive disorder, mild neurocognitive disorder

DOI: 10.3233/JAD-221097

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1219-1227, 2023

Authors: Fischer, Corinne E. | Kortebi, Ines | Karameh, Wael K. | Kumar, Sanjeev | Gallagher, Damien | Golas, Angela | Munoz, David | Barfett, Joseph | Butters, Meryl A. | Bowie, Christopher R. | Flint, Alastair | Rajji, Tarek | Herrmann, Nathan | Pollock, Bruce G. | Mulsant, Benoit | Schweizer, Tom A. | Mah, Linda | and the PACT-MD Study Group

Article Type: Research Article

Abstract: Background: Cardiovascular risk factors (CVRFs) have been linked to both depression and cognitive decline but their role in neuropsychiatric symptoms (NPS) has yet to be clarified. Objective: Understanding the role of CVRFs in the etiology of NPS for prospective treatments and preventive strategies to minimize these symptoms. Methods: We examined the distribution of NPS using the Neuropsychiatric Inventory (NPI) scores in three cohorts from the Prevention of Alzheimer’s Dementia with Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) study: older patients with a lifetime history of major depressive disorder (MDD) in remission, patients with …mild cognitive impairment (MCI), and patients with combined MCI and MDD. We also examined the link between individual NPS and CVRFs, Framingham risk score, and Hachinski ischemic score in a combined sample. Results: Analyses were based on a sample of 140 subjects, 70 with MCI, 38 with MCI plus MDD, and 32 with MDD. There was no effect of age, gender, education, cognition, or CVRFs on the presence (NPI >1) or absence (NPI = 0) of NPS. Depression was the most prevalent affective NPS domain followed by night-time behaviors and appetite changes across all three diagnostic groups. Agitation and aggression correlated negatively while anxiety, disinhibition, night-time behaviors, and irritability correlated positively with CVRFs (all p -values <0.05). Other NPS domains showed no significant association with CVRFs. Conclusion: CVRFs are significantly associated with individual NPI sub-scores but not with total NPI scores, suggesting that different pathologies may contribute to different NPS domains. Show more

Keywords: Affective symptoms, sep alzheimer’s disease, sep cardiovascular diseases, sep cognitive dysfunction, sep dementia, sep major depressive disorder, sep mental status and dementia tests, sep neurobehavioral manifestations

DOI: 10.3233/JAD-181099

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1305-1311, 2019

Authors: Yuen, Kimberley | Rashidi-Ranjbar, Neda | Verhoeff, Nicolaas Paul L.G. | Kumar, Sanjeev | Gallagher, Damien | Flint, Alastair J. | Herrmann, Nathan | Pollock, Bruce G. | Mulsant, Benoit H. | Rajji, Tarek K. | Voineskos, Aristotle N. | Fischer, Corinne E. | Mah, Linda | for the PACt-MD Study Group

Article Type: Research Article

Abstract: Background: Previous studies examining the link between neuropsychiatric symptoms (NPS) and biomarkers of Alzheimer’s disease (AD) may be confounded by remitted or past history of psychiatric illness, which in itself is associated with AD biomarkers such as reduced medial temporal lobe (MTL) volume. Objective: We examined associations between mood and anxiety-related NPS and MTL in older adults with mild cognitive impairment (MCI) free of lifetime history of depression. We hypothesized an inverse relationship between NPS severity and MTL. Methods: Forty-two MCI participants without current or past history of depression or other major psychiatric illness were assessed using the Neuropsychiatric Inventory-Questionnaire …(NPI-Q). Correlation and regression analyses were performed between selected NPI-Q items and regional MTL volumes from structural magnetic resonance imaging. Results: Sleep disturbances were inversely associated with several regional volumes within the MTL. Sleep disturbances remained significantly correlated with left hippocampal and amygdala volume following correction for multiple comparisons. In contrast, depression and anxiety were not correlated with MTL. Conclusions: The relationship between reduced MTL and sleep, but not with depressed or anxious states, in MCI free of lifetime history of depression, suggests a potential mechanism for sleep as a risk factor for AD. The current findings highlight the importance of accounting for remitted psychiatric conditions in studies of the link between NPS and AD biomarkers and support the need for further research on sleep as clinical biomarker of AD and target for AD prevention. Show more

Keywords: Alzheimer’s disease, depression, medial temporal lobe, mild cognitive impairment, neuroimaging biomarkers, neuropsychiatric symptoms, sleep

DOI: 10.3233/JAD-190160

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 413-421, 2019

Authors: Goodman, Michelle S. | Zomorrodi, Reza | Kumar, Sanjeev | Barr, Mera S. | Daskalakis, Zafiris J. | Blumberger, Daniel M. | Fischer, Corinne E. | Flint, Alastair | Mah, Linda | Herrmann, Nathan | Pollock, Bruce G. | Bowie, Christopher R. | Mulsant, Benoit H. | Rajji, Tarek K. | The PACt-MD Study Group

Collaborators: Mulsant, B.H. | Rajji, T.K. | Herrmann, N. | Pollock, B.G. | Lourenco, L. | Blumberger, D.M. | Bowie, C.R. | Butters, M. | Fischer, C.E. | Flint, A. | Gallagher, D. | Golas, A. | Graff, A. | Kennedy, J.L. | Kumar, S. | Mah, L. | Ovaysikia, S. | Rapoport, M. | Thorpe, K. | Verhoeff, N.P.L.G. | Voineskos, A.N.

Article Type: Research Article

Abstract: While several studies have found that neural oscillations play a key role in the functioning of working memory, the nature of aberrant oscillatory activity underlying working memory impairments in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) remains largely unexplored. These individuals often display structural alterations in brain regions and pathways involved in working memory processes and therefore may also display altered oscillatory activity during memory activation. Electroencephalographic (EEG) activity was recorded during the N-back working memory task in three groups: AD (n  = 29), MCI (n  = 100), and healthy controls (HCs; n  = 40). Theta (4–7 Hz) and alpha (7.5–12 Hz) modulation was …measured in response to the stimulus presentation during correct and incorrect responses. This modulation represents the change in EEG activity associated with the stimulus onset and was measured as a ratio of post stimulus power to pre stimulus power. We also assessed the relationship between change in oscillatory power and working memory performance. Compared to HCs, the AD group demonstrated the lowest working memory accuracy and a smaller theta ratio for correct responses on the 2-back condition; the MCI group demonstrated a smaller theta ratio for correct responses on the 3-back condition. Finally, we observed that the theta ratio, but not the alpha ratio, was a significant predictor of working memory performance in the three groups for all conditions. Taken together, these behavioral and electrophysiological results suggest that in addition to impairments in working memory performance, modulation of theta, but not alpha power, may be impaired in MCI and AD. Show more

Keywords: Alpha power, Alzheimer’s disease, electroencephalography, mild cognitive impairment, theta power, working memory

DOI: 10.3233/JAD-181195

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1085-1094, 2019

Authors: Dissanayake, Andrew S. | Tan, Yu Bin | Bowie, Christopher R. | Butters, Meryl A. | Flint, Alastair J. | Gallagher, Damien | Golas, Angela C. | Herrmann, Nathan | Ismail, Zahinoor | Kennedy, James L. | Kumar, Sanjeev | Lanctot, Krista L. | Mah, Linda | Mulsant, Benoit H. | Pollock, Bruce G. | Rajji, Tarek K. | Tau, Michael | Maraj, Anika | Churchill, Nathan W. | Tsuang, Debby | Schweizer, Tom A. | Munoz, David G. | Fischer, Corinne E.

Article Type: Research Article

Abstract: Background: Recent work suggests that APOE ɛ 4/4 females with Alzheimer’s disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). Objective: To examine the interaction of sex and APOE ɛ 4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n  = 252) and 2) patients with probable AD (n  = 7,261). Methods: Regression models examined the interactive effects of sex and APOE ɛ 4 on the number of NPS experienced and NPS Severity. APOE ɛ 3/4 and APOE ɛ 4/4 were pooled in the at-risk cohort due …to the sample size. Results: In the at-risk cohort, there was a significant sex*APOE ɛ 4 interaction (p  = 0.007) such that the association of APOE ɛ 4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOE ɛ 4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOE ɛ 4/4 females had significantly more NPS (IRR = 1.1, p  = 0.001, mean = 3.1) and higher severity scores (b  = 0.31, p  = 0.015, mean = 3.7) than APOE ɛ 3/3 females (meanNPS  = 2.9, meanSeverity  = 3.3). No association was found in males. Conclusion: Our study suggests that sex modifies the association of APOE ɛ 4 on NPS burden. APOE ɛ 4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed. Show more

Keywords: Alzheimer’s disease, APOE4, behavioral and psychological symptoms of dementia, biomarkers, gender differences, major depressive disorder, mild cognitive impairment, neuropsychiatry, Neuropsychiatric Inventory Questionnaire, psychosis

DOI: 10.3233/JAD-220586

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1571-1588, 2022

Authors: Fischer, Corinne E. | Ismail, Zahinoor | Youakim, James M. | Creese, Byron | Kumar, Sanjeev | Nuñez, Nicolas | Ryan Darby, R. | Di Vita, Antonella | D’Antonio, Fabrizia | de Lena, Carlo | McGeown, William J. | Ramit, Ravona | Rasmussen, Jill | Bell, Joanne | Wang, Huali | Bruneau, Marie-Andrée | Panegyres, Peter K. | Lanctôt, Krista L. | Agüera-Ortiz, Luis | Lyketsos, Constantine | Cummings, Jeffrey | Jeste, Dilip V. | Sano, Mary | Devanand, D.P. | Sweet, Robert A. | Ballard, Clive

Article Type: Research Article

Abstract: Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for …current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders , 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders. Show more

Keywords: Alzheimer’s disease, criteria, delusions, hallucinations, mild cognitive impairment, psychosis

DOI: 10.3233/JAD-190828

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1143-1156, 2020

Authors: Rajji, Tarek K. | Bowie, Christopher R. | Herrmann, Nathan | Pollock, Bruce G. | Bikson, Marom | Blumberger, Daniel M. | Butters, Meryl A. | Daskalakis, Zafiris J. | Fischer, Corinne E. | Flint, Alastair J. | Golas, Angela C. | Graff-Guerrero, Ariel | Kumar, Sanjeev | Lourenco, Lillian | Mah, Linda | Ovaysikia, Shima | Thorpe, Kevin E. | Voineskos, Aristotle N. | Mulsant, Benoit H. | for the PACt-MD Study Group

Article Type: Research Article

Abstract: Background: By the time Alzheimer’s disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. Results: PACt-MD (Prevention of Alzheimer’s dementia with Cognitive remediation plus transcranial direct current stimulation …in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants. Conclusion: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD. Show more

Keywords: Alzheimer’s disease and related disorders, cognitive remediation, major depressive disorder, mild cognitive disorder, PACt-MD, prevention, transcranial direct current stimulation, NCT02386670

DOI: 10.3233/JAD-200141

Citation: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 733-751, 2020

Authors: Agüera-Ortiz, Luis | Babulal, Ganesh M. | Bruneau, Marie-Andrée | Creese, Byron | D’Antonio, Fabrizia | Fischer, Corinne E. | Gatchel, Jennifer R. | Ismail, Zahinoor | Kumar, Sanjeev | McGeown, William J. | Mortby, Moyra E. | Nuñez, Nicolas A. | de Oliveira, Fabricio F. | Pereiro, Arturo X. | Ravona-Springer, Ramit | Rouse, Hillary J. | Wang, Huali | Lanctôt, Krista L.

Article Type: Review Article

Abstract: Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present …proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials. Show more

Keywords: Clinical trials, dementia, delusions, hallucinations, investigational therapies, psychotic disorders

DOI: 10.3233/JAD-215483

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1203-1228, 2022

Authors: Kapoor, Arunima | Bartha, Robert | Black, Sandra E. | Borrie, Michael | Freedman, Morris | Gao, Fuqiang | Herrmann, Nathan | Mandzia, Jennifer | Ozzoude, Miracle | Ramirez, Joel | Scott, Christopher J.M. | Symons, Sean | Fischer, Corinne E. | Frank, Andrew | Seitz, Dallas | Wolf, Michael Uri | Verhoeff, Nicolaas Paul L.G. | Naglie, Gary | Reichman, William | Masellis, Mario | Mitchell, Sara B. | Tang-Wai, David F. | Tartaglia, Maria Carmela | Kumar, Sanjeev | Pollock, Bruce G. | Rajji, Tarek K. | Finger, Elizabeth | Pasternak, Stephen H. | ONDRI Investigators | Swartz, Richard H.

Article Type: Research Article

Abstract: Background/Objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer’s disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. Results: Of 210 AD clinical trials, …105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity. Show more

DOI: 10.3233/JAD-191097

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 747-757, 2020

Authors: Ismail, Zahinoor | Agüera-Ortiz, Luis | Brodaty, Henry | Cieslak, Alicja | Cummings, Jeffrey | Fischer, Corinne E. | Gauthier, Serge | Geda, Yonas E. | Herrmann, Nathan | Kanji, Jamila | Lanctôt, Krista L. | Miller, David S. | Mortby, Moyra E. | Onyike, Chiadi U. | Rosenberg, Paul B. | Smith, Eric E. | Smith, Gwenn S. | Sultzer, David L. | Lyketsos, Constantine | for the NPS Professional Interest Area of the International Society of to Advance Alzheimer’s Research and Treatment (NPS-PIA of ISTAART)

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) is a construct that describes the emergence at ≥50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer’s Research and Treatment – Alzheimer’s Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as …described. Objective: To develop an instrument based on ISTAART-AA MBI criteria. Methods: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults. Results: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician. Conclusion: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes. Show more

DOI: 10.3233/JAD-160979

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 929-938, 2017