PRISM :: Browsing by Author "Ismail, Zahinoor"

Browsing by Author "Ismail, Zahinoor"

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Open Access
A scoping review of perceptions from healthcare professionals on antipsychotic prescribing practices in acute care settings
(2022-10-21) Jaworska, Natalia; Moss, Stephana J.; Krewulak, Karla D.; Stelfox, Zara; Niven, Daniel J.; Ismail, Zahinoor; Burry, Lisa D.; Fiest, Kirsten M.
Abstract Background Antipsychotic medications are frequently prescribed in acute care for clinical indications other than primary psychiatric disorders such as delirium. Unfortunately, they are commonly continued at hospital discharge and at follow-ups thereafter. The objective of this scoping review was to characterize antipsychotic medication prescribing practices, to describe healthcare professional perceptions on antipsychotic prescribing and deprescribing practices, and to report on antipsychotic deprescribing strategies within acute care. Methods We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and Web of Science databases from inception date to July 3, 2021 for published primary research studies reporting on antipsychotic medication prescribing and deprescribing practices, and perceptions on those practices within acute care. We included all study designs excluding protocols, editorials, opinion pieces, and systematic or scoping reviews. Two reviewers screened and abstracted data independently and in duplicate. The protocol was registered on Open Science Framework prior to data abstraction (10.17605/OSF.IO/W635Z). Results Of 4528 studies screened, we included 80 studies. Healthcare professionals across all acute care settings (intensive care, inpatient, emergency department) perceived prescribing haloperidol (n = 36/36, 100%) most frequently, while measured prescribing practices reported common quetiapine prescribing (n = 26/36, 76%). Indications for antipsychotic prescribing were delirium (n = 48/69, 70%) and agitation (n = 20/69, 29%). Quetiapine (n = 18/18, 100%) was most frequently prescribed at hospital discharge. Three studies reported in-hospital antipsychotic deprescribing strategies focused on pharmacist-driven deprescribing authority, handoff tools, and educational sessions. Conclusions Perceived antipsychotic prescribing practices differed from measured prescribing practices in acute care settings. Few in-hospital deprescribing strategies were described. Ongoing evaluation of antipsychotic deprescribing strategies are needed to evaluate their efficacy and risk.
Open Access
Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer’s disease and cognitively unimpaired individuals
(2021-03-31) Ng, Kok P; Chiew, Hui; Rosa-Neto, Pedro; Kandiah, Nagaendran; Ismail, Zahinoor; Gauthier, Serge
Abstract The development of in vivo biomarkers of Alzheimer’s disease (AD) has advanced the diagnosis of AD from a clinical syndrome to a biological construct. The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals. While neuropsychiatric symptoms (NPS) are non-cognitive symptoms that are increasingly recognized as early manifestations of AD, the associations of NPS with AD pathophysiology in preclinical AD remain unclear. Here, we review the associations between NPS and AD biomarkers amyloid-β (Aβ), tau and neurodegeneration in preclinical AD and cognitively-unimpaired individuals in 19 eligible English-language publications (8 cross-sectional studies, 10 longitudinal, 1 both cross-sectional and longitudinal). The cross-sectional studies have consistently shown that NPS, particularly depressive and anxiety symptoms, are associated with higher Aβ. The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time. However, most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology. For the association of NPS and neurodegeneration, two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD, respectively. However, evidence for the association between atrophy and NPS in preclinical AD is less consistent. Therefore, future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N) biomarkers, NPS and cognitive decline, but also to elucidate the contribution of comorbid pathology to preclinical AD.
Open Access
Barriers and facilitators to care for agitation and/or aggression among persons living with dementia in long-term care
(2024-04-11) Wong, Britney; Ismail, Zahinoor; Watt, Jennifer; Holroyd-Leduc, Jayna; Goodarzi, Zahra
Abstract Background Agitation and/or aggression affect up to 60% of persons living with dementia in long-term care (LTC). It can be treated via non-pharmacological and pharmacological interventions, but the former are underused in clinical practice. In the literature, there is currently a lack of understanding of the challenges to caring for agitation and/or aggression among persons living with dementia in LTC. This study assesses what barriers and facilitators across the spectrum of care exist for agitation and/or aggression among people with dementia in LTC across stakeholder groups. Methods This was a qualitative study that used semi-structured interviews among persons involved in the care and/or planning of care for people with dementia in LTC. Participants were recruited via purposive and snowball sampling, with the assistance of four owner-operator models. Interviews were guided by the Theoretical Domains Framework and transcribed and analyzed using Framework Analysis. Results Eighteen interviews were conducted across 5 stakeholder groups. Key identified barriers were a lack of agitation and/or aggression diagnostic measures, limited training for managing agitation and/or aggression in LTC, an overuse of physical and chemical restraints, and an underuse of non-pharmacological interventions. Facilitators included using an interdisciplinary team to deliver care and having competent and trained healthcare providers to administer non-pharmacological interventions. Conclusions This study advances care for persons living with dementia in LTC by drawing attention to unique and systemic barriers present across local and national Canadian LTC facilities. Findings will support future implementation research endeavours to eliminate these identified barriers across the spectrum of care, thus improving care outcomes among people with dementia in LTC.
Open Access
Cerebral Small Vessel Disease: Cognitive Reserve and Mediators of Cognitive Decline
(2021-09-24) Durrani, Romella; Smith, Eric E.; Ismail, Zahinoor; Hill, Michael D.; Monchi, Oury; Dukelow, Sean P.; Postuma, Ronald B.
Background: Cerebral small vessel disease (CSVD) is the most common type of cerebrovascular disease that contributes to cognitive decline and dementia. However, persons with the same burden of CSVD often have different cognitive outcomes. Cognitive reserve, defined as the ability to tolerate or adapt to pathology, has been suggested to explain these variations. There are limited studies on cognitive reserve in CSVD, as most studies have focused on Alzheimer’s disease (AD). These studies have also focused on education as the proxy of cognitive reserve, with only a few studies looking at other proxies, such as occupation and leisure activities. Additionally, few studies of cognitive reserve have examined other measures of cerebrovascular disease, beyond white matter hyperintensities (WMH). Objectives: Determine whether cognitive reserve mitigates the deleterious effects of CSVD on cognition, and determine the degree to which cerebral amyloid angiopathy (CAA) biomarkers mediate the effects of CAA on cognition.Methods: Data were analyzed from four multicenter, cross-sectional cohorts. Measures of cerebrovascular disease included: brain infarcts, non-lacunar covert brain infarcts (CBI), WMH, vascular lesion burden, and CAA. Measures of cognitive reserve included: education, occupation, social involvement, physical activity, leisure physical activity, household income, marital status, height, stress, and multilingualism. CAA biomarkers included: WMH, cerebrovascular reactivity (CVR), peak width of skeletonized mean diffusivity (PSMD), mean cortical thickness, and mean cortical thickness in an AD meta-region of interest.Results: WMH, non-lacunar CBI, vascular lesion burden, and CAA were associated with lower cognition. Proxies of cognitive reserve were associated with higher cognition. However, cognitive reserve did not modify the association between CSVD and cognition. CVR, PSMD, and mean cortical thickness in regions typically affected by AD accounted for half of the effects of CAA on cognition; PSMD was the largest contributor.Conclusions: This forms the largest body of work on cognitive reserve within CSVD. Strategies to prevent CSVD-related cognitive decline and dementia include: 1) preventing CSVD, 2) enhancing cognitive reserve, thereby independently increasing cognition---however, this does not mitigate the deleterious effects of CSVD on cognition, and 3) in CAA, maintaining white matter integrity and restoring normal cerebrovascular reactivity.
Open Access
Characterizing Cortical Atrophy in Patients with Cerebral Amyloid Angiopathy: A Cross-Sectional and Longitudinal Analysis
(2019-05-15) Subotic, Arsenije; Smith, Eric Edward; Pike, G. Bruce; Ismail, Zahinoor
This study investigated cortical thickness in participants with Cerebral Amyloid Angiopathy (CAA) cross-sectionally and longitudinally, as well as its relationship with cognition and other markers of CAA pathology using Magnetic Resonance Imaging (MRI). CAA participants had lower global thickness compared to healthy controls (HC) (p=0.03) and greater global thickness compared to a group of participants with Alzheimer’s Disease (AD) (p=0.001). Cross-sectionally in CAA, an association was found between thickness and memory scores (p=0.01) and lower thickness and higher white matter hyperintensity volume (WMH) (p=0.04). Longitudinally, CAA participants had a greater rate of thinning compared to HC (p=0.008). No associations were found between thinning over time and cognition and WMH volume at baseline in CAA. Distinct differences from HC and AD suggest cortical thickness is a possible biomarker of CAA pathology and a potential therapeutic target.
Open Access
Considering Individual Variation in the Search for Neuroimaging Features of Response to Pharmacotherapy for Major Depression
(2022-09) van der Wijk, Gwen Marijke; Protzner, Andrea B.; Kiss, Zelma; Dobson, Keith Stephen; Gratton, Caterina; Ismail, Zahinoor
Many studies investigate the potential of neuroimaging features to predict treatment success for patients with major depression (MD), as this could improve outcomes in clinical practice. However, variable findings and methodological issues limit the generalizability of such research. In addition, we know little about the applicability of features identified in neuroimaging studies at an individual level, which is essential for translation to clinical practice. In this thesis, I examined these issues to advance our understanding of the opportunities and challenges that this field can leverage to get closer to personalized care. First, I investigated the robustness of fMRI functional connectivity features in three important brain networks related to MD and successful treatment using a large, multi-site dataset. I identified stable differences between participants before treatment based on if and how quickly their symptoms decreased during treatment, indicating their potential to predict outcomes. Second, I explored the relative magnitude of individual variation and group differences such as those identified in project 1. Specifically, the similarity in whole-brain fMRI connectivity across everyone, groups (patients vs controls, responders vs non-responders, female vs male participants), sessions (baseline, week 2 and 8) and individuals was quantified to estimate the relative amount of variance explained by each of these sources. Individual-specific connectivity, together with common connectivity across participants and sessions, explained most of the variance in the data, while group differences contributed only a small amount. Third, I examined the group-to-individual generalizability of brain features using EEG. After identifying differences between groups of patients whose symptoms did or did not decrease substantially with treatment, this study explored whether such group features could be identified in individual patients. The results revealed that individual brain features often deviated from group features. Overall, these findings indicate that, though robust features of antidepressant treatment success may be identified at the group level using large samples and thorough standardizing procedures, individual variation likely needs to be considered for these findings to be applicable to individual patients. Future research should examine if individual brain features can accurately inform clinical practice.
Open Access
Dementia risk prediction in individuals with mild cognitive impairment: a comparison of Cox regression and machine learning models
(2022-11-02) Wang, Meng; Greenberg, Matthew; Forkert, Nils D.; Chekouo, Thierry; Afriyie, Gabriel; Ismail, Zahinoor; Smith, Eric E.; Sajobi, Tolulope T.
Abstract Background Cox proportional hazards regression models and machine learning models are widely used for predicting the risk of dementia. Existing comparisons of these models have mostly been based on empirical datasets and have yielded mixed results. This study examines the accuracy of various machine learning and of the Cox regression models for predicting time-to-event outcomes using Monte Carlo simulation in people with mild cognitive impairment (MCI). Methods The predictive accuracy of nine time-to-event regression and machine learning models were investigated. These models include Cox regression, penalized Cox regression (with Ridge, LASSO, and elastic net penalties), survival trees, random survival forests, survival support vector machines, artificial neural networks, and extreme gradient boosting. Simulation data were generated using study design and data characteristics of a clinical registry and a large community-based registry of patients with MCI. The predictive performance of these models was evaluated based on three-fold cross-validation via Harrell’s concordance index (c-index), integrated calibration index (ICI), and integrated brier score (IBS). Results Cox regression and machine learning model had comparable predictive accuracy across three different performance metrics and data-analytic conditions. The estimated c-index values for Cox regression, random survival forests, and extreme gradient boosting were 0.70, 0.69 and 0.70, respectively, when the data were generated from a Cox regression model in a large sample-size conditions. In contrast, the estimated c-index values for these models were 0.64, 0.64, and 0.65 when the data were generated from a random survival forest in a large sample size conditions. Both Cox regression and random survival forest had the lowest ICI values (0.12 for a large sample size and 0.18 for a small sample size) among all the investigated models regardless of sample size and data generating model. Conclusion Cox regression models have comparable, and sometimes better predictive performance, than more complex machine learning models. We recommend that the choice among these models should be guided by important considerations for research hypotheses, model interpretability, and type of data.
Open Access
Detecting agitation and aggression in persons living with dementia: a systematic review of diagnostic accuracy
(2024-06-26) Wong, Britney; Wu, Pauline; Ismail, Zahinoor; Watt, Jennifer; Goodarzi, Zahra
Abstract Objective 40–60% of persons living with dementia (PLWD) experience agitation and/or aggression symptoms. There is a need to understand the best method to detect agitation and/or aggression in PLWD. We aimed to identify agitation and/or aggression tools that are validated against a reference standard within the context of PLWD. Methods Our study was registered on PROSPERO (CRD42020156708). We searched MEDLINE, Embase, and PsycINFO up to April 22, 2024. There were no language or date restrictions. Studies were included if they used any tools or questionnaires for detecting either agitation or aggression compared to a reference standard among PLWD, or any studies that compared two or more agitation and/or aggression tools in the population. All screening and data extraction were done in duplicates. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Data extraction was completed in duplicates by two independent authors. We extracted demographic information, prevalence of agitation and/or aggression, and diagnostic accuracy measures. We also reported studies comparing the correlation between two or more agitation and/or aggression tools. Results 6961 articles were screened across databases. Six articles reporting diagnostic accuracy measures compared to a reference standard and 30 articles reporting correlation measurements between tools were included. The agitation domain of the Spanish NPI demonstrated the highest sensitivity (100%) against the agitation subsection of the Spanish CAMDEX. Single-study evidence was found for the diagnostic accuracy of commonly used agitation scales (BEHAVE-AD, NPI and CMAI). Conclusions The agitation domain of the Spanish NPI, the NBRS, and the PAS demonstrated high sensitivities, and may be reasonable for clinical implementation. However, a limitation to this finding is that despite an extensive search, few studies with diagnostic accuracy measurements were identified. Ultimately, more research is needed to understand the diagnostic accuracy of agitation and/or aggression detection tools among PLWD.
Embargo
Developing a Novel Care Pathway for Symptoms of Agitation or Aggression in Persons Living with Dementia in Long-Term Care: A Multi-Methods Implementation Research Study
(2023-06) Wong, Britney; Goodarzi, Zahra; Holroyd-Leduc, Jayna; Ismail, Zahinoor; Watt, Jennifer
Background: Agitation and/or aggression are common among persons living with dementia (PLWD) in LTC, and together pose a significant burden to residents and their caregivers. Current treatment practices for agitation and/or aggression are highly variable among PLWD in LTC. There is a need to develop a more effective approach to treatment and to explore the barriers and facilitators to providing care for agitation and/or aggression among PLWD in LTC. Objectives: The first objective was to develop an evidence-informed clinical care pathway co-designed with stakeholders, to improve care for agitation and/or aggression among PLWD in LTC. The second objective was to identify barriers and facilitators to agitation and/or aggression care across the spectrum of care. Methods: Objective 1 used a modified Delphi panel to develop the clinical care pathway. Objective 2 used semi-structured interviews with key stakeholders to identify the barriers and facilitators to care. Framework Analysis was used to map identified barriers and facilitators to key behavioral domains of the Theoretical Domains Framework. Results: Crucial pathway features included using an interdisciplinary care team approach across the spectrum of care and featuring a broad range of non-pharmacological interventions. Several statements in our pathway did not reach agreement and require a third round of the Delphi. Perceived barriers for agitation and/or aggression care included a lack of validated tools to detect agitation and/or aggression, inconsistent training practices, and a limited number of available non-pharmacological interventions. Key facilitators were using an interdisciplinary care team and having trained healthcare providers to administer non-pharmacological interventions. Conclusions: Our study advances the state of evidence for agitation and/or aggression care among PLWD in LTC. Our efforts will inform future implementation research strategies working to improve the delivery and management of care. With more effective care approaches, the quality of life of PLWD in LTC will also improve.
Embargo
Difficulty in Transitioning from Medical Residency to Independent Practice in Pathology
(2024-04-26) Ayala, Gabriel Eduardo; Naugler, Christopher; Sidhu, Davinder; Ismail, Zahinoor
Transitioning from residency to medical independent medical practice may be a difficult experience for physicians. In this thesis, I explore this issue amongst Canadian Pathologists through an online survey of 118 practicing pathologists and 11 follow-up in-depth one-on-one interviews. Survey results revealed that only 40% of participants reported that they did not experience difficulty transitioning to independent practice. I used a mixed methods approach to determine themes associated with difficulty transitioning. I then developed a psychological traits profile for pathologists based on the Big 5 psychological traits and looked for differences in psychological profiles between individuals who reported difficulty and those who did not. Only minor differences were observed. The biggest predictor of difficulty transitioning was the Royal College specialty with Anatomic Pathologists experiencing significantly more difficulty than General Pathologists. This difference may relate to increased opportunity for graded responsibility in General Pathology residency training programs. Finally, I explored the way pathology residents perceive different forms of feedback and offered recommendations to residency training programs on ways that feedback could be optimized to best support the transition to independent practice.
Open Access
Effects of adjunctive brexpiprazole on calmness and life engagement in major depressive disorder: post hoc analysis of patient-reported outcomes from clinical trial exit interviews
(2021-12-11) Weiss, Catherine; Meehan, Stine R.; Brown, T. M.; Gupta, Catherine; Mørup, Michael F.; Thase, Michael E.; McIntyre, Roger S.; Ismail, Zahinoor
Abstract Background Though often overlooked, calming patients and increasing their life engagement are key factors in the treatment of major depressive disorder (MDD). This study aimed to test the hypothesis that adjunctive brexpiprazole increases calmness and life engagement among patients with MDD, based on clinical trial exit interviews. Methods This was a pooled analysis of exit interview data from three exploratory, open-label studies of adjunctive brexpiprazole 1–3 mg/day. The studies enrolled 105 outpatients with MDD (DSM-IV-TR criteria), a current depressive episode, and inadequate response to antidepressant treatment during the current episode. Patients were interviewed if they completed the end-of-treatment visit (Week 6 or Week 12, depending on the study). Exit interviews took the form of semi-structured telephone interviews in which patients were asked mostly qualitative questions about their symptoms prior to the start of the study, and about improvements they had noted during treatment. Interview transcripts were reviewed and codes were assigned to calmness and life engagement vocabulary, allowing aggregation of the frequency of improvement in various domains. Results 79.8% (83/104) of patients described improvements consistent with at least one calmness term, most commonly feeling less anxious (46.2%) or less irritable (44.2%). A four-domain concept of patient life engagement was developed in which 88.6% (93/105) of patients described improvements consistent with at least one domain, specifically, emotional (77.1%), physical (75.2%), social (41.9%), and/or cognitive (36.2%). Of the patients who described improvement in calmness, 96.4% (80/83) also described improvement in life engagement. Conclusions Analysis of exit interview data suggests that patients were calmer and more engaged with life following treatment with adjunctive brexpiprazole. Thus, adjunctive brexpiprazole may provide a benefit on subjective patient outcomes in addition to the improvement in depressive symptoms shown by clinical rating scale data. Trial Registration: Data used in this post hoc analysis came from ClinicalTrials.gov identifiers: NCT02012218, NCT02013531, NCT02013609.
Open Access
Explainable prediction of Parkinson’s disease in a large multimodal database
(2023-09-08) Camacho Camacho, Milton Ivan; Forkert, Nils Daniel; Monchi, Oury; Ismail, Zahinoor; LeVan, Pierre
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting millions of people all over the world. Accurate diagnosis is important to enable prompt interventions that can improve disease prognosis. However, the heterogeneity of PD renders an accurate diagnosis challenging, especially early in the disease phase when symptoms are known to be subtle. Thus, it is imperative to obtain reliable, non-invasive, in-vivo biomarkers for PD diagnosis. Within this context, the overarching aim of this work is to develop accurate explainable deep learning models trained from a large multimodal magnetic resonance imaging (MRI) database to classify PD and healthy controls and capable of identifying structural changes associated with PD. Therefore, the objectives of this thesis are: (1) to investigate the use of T1-weighted brain MRI as a biomarker of macro-structural changes associated with PD; (2) to investigate a combination of T1-weighted and diffusion tensor MRI as a fusion of micro- and macro-structural brain morphology and its relationship with PD. To achieve these objectives, one of the largest multi-center imaging databases of over 2,000 PD and control subjects was pooled and preprocessed as the first step. Second, an explainable deep learning model was developed to accurately classify PD patients while revealing important brain regions. Third, a multimodal explainable deep learning model was trained enabling a more in-depth understanding of the interplay between the micro- and macro-structural properties of specific brain regions and the disease. The results of this work offer an important insight into structural brain changes as non-invasive, in-vivo biomarkers of PD through an in-depth analysis of associated brain regions using large multicenter data. Deep learning models are proposed to provide generalizable and robust PD classification resulting in a 0.87 and 0.89 area under the receiver operating characteristic curve for the best unimodal and multimodal approaches, respectively. Lastly, explainability methods identified brain regions in line with current knowledge of the disease providing further evidence for the clinical utility of the developed methods. This work presents relevant findings and novel methodologies that could aid improving PD diagnosis and the acceptance of computer-aided diagnosis systems targeting PD.
Open Access
Facilitators and barriers to deprescribing antipsychotic medications in critically ill adult patients at transitions of care
(2022-07-09) Jaworska, Natalia; Fiest, Kirsten; Niven, Daniel; Ismail, Zahinoor
Antipsychotic medications are prescribed to critically ill adult patients in the intensive care unit (ICU) for clinical indications including delirium, agitation, and sleep disturbances. While there is some evidence for their use in managing agitation, antipsychotic medications have not convincingly shown efficacy for the management of delirium or sleep and are often continued at transitions of care in critically ill patients when they may no longer be necessary or appropriate. The current literature on antipsychotic minimization and deprescribing in critically ill patients is sparse lacking evaluation of underlying facilitators and barriers informing current antipsychotic prescribing practices that may be important in the development of effective minimization and deprescribing strategies. The studies presented in this thesis address knowledge gaps regarding antipsychotic prescribing and deprescribing practices among inpatient healthcare professionals who care for patients with and following critical illness. Based on a qualitative study with semi-structured interviews of 21 healthcare professionals, seven relevant domains from the Theoretical Domains Framework (TDF) contributing to antipsychotic prescribing and deprescribing were identified. A subsequent scoping review of the literature identified differences between healthcare professional perceived and actual prescribing practices, with few in-hospital deprescribing strategies available to guide practice. Thereafter, a nationwide modified Delphi consensus process informed by the qualitative study and scoping review identified consensus statements for antipsychotic minimization activities and antipsychotic deprescribing strategies for patients with and following critical illness. The results of these studies characterize and catalogue relevant priority facilitators and barriers to antipsychotic minimization and deprescribing in critically ill adult patients during their hospitalization to support best clinical prescribing practices.
Open Access
Incidence and Risk Factors for Hyponatremia in Patients Newly Prescribed Citalopram
(2019-04-26) Shysh, Andrea Christine; Naugler, Christopher T.; Sidhu, Davinder; Ismail, Zahinoor
Hyponatremia is a common and under-recognized adverse drug reaction of citalopram. This study aims to determine the incidence of hyponatremia and to identify risk factors in a large, population-based cohort initiating new prescriptions for citalopram. Following approval from the ethics review board, data were obtained from Alberta Information Network databases to identify patients with new citalopram prescriptions from 2010-2017, inclusive. Hyponatremia was defined as serum sodium level <135 mmol/L. Associations were determined by performing Cox regression with time-varying covariate analysis, with the development of hyponatremia as the dependent variable. This is the first large-scale, population-based study to explore risk factors, based solely on laboratory serum data, for the development of hyponatremia in patients initiating citalopram therapy. We report a 16.7% incidence of hyponatremia after starting citalopram treatment and significant risk factors include lower baseline sodium, concurrent thiazide diuretic use, older age, and male sex.
Open Access
Mild behavioral impairment in early Alzheimer’s disease and its association with APOE and BDNF risk genetic polymorphisms
(2024-01-26) Matuskova, Veronika; Veverova, Katerina; Jester, Dylan J.; Matoska, Vaclav; Ismail, Zahinoor; Sheardova, Katerina; Horakova, Hana; Cerman, Jiri; Laczó, Jan; Andel, Ross; Hort, Jakub; Vyhnalek, Martin
Abstract Background Mild behavioral impairment (MBI) has been commonly reported in early Alzheimer’s disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity. Methods We included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations. Results MBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared. Conclusions MBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation.
Open Access
Mild behavioral impairment is related to frailty in non-dementia older adults: a cross-sectional study
(2020-11-27) Fan, Shaoyi; Liang, Ximin; Yun, Tianchan; Pei, Zhong; Hu, Bin; Ismail, Zahinoor; Yang, Zhimin; Xu, Fuping
Abstract Background Frailty and cognitive decline are highly prevalent among older adults. However, the relationship between frailty and mild behavioral impairment (MBI), a dementia risk syndrome characterized by later-life emergence of persistent neuropsychiatric symptoms, has yet to be elucidated. We aimed to evaluate the associations between MBI and frailty in older adults without dementia. Methods In this cross-sectional study, a consecutive series of 137 older adults without dementia in the Anti-Aging Study, recruited from primary care clinics, were enrolled. Frailty was estimated using the Fried phenotype. MBI was evaluated by the Mild Behavioral Impairment Checklist (MBI-C) at a cut-off point of > 8. Cognition was assessed with the Chinese versions of the Montreal Cognitive Assessment (MoCA-BC) and Mini-mental State Examination (MMSE). Multivariable logistic regression was performed to estimate the relationship between MBI and objective cognition with frailty status. Results At baseline, 30.7% of the older adults had frailty and 18.2% had MBI (MBI+ status). Multivariable logistic regression analysis demonstrated that compared to those without MBI (MBI- status), MBI+ was more likely to have frailty (odds ratio [OR] = 7.44, 95% CI = 1.49–37.21, p = 0.02). Frailty and MBI were both significantly associated with both MMSE and MoCA-BC score (p < 0.05). Conclusions Both frailty and MBI status were associated with higher odds of cognitive impairment. MBI was significantly associated with an increased risk of having frailty in the absence of dementia. This association merits further study to identify potential strategies for the early detection, prevention and therapeutic intervention of frailty.
Open Access
Mild behavioral impairment: measurement and clinical correlates of a novel marker of preclinical Alzheimer’s disease
(2022-01-05) Creese, Byron; Ismail, Zahinoor
Abstract Background Late-life onset neuropsychiatric symptoms are established risk factors for dementia. The mild behavioral impairment (MBI) diagnostic framework was designed to standardize assessment to determine dementia risk better. In this Mini Review, we summarize the emerging clinical and biomarker evidence, which suggests that for some, MBI is a marker of preclinical Alzheimer’s disease. Main MBI is generally more common in those with greater cognitive impairment. In community and clinical samples, frequency is around 10–15%. Mounting evidence in cognitively normal samples links MBI symptoms with known AD biomarkers for amyloid, tau, and neurodegeneration, as well as AD risk genes. Clinical studies have found detectable differences in cognition associated with MBI in cognitively unimpaired people. Conclusion The emerging evidence from biomarker and clinical studies suggests MBI can be an early manifestation of underlying neurodegenerative disease. Future research must now further validate MBI to improve identification of those at the very earliest stages of disease.
Open Access
Neuroimaging Biomarkers for Youth At-Risk for Serious Mental Illness
(2020-08) Nogovitsyn, Nikita; MacQueen, Glenda M.; Addington, Jean M.; Ismail, Zahinoor; Protzner, Andrea; Taylor, Valerie H.
Background: Serious mental illness (SMI) is a constellation of psychiatric illnesses, commonly referring to major depressive disorder (MDD), bipolar disorder(s) (BD), and schizophrenia (SCZ). The diagnosis of SMI relies on a descriptive collection of behaviors with no objective measurements. Young individuals with early signs of developing mental illness are often misdiagnosed or diagnosed at later stages of illness when the opportunity for effective early intervention has passed. Therefore, there is a need for biomarkers that can identify youth at risk for SMI and stratify individuals into clinical stages so that appropriate interventions can be offered. Objective: The overreaching goal of my research is to enhance our understanding of the neurobiological changes underlying the early brain pathophysiology of (SMI). The ultimate aim of this dissertation is to identify neurobiological biomarkers for SMI that will have diagnostic or informative value in the classification of risk stages. Methods: By making use of data generated from two large Canadian studies, the Canadian Psychiatric Risk and Outcome Study (PROCAN), and the Canadian Biomarker Integration Network in Depression (CAN-BIND), I investigate specific structural and functional brain changes accompanying various stages risk and evolution of SMI. Results: This manuscript-based thesis presents structural and functional neuroimaging findings that parallel clinical presentation in youth-at-risk and adults with an existing mood disorder. Subtle structural changes within the hippocampus, amygdala, and thalamus were found in symptomatic at-risk youth with either attenuated or distress syndromes. Volume deficits within the body of the hippocampus were detected even in asymptomatic youth at risk due to the family history of an SMI. Moreover, in at-risk youth with a history of childhood abuse, structural deficits within the basal nuclei of the amygdala mediated the severity of depressive and anxiety symptoms at present. In adult patients diagnosed with MDD, specific patterns of hippocampal disproportions were not only indicative of depression status but also informed about the rate and the likelihood of successful antidepressant treatment. While deviations in subcortical limbic structures supported the transdiagnostic clinical staging model, functional connectivity changes within cerebello-limbic pathways were nearly exclusively indicative of high clinical risk for psychosis. Conclusions: Distributed limbic brain changes can precede the clinical onset of the mental illness, possibly, reflecting the cumulative impact of pernicious effects of stress. Together, these results can be offered in support of a transdiagnostic clinical staging for youth at risk of SMI.
Open Access
Neuroimaging Correlates of Gait Control in Cerebral Amyloid Angiopathy
(2023-01-16) Sharma, Breni; Smith, Eric E.; Harris, Ashley; Ismail, Zahinoor; McCreary, Cheryl R.
Cerebral amyloid angiopathy (CAA) is the second most common subtype of cerebral small vessel disease (CSVD) and is characterized by the buildup of beta-amyloid protein in the walls of small-medium sized arteries and arterioles of the leptomeninges. Much is known about common clinical manifestations of the disease, such as presence of white matter hyperintensities, lacunar infarcts, cerebral microbleeds, cortical superficial siderosis, and phenotypic presentations, such as the cognitive profile of CAA and its contribution to neurodegeneration and dementia. However, little had been known about the gait profile of CAA or the neural correlates underlying any abnormalities observed, such as grey matter atrophy, white matter damage, or brain iron accumulation. To address these gaps in the literature, I first conducted a systematic review and meta-analysis of the existing literature covering CSVD and its relation to gait and falls. Once evident that gait difficulties were a feature of CSVD as a whole, I examined gait abilities of patients with CAA, when compared to normal controls (NC), patients with Alzheimer’s disease (AD), and mild cognitive impairment (MCI). With this, I also looked at associations with falls history and fear of falling, as well as the relationships between gait ability and cognition, WMH volume, and CMB count. Significant gait impairments were found in CAA, prompting an examination of associations between these impairments and grey and white matter damage and iron content in select brain regions. In CSVD, there was a general consensus across studies of an association between greater CSVD burden and worse gait and greater falls. Looking specifically at CAA, significant impairments were found in gait compared to NC but not to AD. Further investigation of this lead to associations between worse gait and grey matter atrophy in frontal, AD-affected, and subcortical regions and with greater white matter structural damage. Iron content, however, did not differ between CAA and NC. Overall, gait appears to be negatively impacted by CAA pathology. Further examination of neural correlates may help to better understand the disease and incorporation of the current findings may help to inform clinicians on the functional outcomes of CAA patients.
Open Access
Neuropsychiatric Symptoms and Incident Cognitive Decline and Dementia in Cognitively Normal Older Adults: A Systematic Review and Meta-Analysis
(2022-06) Elbayoumi, Heba; Ismail, Zahinoor; Patten, Scott; Goodarzi, Zahra; Bulloch, Andrew; Pringsheim, Tamara Milka
Objective: To determine risks of cognitive decline or dementia in cognitively normal cohorts with neuropsychiatric symptoms (NPS), stratified by mild behavioral impairment (MBI) domains. Methods: A systematic search (MEDLINE, EMBASE, and PSYCINFO) was completed up to January 2022. Pooled hazard ratios (HR) with Standard Error (SE), I2, and tau2 were determined utilizing DerSimonian-Laird random-effects models. Heterogeneity and publication bias were investigated. PRISMA and MOOSE checklists were followed. Results: Of 12,674 screened abstracts, 36 prospective studies representing 326,739 participants were included. Risks (HR) for incident cognitive decline or dementia by MBI domain were: 1) apathy 2.00 (95%CI:1.57-2.57); 2) affect 1.61 (95%CI:1.45-1.80; adjusted 1.44, 95%CI:1.30-1.61); 3) agitation 3.07 (95%CI: 2.15-4.38); 4) social inappropriateness 3.84 (95%CI:1.54-9.55); and 5) psychosis 3.99 (95%CI:3.05-5.23). Heterogeneity was most evident in affect (I2=86.56%, tau2=0.04), with time and NPS ascertainment as the main contributors. Conclusion: Cognitively normal older adults with NPS are at greater risk for mild cognitive impairment and dementia than those without NPS. Risks differ between the 5 MBI domains.