Publications by authors named "Zahinoor Ismail"

143 Publications

Neural Correlates of Mild Behavioral Impairment: A Functional Brain Connectivity Study Using Resting-State Functional Magnetic Resonance Imaging.

J Alzheimers Dis 2021 ;83(3):1221-1231

Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.

Background: Mild behavioral impairment (MBI) is associated with accelerated cognitive decline and greater risk of dementia. However, the neural correlates of MBI have not been completely elucidated.

Objective: The study aimed to investigate the correlation between cognitively normal participants and participants with amnestic mild cognitive impairment (aMCI) using resting-state functional magnetic resonance imaging.

Methods: The study included 30 cognitively normal participants and 13 participants with aMCI (20 men and 23 women; mean age, 76.9 years). The MBI was assessed using the MBI checklist (MBI-C). Region of interest (ROI)-to-ROI analysis was performed to examine the correlation between MBI-C scores and functional connectivity (FC) of the default mode network, salience network, and frontoparietal control network (FPCN). Age, Mini-Mental State Examination score, sex, and education were used as covariates. A p-value of 0.05, with false discovery rate correction, was considered significant.

Results: A negative correlation was observed between the MBI-C total score and FC of the left posterior parietal cortex with the right middle frontal gyrus. A similar result was obtained for the MBI-C affective dysregulation domain score.

Conclusion: FPCN dysfunction was detected as a neural correlate of MBI, especially in the affective dysregulation domain. This dysfunction may be associated with cognitive impairment in MBI and conversion of MBI to dementia; however, further longitudinal data are needed to examine this relationship.
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http://dx.doi.org/10.3233/JAD-210628DOI Listing
January 2021

Non-pharmacologic interventions to treat apathy in Parkinson's disease: A realist review.

Clin Park Relat Disord 2021 25;4:100096. Epub 2021 May 25.

Department of Community Health Sciences, University of Calgary, 3D10, 3280 Hospital Drive NW, Calgary, Alberta T2N 4Z6, Canada.

Introduction: There is a diverse body of evidence investigating non-pharmacological treatment options for apathy in Parkinson's disease (PD). We aimed to better understand the context and mechanisms by which non-pharmacological interventions may improve apathy in persons with PD.

Methods: We conducted a realist review of the body of evidence investigating treatment options for apathy in PD. Study authors used findings from a preceding scoping review to identify initial program theory. We then update the scoping review, which was originally conducted in 2017. Two authors independently reviewed and extracted data from studies that discussed non-pharmacological treatment options for apathy in PD. Any data concerning context, mechanisms, and outcomes of interventions for apathy in PD were extracted, synthesized, and analyzed.

Results: Our review included nine studies. We categorized studies into two categories, exercise and mindfulness. There were seven exercise interventions included. Exercise interventions evaluated group exercise compared to individual exercise, aerobic exercise, dance, Nordic walking, and an equine program. There were two mindfulness interventions.

Conclusion: Exercise interventions work best for persons with PD and apathy who are not significantly physically or cognitively impaired, and who have access to transportation, adapted programs, and specialized coaches. Exercise may improve apathy through goal-directed behaviour change and engagement in social interactions. Mindfulness interventions work best for persons with PD and apathy who are not significantly cognitively impaired, have caregiver support, and may improve apathy by targeting the emotional, cognitive, and goal-directed domains that define apathy.
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http://dx.doi.org/10.1016/j.prdoa.2021.100096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299975PMC
May 2021

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Am J Geriatr Psychiatry 2021 Jul 1. Epub 2021 Jul 1.

Division of Geriatric Psychiatry, First Department of Psychiatry, National and Kapodistrian University of Athens, Athens, Greece.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.
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http://dx.doi.org/10.1016/j.jagp.2021.06.016DOI Listing
July 2021

Agitation in Alzheimer's disease: Novel outcome measures reflecting the International Psychogeriatric Association (IPA) agitation criteria.

Alzheimers Dement 2021 Jun 16. Epub 2021 Jun 16.

Gerontopole Alzheimer Clinical and Research Center, University Hospital of Toulouse (CHU Toulouse), URM 1295, CERPOP, Inserm, UPS, Université de Toulouse, Toulouse, France.

Introduction: The 2017 European Union-North American Clinical Trials in Alzheimer's Disease Task Force recommended development of clinician-rated primary outcome measures for Alzheimer's disease (AD) agitation trials, incorporating International Psychogeriatric Association (IPA) criteria.

Methods: In a modified Delphi process, Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory-Clinician (NPI-C) items were mapped to IPA agitation domains generating novel instruments, CMAI-IPA and NPI-C-IPA. Validation in the Agitation and Aggression AD Cohort (A3C) assessed minimal clinically important differences (MCIDs), change sensitivity, and predictive validity.

Results: MCID was -17 (odds ratio [OR] = 14.9, 95% confidence interval [CI] = 6.8-32.6) for CMAI; -5 (OR = 9.3, 95% CI = 4.0-21.2) for CMAI-IPA; -3 (OR = 11.9, 95% CI = 4.1-34.8) for NPI-C-A+A; and -5 (OR = 7.8, 95% CI = 3.4-17.9) for NPI-C-IPA at 3 months. Areas under the curve suggested no scale better predicted global clinician ratings. Sensitivity to change for all measures was high.

Conclusion: Internal consistency and reliability analyses demonstrated better accuracy for the NPI-C-IPA than for the CMAI-IPA and can be used for agitation clinical trial inclusion, and for response to intervention.
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http://dx.doi.org/10.1002/alz.12335DOI Listing
June 2021

D-cycloserine normalizes long-term motor plasticity after transcranial magnetic intermittent theta-burst stimulation in major depressive disorder.

Clin Neurophysiol 2021 08 21;132(8):1770-1776. Epub 2021 Apr 21.

Department of Psychiatry, University of Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Mathison Centre for Mental Health Research and Education, Calgary, Alberta, Canada. Electronic address:

Objectives: Major Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD.

Methods: We conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day.

Results: Acute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC.

Conclusion: MDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism.

Significance: Agonism of NMDA receptors rescues iTBS motor plasticity in MDD.
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http://dx.doi.org/10.1016/j.clinph.2021.04.002DOI Listing
August 2021

Mild Behavioral Impairment Is Associated With Atrophy of Entorhinal Cortex and Hippocampus in a Memory Clinic Cohort.

Front Aging Neurosci 2021 24;13:643271. Epub 2021 May 24.

Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.

Objectives: Mild behavioral impairment (MBI) is a syndrome describing late-onset persistent neuropsychiatric symptoms (NPS) in non-demented older adults. Few studies to date have investigated the associations of MBI with structural brain changes. Our aim was to explore structural correlates of NPS in a non-demented memory clinic sample using the Mild Behavioral Impairment Checklist (MBI-C) that has been developed to measure MBI.

Methods: One hundred sixteen non-demented older adults from the Czech Brain Aging Study with subjective cognitive concerns were classified as subjective cognitive decline ( = 37) or mild cognitive impairment ( = 79). Participants underwent neurological and neuropsychological examinations and brain magnetic resonance imaging (MRI) (1.5 T). The Czech version of the MBI-C was administered to participants' informants. Five selected brain regions were measured, namely, thicknesses of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and entorhinal cortex (ERC) and volume of the hippocampus (HV), and correlated with MBI-C total and domain scores.

Results: Entorhinal cortex was associated with MBI-C total score ( = -0.368, < 0.001) and with impulse dyscontrol score ( = -0.284, = 0.002). HV was associated with decreased motivation ( = -0.248, = 0.008) and impulse dyscontrol score ( = -0.240, = 0.011).

Conclusion: Neuropsychiatric symptoms, particularly in the MBI impulse dyscontrol and motivation domains, are associated with medial temporal lobe atrophy in a clinical cohort of non-demented older adults. This study supports earlier involvement of temporal rather than frontal regions in NPS manifestation. Since these regions are typically affected early in the course of Alzheimer's disease (AD), the MBI-C may potentially help further identify individuals at-risk of developing AD dementia.
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http://dx.doi.org/10.3389/fnagi.2021.643271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180573PMC
May 2021

Plasma β-Amyloid in Mild Behavioural Impairment - Neuropsychiatric Symptoms on the Alzheimer's Continuum.

J Geriatr Psychiatry Neurol 2021 May 26:8919887211016068. Epub 2021 May 26.

Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Introduction: Simple markers are required to recognize older adults at higher risk for neurodegenerative disease. Mild behavioural impairment (MBI) and plasma β-amyloid (Aβ) have been independently implicated in the development of incident cognitive decline and dementia. Here we studied the associations between MBI and plasma Aβ/Aβ.

Methods: Participants with normal cognition (n = 86) or mild cognitive impairment (n = 53) were selected from the Alzheimer's Disease Neuroimaging Initiative. MBI scores were derived from Neuropsychiatric Inventory items. Plasma Aβ/Aβ ratios were assayed using mass spectrometry. Linear regressions were fitted to assess the association between MBI total score as well as MBI domain scores with plasma Aβ/Aβ.

Results: Lower plasma Aβ/Aβ was associated with higher MBI total score ( = 0.04) and greater affective dysregulation ( 0.04), but not with impaired drive/motivation ( 0.095) or impulse dyscontrol ( 0.29) MBI domains.

Conclusion: In persons with normal cognition or mild cognitive impairment, MBI was associated with low plasma Aβ/Aβ. Incorporating MBI into case detection may help capture preclinical and prodromal Alzheimer's disease.
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http://dx.doi.org/10.1177/08919887211016068DOI Listing
May 2021

The Association Between Diabetes Mellitus and Mild Behavioral Impairment Among Mild Cognitive Impairment: Findings from Singapore.

J Alzheimers Dis 2021 ;82(1):411-420

Department of Neurology, National Neuroscience Institute, Singapore, Singapore.

Background: Mild behavioral impairment (MBI) describes persistent behavioral changes in later life as an at-risk state for dementia. While cardiovascular risk factors (CVRFs) are linked to dementia, it is uncertain how CVRFs are associated with MBI.

Objective: To determine the prevalence of MBI and its association with CVRFs among cognitively normal (CN) and mild cognitive impairment (MCI) individuals in Singapore.

Methods: 172 individuals (79 CN and 93 MCI) completed the MBI-checklist (MBI-C). The prevalence of MBI and MBI-C sub-domain characteristics among CN and MCI were examined. Regression models evaluated the relationships between MBI-C sub-domain scores with CVRFs.

Results: The prevalence of MBI and mean MBI-C total score were significantly higher among MCI than CN (34.4%versus 20.3%, p = 0.022 and 7.01 versus 4.12, p = 0.04). The highest and lowest-rated sub-domains among CN and MCI were impulse dyscontrol and abnormal thoughts and perception respectively. Within the MCI cohort, a higher proportion of individuals with diabetes mellitus (DM) had MBI compared to individuals without DM (28.1%versus 10.4%, p = 0.025). The interaction of DM and MCI cohort resulted in significantly higher mean MBI-C total, decreased motivation, emotional dysregulation, impulse dyscontrol, and abnormal thoughts and perception sub-domain scores.

Conclusion: The prevalence of MBI is higher among a Singapore cohort compared to Caucasian cohorts. The associations of DM with both the presence and severity of MBI among MCI suggest that DM may be a risk factor for MBI. The optimization of DM may be a potential therapeutic approach to improve clinical outcomes among MCI with MBI.
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http://dx.doi.org/10.3233/JAD-210037DOI Listing
September 2021

Factors Associated with Hyponatremia in Patients Newly Prescribed Citalopram: A Retrospective Observational Study.

Drugs Real World Outcomes 2021 May 23. Epub 2021 May 23.

Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada.

Background: Hyponatremia is a common and under-recognized adverse drug reaction of selective serotonin re-uptake inhibitor (SSRI) antidepressants. Despite its clinical importance, there are few large-scale studies on the factors associated with hyponatremia.

Objective: The aim of this study was to determine the incidence of hyponatremia and to identify patient factors associated with hyponatremia in a large, population-based cohort initiating new prescriptions for citalopram.

Methods: We included all patients with a new prescription for citalopram during 2010-2017, inclusive, with baseline and post-initiation serum sodium values available. Data were obtained from an Alberta Health Pharmacy database to identify new citalopram prescriptions. Laboratory values for patients with new prescriptions were obtained from linked Calgary Laboratory Services data. Incident hyponatremia was defined as serum sodium level < 135 mmol/L, following prescription initiation. Associations were determined by performing Cox regression with time-varying covariate analysis, with the development of hyponatremia as the dependent variable.

Results: A total of 19,679 patients with new prescriptions were identified; 12,842 females and 6837 males. The mean age was 55.48 years (SD 21.35). Of these patients, 3250 (16.5%) developed hyponatremia, 1996 (15.5% of) females and 1254 (18.3% of) males (p = 0.002). Cox regression showed significant associations of hyponatremia with lower baseline sodium (HR 0.788), older age (HR 1.029), thiazide diuretic use (HR 1.141), and male sex (HR 1.168). Pharmaceutical manufacturer or strength of citalopram did not have significant effects on the development of hyponatremia.

Conclusion: This study provides additional data on the predictors of hyponatremia among patients initiating citalopram therapy. We report a 16.5% incidence of hyponatremia after starting citalopram treatment, and significant new findings include a higher incidence in males. This is the first published incidence of hyponatremia following the initiation of citalopram treatment across all ages in Canada.
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http://dx.doi.org/10.1007/s40801-021-00257-4DOI Listing
May 2021

Cortical Thickness and Its Association with Clinical Cognitive and Neuroimaging Markers in Cerebral Amyloid Angiopathy.

J Alzheimers Dis 2021 ;81(4):1663-1671

Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Background: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood.

Objective: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA.

Methods: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region.

Results: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) -0.047 mm, 95% confidence interval (CI) -0.088, -0.005, p = 0.03), and lower in AD compared to CAA (MD -0.104 mm, 95% CI -0.165, -0.043, p = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD -0.07 mm, 95% CI -0.13 to -0.01, p = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2 = 0.10; p = 0.05) and higher white matter hyperintensity volume (R2 = 0.09, p = 0.04).

Conclusion: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.
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http://dx.doi.org/10.3233/JAD-210138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293635PMC
September 2021

Diagnostic criteria for apathy in neurocognitive disorders.

Alzheimers Dement 2021 May 5. Epub 2021 May 5.

Sunnybrook Research Institute, Toronto, Ontario, Canada.

Introduction: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed.

Methods: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019.

Results: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies.

Discussion: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.
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http://dx.doi.org/10.1002/alz.12358DOI Listing
May 2021

Reliability and Validity of the Chinese Version of Mild Behavioral Impairment Checklist in Mild Cognitive Impairment and Mild Alzheimer's Disease.

J Alzheimers Dis 2021 ;81(3):1141-1149

Dementia Care & Research Center, Beijing Dementia Key Lab, Peking University Institute of Mental Health (Sixth Hospital), Beijing, China.

Background: Mild behavioral impairment (MBI) has been proposed as an early manifestation of dementia. The Mild Behavioral Impairment Checklist (MBI-C) may help identify MBI in prodromal and preclinical dementia.

Objective: The study aimed to evaluate the reliability and validity of the Chinese version of MBI-C in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD), and to explore the structure of the five factors of the MBI-C in Chinese culture.

Methods: Sixty dyads of MCI and mild AD (MCI, n = 33; mild AD, n = 35) were recruited. The informants completed the MBI-C and Neuropsychiatric Inventory Questionnaire (NPI-Q) and were interviewed for clinician rating of the NPI. The Cronbach's coefficient was used to measure the structural reliability of the MBI-C. The criterion-validity was evaluated with the correlation coefficient between the MBI-C and the total scores of NPI-Q and NPI. Exploratory factor analysis was conducted to investigate the structure of the MBI-C.

Results: The Cronbach's α coefficient was 0.895. The MBI-C total score was positively correlated with all five domains (r = 0.577∼0.840). The total score of MBI-C was significantly correlated with the total scores of NPI-Q (r = 0.714) and NPI (r = 0.749). Similarly, the five domain scores of MBI-C were significantly correlated with the factor and total scores of NPI-Q (r = 0.312∼0.673) and NPI (r = 0.389∼0.673). The components of each factor in Chinese version of MBI-C were slightly different from those of the a priori defined domains (χ2 = 1818.202, df = 496, p < 0.001).

Conclusion: The Chinese version of MBI-C has good reliability and validity, and can be used to evaluate the psychological and behavioral changes in MCI and mild AD.
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http://dx.doi.org/10.3233/JAD-210098DOI Listing
September 2021

Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer's disease and cognitively unimpaired individuals.

Transl Neurodegener 2021 03 31;10(1):11. Epub 2021 Mar 31.

The McGill University Research Centre for Studies in Aging, Montreal, Canada.

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.
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http://dx.doi.org/10.1186/s40035-021-00236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011383PMC
March 2021

Neural correlates of the impulse dyscontrol domain of mild behavioral impairment.

Int J Geriatr Psychiatry 2021 09 9;36(9):1398-1406. Epub 2021 Apr 9.

Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Objectives: Agitation and aggression are common in dementia and pre-dementia. The dementia risk syndrome mild behavioral impairment (MBI) includes these symptoms in the impulse dyscontrol domain. However, the neural circuitry associated with impulse dyscontrol in neurodegenerative disease is not well understood. The objective of this work was to investigate if regional micro- and macro-structural brain properties were associated with impulse dyscontrol symptoms in older adults with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD).

Methods: Clinical, neuropsychiatric, and T1-weighted and diffusion-tensor magnetic resonance imaging (DTI) data from 80 individuals with and 123 individuals without impulse dyscontrol were obtained from the AD Neuroimaging Initiative. Linear mixed effect models were used to assess if impulse dyscontrol was related to regional DTI and volumetric parameters.

Results: Impulse dyscontrol was present in 17% of participants with NC, 43% with MCI, and 66% with AD. Impulse dyscontrol was associated with: (1) lower fractional anisotropy (FA), and greater mean, axial, and radial diffusivity in the fornix; (2) lesser FA and greater radial diffusivity in the superior fronto-occipital fasciculus; (3) greater axial diffusivity in the cingulum; (4) greater axial and radial diffusivity in the uncinate fasciculus; (5) gray matter atrophy, specifically, lower cortical thickness in the parahippocampal gyrus.

Conclusion: Our findings provide evidence that well-established atrophy patterns of AD are prominent in the presence of impulse dyscontrol, even when disease status is controlled for, and possibly in advance of dementia. Our findings support the growing evidence for impulse dyscontrol symptoms as an early manifestation of AD.
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http://dx.doi.org/10.1002/gps.5540DOI Listing
September 2021

Genetic risk for Alzheimer's disease, cognition, and mild behavioral impairment in healthy older adults.

Alzheimers Dement (Amst) 2021 17;13(1):e12164. Epub 2021 Mar 17.

Medical School College of Medicine and Health University of Exeter Exeter UK.

Background: The neuropsychiatric syndrome mild behavioral impairment (MBI) describes an at-risk state for dementia and may be a useful screening tool for sample enrichment. We hypothesized that stratifying a cognitively normal sample on MBI status would enhance the association between genetic risk for Alzheimer's disease (AD) and cognition.

Methods: Data from 4458 participants over age 50 without dementia was analyzed. A cognitive composite score was constructed and the MBI Checklist was used to stratify those with MBI and those without. Polygenic scores for AD were generated using summary statistics from the IGAP study.

Results: AD genetic risk was associated with worse cognition in the MBI group but not in the no MBI group (MBI: β = -0.09, 95% confidence interval: -0.13 to -0.03,  = 0.002, = 0.003). The strongest association was in those with more severe MBI aged ≥65.

Conclusions: MBI is an important feature of aging; screening on MBI may be a useful sample enrichment strategy for clinical research.
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http://dx.doi.org/10.1002/dad2.12164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968121PMC
March 2021

Patterns of brain activity during a set-shifting task linked to mild behavioral impairment in Parkinson's disease.

Neuroimage Clin 2021 13;30:102590. Epub 2021 Feb 13.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, Calgary, Alberta, Canada; Department of Radiology, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for incident cognitive decline and dementia. Prior studies have reported that neuropsychiatric symptoms are associated with cognitive abilities in Parkinson's disease (PD) patients, and we have recently found a strong correlation between MBI and cognitive performance. However, the underlying neural activity patterns of cognitive performance linked to MBI in PD are unknown. Fifty-nine non-demented PD patients and 26 healthy controls were scanned using fMRI during performance of a modified version of the Wisconsin card sorting task. MBI was evaluated using the MBI-checklist, and PD patients were divided into two groups, PD-MBI and PD-noMBI. Compared to the PD-noMBI group and healthy controls, the PD-MBI group revealed less activation in the prefrontal and posterior parietal cortices, and reduced deactivation in the medial temporal region. These results suggest that in PD, MBI reflects deficits in the frontoparietal control network and the hippocampal memory system.
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http://dx.doi.org/10.1016/j.nicl.2021.102590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907973PMC
July 2021

Association Between BDNF Val66Met Polymorphism and Mild Behavioral Impairment in Patients With Parkinson's Disease.

Front Neurol 2020 14;11:587992. Epub 2021 Jan 14.

Department of Clinical Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.

Neuropsychiatric symptoms (NPS) are common in Parkinson's disease (PD) and have demonstrated an association with the p. Val66Met, a polymorphism in the gene. Mild behavioral impairment (MBI) is a validated syndrome describing emergent and persistent NPS in older adults as a marker of potential cognitive decline and dementia. This study investigated if PD patients with the Met allele were more likely to have MBI and whether they had impairments in specific domains of MBI using the Mild Behavioral Impairment Checklist (MBI-C) as the MBI ascertainment tool. One hundred forty-six PD patients were screened for neuropsychiatric and cognitive impairments with the MBI-C and the Montreal Cognitive Assessment (MoCA). All participants were genotyped for the p.Val66Met single-nucleotide polymorphism (SNP) using TaqMan Genotyping Assay. Statistical analysis was performed using multiple linear and logistic regression models. Met carriers had a 2 times higher likelihood of being MBI positive (MBI-C total score ≥8) than Val carriers. Met carriers had significantly higher MBI-C total scores and significantly greater impairments in the mood/anxiety and the psychotic domains of MBI-C compared to Val carriers. These findings indicate that the Met allele is associated with a higher neuropsychiatric burden in PD.
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http://dx.doi.org/10.3389/fneur.2020.587992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874164PMC
January 2021

Mild Behavioral Impairment and Subjective Cognitive Decline Predict Cognitive and Functional Decline.

J Alzheimers Dis 2021 ;80(1):459-469

Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.

Background: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease).

Objective: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline.

Methods: Cognitively normal participants were followed up annually at Alzheimer's Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome.

Results: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR >0, including 23.1% of the MBI+group, 23.5% of the SCD+group, and 30.9% of the intersection group of both MBI+and SCD+participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42-5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57-6.34] for MBI+SCD- (20.7%), and 8.15 [5.71-11.64] for MBI+SCD+(30.9%).

Conclusion: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment.
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http://dx.doi.org/10.3233/JAD-201184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075401PMC
September 2021

CCCDTD5: Clinical role of neuroimaging and liquid biomarkers in patients with cognitive impairment.

Alzheimers Dement (N Y) 2020 22;6(1):e12098. Epub 2021 Jan 22.

Centre hospitalier de l'université de Montréal Montreal Canada.

Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTDs) have provided evidence-based dementia diagnostic and treatment guidelines for Canadian clinicians and researchers. We present the results from the Neuroimaging and Fluid Biomarkers Group of the 5th CCCDTD (CCCDTD5), which addressed topics chosen by the steering committee to reflect advances in the field and build on our previous guidelines. Recommendations on Imaging and Fluid Biomarker Use from this Conference cover a series of different fields. Prior structural imaging recommendations for both computerized tomography (CT) and magnetic resonance imaging (MRI) remain largely unchanged, but MRI is now more central to the evaluation than before, with suggested sequences described here. The use of visual rating scales for both atrophy and white matter anomalies is now included in our recommendations. Molecular imaging with [F]-fluorodeoxyglucose ([18F]-FDG) Positron Emisson Tomography (PET) or [Tc]-hexamethylpropyleneamine oxime/ethylene cysteinate dimer ([Tc]-HMPAO/ECD) Single Photon Emission Tomography (SPECT), should now decidedly favor PET. The value of [F]-FDG PET in the assessment of neurodegenerative conditions has been established with greater certainty since the previous conference, and it has now been recognized as a useful biomarker to establish the presence of neurodegeneration by a number of professional organizations around the world. Furthermore, the role of amyloid PET has been clarified and our recommendations follow those from other groups in multiple countries. SPECT with [I]-ioflupane (DaTscan) is now included as a useful study in differentiating Alzheimer's disease (AD) from Lewy body disease. Finally, liquid biomarkers are in a rapid phase of development and, could lead to a revolution in the assessment AD and other neurodegenerative conditions at a reasonable cost. We hope these guidelines will be useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence-based approach to the use of neuroimaging and liquid biomarkers in clinical dementia evaluation and management.
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http://dx.doi.org/10.1002/trc2.12098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821956PMC
January 2021

Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.

Transl Psychiatry 2021 01 26;11(1):76. Epub 2021 Jan 26.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, SUS, Malmö, Sweden.

Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer's disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is further debated if MBI precedes cognitive deficits in AD. Here, we explored potential mechanisms by which MBI is related to AD, this by studying associations between MBI and tau in preclinical AD. In all, 50 amyloid-β-positive cognitively unimpaired subjects (part of the BioFINDER-2 study) underwent MBI-checklist (MBI-C) to assess MBI, and the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) delayed word recall (ADAS-DR) to assess episodic memory. Early tau pathology was determined using tau-PET ([F]RO948 retention in entorhinal cortex/hippocampus) and cerebrospinal fluid (CSF) P-tau. Regression models were used to test for associations. We found that higher tau-PET signal in the entorhinal cortex/hippocampus and CSF P-tau levels were associated with higher MBI-C scores (β = 0.010, SE = 0.003, p = 0.003 and β = 1.263, SE = 0.446, p = 0.007, respectively). When MBI-C and ADAS-DR were entered together in the regression models, tau-PET (β = 0.009, p = 0.009) and CSF P-tau (β = 0.408, p = 0.006) were predicted by MBI-C, but not ADAS-DR. We conclude that in preclinical AD, MBI is associated with tau independently from memory deficits. This denotes MBI as an important early clinical manifestation related to tau pathology in AD.
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http://dx.doi.org/10.1038/s41398-021-01206-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838407PMC
January 2021

Mortality Risk Models for Persons with Dementia: A Systematic Review.

J Alzheimers Dis 2021 ;80(1):103-111

Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: Persons with dementia have higher mortality than the general population. Objective, standardized predictions of mortality risk in persons with dementia could help with planning resources for care close to the end of life.

Objective: To systematically review prediction models for risk of death in persons with dementia.

Methods: The Medline and PsycInfo databases were searched on November 29, 2020, for prediction models estimating the risk of death in persons with dementia. Study quality was assessed using the Prediction model Risk Of Bias ASsessment Tool.

Results: The literature search identified 2,828 studies, of which 18 were included. These studies described 16 different prediction models with c statistics mostly ranging from 0.67 to 0.79. Five models were externally validated, of which four were applicable. There were two models that were both applicable and had reasonably low risk of bias. One model predicted risk of death at six months in persons with advanced dementia residing in a nursing home. The other predicted risk of death at three years in persons seen in primary care practice or a dementia specialty clinic, derived from a nationwide registry in Sweden but not externally validated.

Conclusion: Valid, applicable models with low risk of bias were found in two settings: advanced dementia in a nursing home and outpatient practices. The outpatient model requires external validation. Better models are needed for persons with mild to moderate dementia in nursing homes, a common demographic. These models may be useful for educating persons living with dementia and care partners and directing resources for end of life care.Registration:The study protocol is registered on PROSPERO as RD4202018076.
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http://dx.doi.org/10.3233/JAD-201364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075391PMC
September 2021

Understanding the impact of the COVID-19 pandemic on well-being and virtual care for people living with dementia and care partners living in the community.

Dementia (London) 2021 Aug 31;20(6):2007-2023. Epub 2020 Dec 31.

Hotchkiss Brain Institute, University of Calgary, Canada; Department of Clinical Neurosciences, University of Calgary, Canada.

The COVID-19 pandemic has necessitated public health measures that have impacted the provision of care for people living with dementia and their families. Additionally, the isolation that results from social distancing may be harming well-being for families as formal and informal supports become less accessible. For those living with dementia and experiencing agitation, social distancing may be even harder to maintain, or social distancing could potentially aggravate dementia-related neuropsychiatric symptoms. To understand the lived experience of social and physical distancing during the COVID-19 pandemic in Canada, we remotely interviewed 21 participants who normally attend a dementia specialty clinic in Calgary, Alberta, during a period where essential businesses were closed and health care had abruptly transitioned to telemedicine. A reflexive thematic analysis was used to analyze the interview and field note data. The impacts of the public health measures in response to the pandemic emerged through iterative analysis in three main categories of experience: (1) personal, (2) health services, and (3) health status (of both persons living with dementia and care partner). Isolation and mental health needs emerged as important impacts to family experiences. This in-depth understanding of the needs and experiences of the pandemic for people living with dementia suggests that innovative means are urgently needed to facilitate provision of remote medicine and also social interaction and integration.
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http://dx.doi.org/10.1177/1471301220977639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952494PMC
August 2021

Repetitive Transcranial Magnetic Stimulation for the Treatment of Post-traumatic Stress Disorder: A Systematic Review and Network Meta-analysis: La Stimulation Magnétique Transcrânienne Répétitive Pour le Traitement du Trouble de Stress Post-Traumatique : Une Revue Systématique et une Méta-Analyse en Réseau.

Can J Psychiatry 2021 09 23;66(9):763-773. Epub 2020 Dec 23.

Department of Psychiatry, 5620McGill University, Montreal, Quebec, Canada.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment modality for Post-traumatic stress disorder (PTSD). Several targets and stimulation parameters have been investigated, and while previous meta-analyses have suggested that rTMS is efficacious, these have pooled different stimulation parameters and targets, and the relative efficacy of each is unknown.

Methods: We therefore performed a systematic review and network meta-analysis of randomized controlled trials (RCTs) by searching MEDLINE, EMBASE, CENTRAL, and PsycINFO and retaining RCTs with at least 5 individuals per arm and clinician-rated PTSD symptoms (PROSPERO CRD42019134984). We adhered to PRISMA guidelines, and 2 independent reviewers screened studies for eligibility and extracted the primary outcome of clinician-rated PTSD symptoms. Dropouts were extracted as a proxy for acceptability. Random effects pairwise meta-analyses and a network meta-analysis were performed.

Results: We synthesize data from 10 RCTs with a total of 421 participants. Two rTMS interventions targeting the right dorsolateral prefrontal cortex (DLPFC) improved PTSD symptoms relative to sham: low-frequency stimulation (SMD = 0.70; 95% CI, 0.22 to 1.18) and high-frequency stimulation (SMD = 0.71; 95% CI, 0.11 to 1.31). Medial PFC dTMS, right DLPFC intermittent theta-burst stimulation, and left DLPFC high-frequency stimulation did not separate from sham. Dropouts as a proxy for acceptability revealed no differences between any of the active conditions or sham nor did any of the active conditions differ from each other.

Conclusion: The current literature does not support efficacy differences between interventions; however, protocols stimulating the right DLPFC appear superior to sham. It is unclear whether this reflects heterogeneity in pathology requiring a personalized medicine approach or nonspecific mechanisms of rTMS.
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http://dx.doi.org/10.1177/0706743720982432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504289PMC
September 2021

Evaluating the Real-World Representativeness of Participants with Mild Cognitive Impairment in Canadian Research Protocols: a Comparison of the Characteristics of a Memory Clinic Patients and Research Samples.

Can Geriatr J 2020 Dec 1;23(4):297-328. Epub 2020 Dec 1.

Hotchkiss Brain Institute, Calgary, AB.

Background: Studies of mild cognitive impairment (MCI) employ rigorous eligibility criteria, resulting in sampling that may not be representative of the broader clinical population.

Objective: To compare the characteristics of MCI patients in a Calgary memory clinic to those of MCI participants in published Canadian studies.

Methods: Clinic participants included 555 MCI patients from the PROspective Registry of Persons with Memory SyMPToms (PROMPT) registry in Calgary. Research participants included 4,981 individuals with MCI pooled from a systematic literature review of 112 original, English-language peer-reviewed Canadian studies. Both samples were compared on baseline sociodemographic variables, medical and psychiatric comorbidities, and cognitive performance for MCI due to Alzheimer's disease and Parkinson's disease.

Results: Overall, clinic patients tended to be younger, more often male, and more educated than research participants. Psychiatric disorders, traumatic brain injury, and sensory impairment were commonplace in PROMPT (up to 83% affected) but > 80% studies in the systematic review excluded these conditions. PROMPT patients also performed worse on global cognition measures than did research participants.

Conclusion: Stringent eligibility criteria in Canadian research studies excluded a considerable subset of MCI patients with comorbid medical or psychiatric conditions. This exclusion may contribute to differences in cognitive performance and outcomes compared to real-world clinical samples.
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http://dx.doi.org/10.5770/cgj.23.416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704078PMC
December 2020

Mild behavioral impairment is related to frailty in non-dementia older adults: a cross-sectional study.

BMC Geriatr 2020 11 27;20(1):510. Epub 2020 Nov 27.

The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, 111 Dade Road, Guangzhou, People's Republic of China.

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.
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http://dx.doi.org/10.1186/s12877-020-01903-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694410PMC
November 2020

CCCDTD5 recommendations on early and timely assessment of neurocognitive disorders using cognitive, behavioral, and functional scales.

Alzheimers Dement (N Y) 2020 11;6(1):e12057. Epub 2020 Nov 11.

Departments of Psychiatry Clinical Neurosciences, Community Health Sciences Hotchkiss Brain Institute and O'Brien Institute for Public Health University of Calgary Calgary Alberta Canada.

Introduction: Earlier diagnosis of neurocognitive disorders and neurodegenerative disease is needed to implement preventative interventions, minimize harm, and reduce risk of exploitation in the context of undetected disease. Along the spectrum from subjective cognitive decline (SCD) to dementia, evidence continues to emerge with respect to detection, staging, and monitoring. Updates to previous guidelines are required for clinical practice.

Methods: A subcommittee of the 5th Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed emerging evidence to address the following: (1) Is there a role for screening at-risk patients without clinical concerns? In what context is assessment for dementia appropriate? (2) What tools can be used to evaluate patients in whom cognitive decline is suspected? (3) What important information can be gained from an informant, using which measures? (4) What instruments can be used to get more in-depth information to diagnose mild cognitive impairment (MCI) or dementia? (5) What is the approach to those with cognitive concerns but without objective changes (ie, SCD)? (6) How do we track response to treatment and change over time? The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate quality of the evidence and strength of the recommendations.

Results: We recommend instruments to assess and monitor cognition, behavior, and function across the cognitive spectrum, including reports from patient and informant. We recommend against screening asymptomatic older adults but recommend investigation for self- or informant reports of changes in cognition, emergence of behavioral or psychiatric symptoms, or decline in function or self-care. Standardized assessments should be used for cognitive and behavioral change that have sufficient validity for use in clinical practice.

Discussion: The CCCDTD5 provides evidence-based recommendations for detection, assessment, and monitoring of neurocognitive disorders. Although these guidelines were developed for use in Canada, they may also be useful in other jurisdictions.
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http://dx.doi.org/10.1002/trc2.12057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657153PMC
November 2020

Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)5: Guidelines for management of vascular cognitive impairment.

Alzheimers Dement (N Y) 2020 11;6(1):e12056. Epub 2020 Nov 11.

Department of Medicine (Neurology) Hurvitz Brain Sciences Research Program LC Campbell Cognitive Neurology Unit Canadian Partnership for Stroke Recovery University of Toronto Toronto Canada.

Introduction: Vascular disease is a common cause of dementia, and often coexists with other brain pathologies such as Alzheimer's disease to cause mixed dementia. Many of the risk factors for vascular disease are treatable. Our objective was to review evidence for diagnosis and treatment of vascular cognitive impairment (VCI) to issue recommendations to clinicians.

Methods: A subcommittee of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed areas of emerging evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assign the quality of the evidence and strength of the recommendations.

Results: Using standardized diagnostic criteria, managing hypertension to conventional blood pressure targets, and reducing risk for stroke are strongly recommended. Intensive blood pressure lowering in middle-aged adults with vascular risk factors, using acetylsalicylic acid in persons with VCI and covert brain infarctions but not if only white matter lesions are present, and using cholinesterase inhibitors are weakly recommended.

Conclusions: The CCCDTD has provided evidence-based recommendations for diagnosis and management of VCI for use nationally in Canada, that may also be of use worldwide.
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http://dx.doi.org/10.1002/trc2.12056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657196PMC
November 2020

CCCDTD5 recommendations on early non cognitive markers of dementia: A Canadian consensus.

Alzheimers Dement (N Y) 2020 17;6(1):e12068. Epub 2020 Oct 17.

Division of Neurology Department of Medicine University of Alberta Edmonton Alberta Canada.

Introduction: Cognitive impairment is the hallmark of Alzheimer's disease (AD) and related dementias. However, motor decline has been recently described as a prodromal state that can help to detect at-risk individuals. Similarly, sensory changes, sleep and behavior disturbances, and frailty have been associated with higher risk of developing dementia. These clinical findings, together with the recognition that AD pathology precedes the diagnosis by many years, raises the possibility that non-cognitive changes may be early and non-invasive markers for AD or, even more provocatively, that treating non-cognitive aspects may help to prevent or treat AD and related dementias.

Methods: A subcommittee of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia reviewed areas of emerging evidence for non-cognitive markers of dementia. We examined the literature for five non-cognitive domains associated with future dementia: motor, sensory (hearing, vision, olfaction), neuro-behavioral, frailty, and sleep. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assign the strength of the evidence and quality of the recommendations. We provide recommendations to primary care clinics and to specialized memory clinics, answering the following main questions: (1) What are the non-cognitive and functional changes associated with risk of developing dementia? and (2) What is the evidence that sensory, motor, behavioral, sleep, and frailty markers can serve as potential predictors of dementia?

Results: Evidence supported that gait speed, dual-task gait speed, grip strength, frailty, neuropsychiatric symptoms, sleep measures, and hearing loss are predictors of dementia. There was insufficient evidence for recommending assessing olfactory and vision impairments as a predictor of dementia.

Conclusions: Non-cognitive markers can assist in identifying people at risk for cognitive decline or dementia. These non-cognitive markers may represent prodromal symptoms and several of them are potentially amenable to treatment that might delay the onset of cognitive decline.
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http://dx.doi.org/10.1002/trc2.12068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568425PMC
October 2020

FLAME: A computerized neuropsychological composite for trials in early dementia.

Alzheimers Dement (Amst) 2020 14;12(1):e12098. Epub 2020 Oct 14.

St Lukes Campus The University of Exeter Medical School Exeter UK.

Introduction: Sensitive neuropsychological tests are needed to improve power for clinical trials in early Alzheimer's disease (AD).

Methods: To develop a neuropsychological composite (FLAME - Factors of Longitudinal Attention, Memory and Executive Function), we assessed, 10,714 participants over the age of 50 from PROTECT with validated computerized assessments for 2 years. A factorial analysis was completed to identify the key cognitive factors in all participants, and further analyses examined sensitivity to change in people with stage 2/3 early Alzheimer's disease (AD) according to the US Food and Drug Administration (FDA) framework.

Results: The FLAME composite score (speed of attention, accuracy of attention, memory, and executive function) distinguished between normal cognition and stage 2/3 early AD at baseline, and was sensitive to cognitive and global/functional decline over 2 years, with the potential to improve power for clinical trials.

Discussion: FLAME is sensitive to change, providing a straightforward approach to reduce sample size for RCTs in early AD.

Conclusion: FLAME is a useful computerized neuropsychology composite with utility for clinical trials focusing on cognition.
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http://dx.doi.org/10.1002/dad2.12098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560493PMC
October 2020

Depression prevalence using the HADS-D compared to SCID major depression classification: An individual participant data meta-analysis.

J Psychosom Res 2020 12 23;139:110256. Epub 2020 Sep 23.

Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; Faculty of Psychology, Open University of the Netherlands, Heerlen, The Netherlands; Department of Health Services Research, CAPHRI School for Public Health and Primary, Maastricht University, Maastricht, The Netherlands. Electronic address:

Objectives: Validated diagnostic interviews are required to classify depression status and estimate prevalence of disorder, but screening tools are often used instead. We used individual participant data meta-analysis to compare prevalence based on standard Hospital Anxiety and Depression Scale - depression subscale (HADS-D) cutoffs of ≥8 and ≥11 versus Structured Clinical Interview for DSM (SCID) major depression and determined if an alternative HADS-D cutoff could more accurately estimate prevalence.

Methods: We searched Medline, Medline In-Process & Other Non-Indexed Citations via Ovid, PsycINFO, and Web of Science (inception-July 11, 2016) for studies comparing HADS-D scores to SCID major depression status. Pooled prevalence and pooled differences in prevalence for HADS-D cutoffs versus SCID major depression were estimated.

Results: 6005 participants (689 SCID major depression cases) from 41 primary studies were included. Pooled prevalence was 24.5% (95% Confidence Interval (CI): 20.5%, 29.0%) for HADS-D ≥8, 10.7% (95% CI: 8.3%, 13.8%) for HADS-D ≥11, and 11.6% (95% CI: 9.2%, 14.6%) for SCID major depression. HADS-D ≥11 was closest to SCID major depression prevalence, but the 95% prediction interval for the difference that could be expected for HADS-D ≥11 versus SCID in a new study was -21.1% to 19.5%.

Conclusions: HADS-D ≥8 substantially overestimates depression prevalence. Of all possible cutoff thresholds, HADS-D ≥11 was closest to the SCID, but there was substantial heterogeneity in the difference between HADS-D ≥11 and SCID-based estimates. HADS-D should not be used as a substitute for a validated diagnostic interview.
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http://dx.doi.org/10.1016/j.jpsychores.2020.110256DOI Listing
December 2020
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