Heterogeneity of Cognition in Older Adults with Remitted Major Depressive Disorder: A Latent Profile Analysis.

OBJECTIVES: To identify data-driven cognitive profiles in older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI) and examine how the profiles differ regarding demographic, clinical, and neuroimaging measures. DESIGN: Secondary cross-sectional analysis using latent profile analysis. SETTING: Multisite clinical trial in Toronto, Canada. PARTICIPANTS: One hundred seventy-eight participants who met DSM-5 criteria for rMDD without MCI (rMDD-MCI; n = 60) or with MCI (rMDD + MCI; n = 118). MEASUREMENTS: Demographic, clinical, neuroimaging measures, and domain scores from a neuropsychological battery assessing verbal memory, visuospatial memory, processing speed, working memory, language, and executive function. RESULTS: We identified three latent profiles: Profile 1 (poor cognition; n = 75, 42.1%), Profile 2 (intermediate cognition; n = 75, 42.1%), and Profile 3 (normal cognition; n = 28, 15.7%). Compared to participants with Profile 3, those with Profile 1 or 2 were older, had lower education, experienced a greater burden of medical comorbidities, and were more likely to have MCI. The profiles did not differ on the severity of residual symptoms, age of onset of rMDD, number of depressive episodes, psychotropic medication, cerebrovascular risk, ApoE4 carrier status, or family history of depression, dementia, or Alzheimer's disease. The profiles differed in cortical thickness of 15 regions, with the most prominent effects for left precentral and pars opercularis, and right inferior parietal and supramarginal. CONCLUSION: Older patients with rMDD can be grouped cross-sectionally based on data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. Future research should determine the differential risk for dementia of these data-driven subgroups.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders.

In this narrative review, we examine biological processes linking psychological stress and cognition, with a focus on how psychological stress can activate multiple neurobiological mechanisms that drive cognitive decline and behavioral change. First, we describe the general neurobiology of the stress response to define neurocognitive stress reactivity. Second, we review aspects of epigenetic regulation, synaptic transmission, sex hormones, photoperiodic plasticity, and psychoneuroimmunological processes that can contribute to cognitive decline and neuropsychiatric conditions. Third, we explain mechanistic processes linking the stress response and neuropathology. Fourth, we discuss molecular nuances such as an interplay between kinases and proteins, as well as differential role of sex hormones, that can increase vulnerability to cognitive and emotional dysregulation following stress. Finally, we explicate several testable hypotheses for stress, neurocognitive, and neuropsychiatric research. Together, this work highlights how stress processes alter neurophysiology on multiple levels to increase individuals' risk for neurocognitive and psychiatric disorders, and points toward novel therapeutic targets for mitigating these effects. The resulting models can thus advance dementia and mental health research, and translational neuroscience, with an eye toward clinical application in cognitive and behavioral neurology, and psychiatry.

Effect of prior pharmacotherapy on remission with sequential bilateral theta-burst versus standard bilateral repetitive transcranial magnetic stimulation in treatment-resistant late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is used for treatment of late-life depression. In the FOUR-D study, sequential bilateral theta-burst stimulation (TBS) had comparable remission rates to standard bilateral rTMS. Data were analysed from the FOUR-D trial to compare remission rates between two types of rTMS based on the number and class of prior medication trials. The remission rate was higher in participants with ≤1 previous trial (43.9%) than in participants with 2 previous trials (26.5%) or ≥3 previous trials (24.6%; χ² = 6.36, d.f. = 2, P = 0.04). Utilising rTMS earlier in late-life depression may lead to better outcomes.

A cross-sectional study of cognitive performance in bipolar disorder across the lifespan: the cog-BD project.

BACKGROUND: Neuroprogressive models of the trajectory of cognitive dysfunction in patients with bipolar disorder (BD) have been proposed. However, few studies have explored the relationships among clinical characteristics of BD, cognitive dysfunction, and aging. METHODS: We conducted a cross-sectional analysis in euthymic participants with the MATRICS Cognitive Consensus Battery, the Trail Making Test B, the Stroop Test, and the Wechsler Test of Adult Reading. Age- and gender-equated control participants without a mental disorder ['Healthy Controls' - HC)] were assessed similarly. We compared cognitive performance both globally and in seven domains in four groups: younger BD (age ⩽49 years; n = 70), older BD (age ⩾50 years; n = 48), younger HC (n = 153), and older HC (n = 44). We also compared the BD and HC groups using age as a continuous measure. We controlled for relevant covariates and applied a Bonferroni correction. RESULTS: Our results support both an early impairment ('early hit') model and an accelerated aging model: impairment in attention/vigilance, processing speed, and executive function/working memory were congruent with the accelerated aging hypothesis whereas impairment in verbal memory was congruent with an early impairment model. BD and HC participants exhibited similar age-related decline in reasoning/problem solving and visuospatial memory. There were no age- or diagnosis-related differences in social cognition. CONCLUSION: Our findings support that different cognitive domains are affected differently by BD and aging. Longitudinal studies are needed to explore trajectories of cognitive performance in BD across the lifespan.

Lipopolysaccharide, Immune Biomarkers and Cerebral Amyloid-Beta Deposition in Older Adults With Mild Cognitive Impairment & Major Depressive Disorder.

OBJECTIVE: Inflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD). DESIGN: Cross-sectional analysis. SETTING: Five academic health centers in Toronto. PARTICIPANTS: Older adults with MCI with/without rMDD. MEASUREMENTS: We investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation - Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography. RESULTS: Among 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta - 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22). CONCLUSION: In this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition.

About time: neurocognitive correlates of stimulus-bound and other time setting errors in the Clock Drawing Test.

OBJECTIVE: Previous findings suggest that time setting errors (TSEs) in the Clock Drawing Test (CDT) may be related mainly to impairments in semantic and executive function. Recent attempts to dissociate the classic stimulus-bound error (setting the time to "10 to 11" instead of "10 past 11") from other TSEs, did not support hypotheses regarding this error being primarily executive in nature or different from other time setting errors in terms of neurocognitive correlates. This study aimed to further investigate the cognitive correlates of stimulus-bound errors and other TSEs, in order to trace possible underlying cognitive deficits. METHODS: We examined cognitive test performance of participants with preliminary diagnoses associated with mild cognitive impairment. Among 490 participants, we identified clocks with stimulus-bound errors (n = 78), other TSEs (n = 41), other errors not related to time settings (n = 176), or errorless clocks (n = 195). RESULTS: No differences were found on any dependent measure between the stimulus-bound and the other TSErs groups. Group comparisons suggested TSEs in general, to be associated with lower performance on various cognitive measures, especially on semantic and working memory measures. Regression analysis further highlighted semantic and verbal working memory difficulties as being the most prominent deficits associated with these errors. CONCLUSION: TSEs in the CDT may indicate underlying deficits in semantic function and working memory. In addition, results support previous findings related to the diagnostic value of TSEs in detecting cognitive impairment.

Assessing the Longitudinal Relationship between Theta-Gamma Coupling and Working Memory Performance in Older Adults.

Theta-gamma coupling (TGC) is a neurophysiologic mechanism that supports working memory (WM). TGC is associated with N-back performance, a WM task. Similar to TGC, theta and alpha event-related synchronization (ERS) and desynchronization (ERD) are also associated with WM. Few studies have examined the longitudinal relationship between WM performance and TGC, ERS, or ERD. This study aimed to determine if changes in WM performance are associated with changes in TGC (primary aim), as well as theta and alpha ERS or ERD over 6 to 12 weeks. Participants included 62 individuals aged 60 and older with no neuropsychiatric conditions or with remitted Major Depressive Disorder (MDD) and no cognitive disorders. TGC, ERS, and ERD were assessed using electroencephalography (EEG) during the N-back task (3-back condition). There was an association between changes in 3-back performance and changes in TGC, alpha ERD and ERS, and theta ERS in the control group. In contrast, there was only a significant association between changes in 3-back performance and changes in TGC in the subgroup with remitted MDD. Our results suggest that the relationship between WM performance and TGC is stable over time, while this is not the case for changes in theta and alpha ERS and ERD.

Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function.

OBJECTIVE: Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. METHODS: We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates. RESULTS: Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs. CONCLUSIONS: NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.

Impact of psychotropic medications on cognition among older adults: a systematic review.

OBJECTIVES: The aim of this systematic review is to examine the cognitive impact of psychotropic medications including benzodiazepines, antidepressants, mood stabilizers, antipsychotics, or a combination of these drugs on older adults. DESIGN: Systematic review. SETTING: We searched Medline, PsycINFO, and Embase through the Ovid platform, CINAHL through EBSCO, and Web of Science. PARTICIPANTS AND INTERVENTIONS: Randomized control trials (RCTs) and cohort studies that used a validated scale to measure cognition with a follow-up period of at least six months were included. MEASUREMENT: The primary outcome of interest was cognitive change associated with psychotropic medication use. RESULTS: A total of 7551 articles were identified from the primary electronic literature search across the five databases after eliminating duplicates. Based on full-text analysis, 27 articles (two RCTs, 25 cohorts) met the inclusion criteria. Of these, nine each examined the impact of benzodiazepines and antidepressants, five examined psychotropic combinations, three on antipsychotic drugs, and one on the effects of mood stabilizers. CONCLUSIONS: This is the first systematic review to examine the cognitive impact of multiple psychotropic drug classes in older adults over an extended follow-up period (six months or more) using robust sample sizes, drug-free control groups, and validated cognitive instruments. We found evidence to indicate cognitive decline with the cumulative use of benzodiazepines and the use of antidepressants, especially those with anticholinergic properties among older adults without cognitive impairment at baseline. Further, the use of antipsychotics and psychotropic combinations is also associated with cognitive decline in older adults.

Effects of repetitive paired associative stimulation on brain plasticity and working memory in Alzheimer's disease: a pilot randomized double-blind-controlled trial.

DESIGN: Pilot randomized double-blind-controlled trial of repetitive paired associative stimulation (rPAS), a paradigm that combines transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) with peripheral median nerve stimulation. OBJECTIVES: To study the impact of rPAS on DLPFC plasticity and working memory performance in Alzheimer's disease (AD). METHODS: Thirty-two patients with AD (females = 16), mean (SD) age = 76.4 (6.3) years were randomized 1:1 to receive a 2-week (5 days/week) course of active or control rPAS. DLPFC plasticity was assessed using single session PAS combined with electroencephalography (EEG) at baseline and on days 1, 7, and 14 post-rPAS. Working memory and theta-gamma coupling were assessed at the same time points using the N-back task and EEG. RESULTS: There were no significant differences between the active and control rPAS groups on DLPFC plasticity or working memory performance after the rPAS intervention. There were significant main effects of time on DLPFC plasticity, working memory, and theta-gamma coupling, only for the active rPAS group. Further, on post hoc within-group analyses done to generate hypotheses for future research, as compared to baseline, only the rPAS group improved on post-rPAS day 1 on all three indices. Finally, there was a positive correlation between working memory performance and theta-gamma coupling. CONCLUSIONS: This study did not show a beneficial effect of rPAS for DLPFC plasticity or working memory in AD. However, post hoc analyses showed promising results favoring rPAS and supporting further research on this topic. (Clinicaltrials.gov-NCT01847586).

Walking Alongside: Views of Family Members on Medical Assistance in Dying for Mental Illness as the Sole Underlying Medical Condition.

Medical assistance in dying (MAiD) was introduced into Canadian federal legislation in 2016. Mental illness as the sole underlying medical condition (MI-SUMC) is currently excluded from eligibility; such exclusion is scheduled to expire on March 17, 2024. Irremediability, capacity, quality of life, autonomy, family involvement, and healthcare system constraints have been debated intensively. Recent studies have not explored the views of family members of persons with mental illness on MAiD MI-SUMC. This study aimed to fill this knowledge gap. Twenty-five Ontario residents who had a loved one with mental illness participated. A persona-scenario exercise was designed to explore participants' views on MAiD MI-SUMC in hypothetical situations. Reflexive thematic analysis was used to analyze the data. A lived experience-advisory panel was engaged throughout the study. Seven themes were developed: Witnessing suffering; A road with barriers and limitations; Societal barriers; The unknowns of mental illness; Individual choices: the life or death that a person wants; MAiD MI-SUMC as an acceptable choice when suffering cannot be relieved with available treatments and supports; and The emotional outcome. Participants constructed their views based on their experience of supporting a loved one with mental illness. MAiD MI-SUMC was perceived as a multifaceted issue, whose acceptability and potential introduction required a concurrent exploration and discussion of the challenges arising due to limitations of the healthcare system, the opportunities and limits to family involvement, and the value of patient autonomy.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Rare neurovascular genetic and imaging markers across neurodegenerative diseases.

INTRODUCTION: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status. METHODS: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1). RESULTS: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood. DISCUSSION: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

Impact of Integrated Care Pathways Within the Framework of Collaborative Care on Older Adults With Anxiety, Depression, or Mild Cognitive Impairment.

OBJECTIVES: To evaluate the impact of an Integrated Care Pathway (ICP) within a collaborative care framework for anxiety, depression and mild cognitive impairment (MCI) on clinical outcomes, quality of life, and time to treatment initiation. DESIGN: Prospective Cohort study. SETTING: Primary care practices in Toronto and Hamilton, Ontario, Canada. PARTICIPANTS: Patients of participating primary care practices born in the years 1950 to 1958. SAMPLE SIZE: Target 150 participants, 75 in ICP and 75 in Treatment-As-Usual (TAU) arm. INTERVENTION: ICP within a collaborative care framework and TAU. METHODS AND RESULTS: One hundred forty-five participants with anxiety, depression or MCI, from five primary care practices were enrolled: 69 were managed as per ICP and 76 as per TAU. All underwent outcome assessments at 6, 12, 18, and 24 months. Compared to TAU, ICP participants had a significantly higher rate of improvement in depression symptoms (ß = -0.620, F (1, 256) = 4.10, p = 0.044), anxiety symptoms (ß = -0.593, F (1, 223) = 4.00, p = 0.047), and quality of life (ß = 1.351, F(1, 358) = 6.58, p = 0.011). The ICP group had also a significantly higher "hazard" of treatment initiation (HR = 3.557; 95% CI: [2.228, 5.678]; p < 0.001) after controlling for age, gender and baseline severity of symptoms compared to TAU group. CONCLUSIONS: Use of an ICP within a collaborative care framework in primary care settings for anxiety, depression and MCI among older adults, results in faster reductions in clinical symptoms and improvement in quality of life compared to usual care, as well as faster access to recommended treatments.

Diagnostic Precision in the Detection of Mild Cognitive Impairment: A Comparison of Two Approaches.

OBJECTIVE: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria. DESIGN: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial. SETTING: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto. PARTICIPANTS: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both. MEASUREMENTS: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses. RESULTS: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele. CONCLUSION: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia.

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative.

OBJECTIVES: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders? METHODS/DESIGN: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. RESULTS: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. CONCLUSIONS: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions.

Impact of standardizing care for agitation in dementia using an integrated care pathway on an inpatient geriatric psychiatry unit.

OBJECTIVES: This study examined the effectiveness of an integrated care pathway (ICP), including a medication algorithm, to treat agitation associated with dementia. DESIGN: Analyses of data (both prospective and retrospective) collected during routine clinical care. SETTING: Geriatric Psychiatry Inpatient Unit. PARTICIPANTS: Patients with agitation associated with dementia (n = 28) who were treated as part of the implementation of the ICP and those who received treatment-as-usual (TAU) (n = 28) on the same inpatient unit before the implementation of the ICP. Two control groups of patients without dementia treated on the same unit contemporaneously to the TAU (n = 17) and ICP groups (n = 36) were included to account for any secular trends. INTERVENTION: ICP. MEASUREMENTS: Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory Questionnaire (NPIQ), and assessment of motor symptoms were completed during the ICP implementation. Chart review was used to obtain length of inpatient stay and rates of psychotropic polypharmacy. RESULTS: Patients in the ICP group experienced a reduction in their scores on the CMAI and NPIQ and no changes in motor symptoms. Compared to the TAU group, the ICP group had a higher chance of an earlier discharge from hospital, a lower rate of psychotropic polypharmacy, and a lower chance of having a fall during hospital stay. In contrast, these outcomes did not differ between the two control groups. CONCLUSIONS: These preliminary results suggest that an ICP can be used effectively to treat agitation associated with dementia in inpatients. A larger randomized study is needed to confirm these results.

Vagally Mediated Heart Rate Variability Is Associated With Executive Function Changes in Patients With Treatment-Resistant Depression Following Magnetic Seizure Therapy.

OBJECTIVES: Magnetic seizure therapy (MST) is a novel investigational brain stimulation modality for patients with treatment-resistant depression (TRD). MST is a potential alternative seizure-based treatment to electroconvulsive therapy (ECT), given that it may offer equivalent antidepressant efficacy, yet with a relative sparing of cognitive functioning. Heart rate variability (HRV) is a marker of central autonomic functioning. We aimed to explore the relationships among baseline HRV, age, clinical outcome, and executive function following MST, in patients with TRD. MATERIALS AND METHODS: Eighty-eight TRD patients (55 females; 18-70 years) were enrolled and 48 patients completed a course of MST in an open-label study. Patients received MST treatments two to three times per week, using one of three stimulation frequencies (ie, 100 Hz, 50 Hz, or 25 Hz) at 100% stimulator output. Root mean square of the successive R-R differences (RMSSD), an index of HRV, was computed from a baseline electrocardiogram (ECG) recording. Clinical symptoms were assessed using the Hamilton Depression Rating Scale (HAM-D24) and the Quick Inventory of Depressive Symptomatology (QIDS16). Executive function was assessed using the Trail Making Test and the Mazes Test from the MATRICS battery. RESULTS: Baseline RMSSD was correlated with baseline HAM-D24 (r = -0.340, p = 0.001) and baseline Mazes Test (r = 0.417, p = 0.0007) but not with baseline Trail Making Test. Furthermore, baseline RMSSD was not correlated with changes on the HAM-D24, QIDS16, or total scores on the Trail Making Test. However, there was a significant correlation between baseline RMSSD and improvement on the Mazes Test following MST (r = 0.502, p = 0.0004). CONCLUSIONS: Since this is an open-label trial, the influence of the placebo effect cannot be excluded. However, our results suggest that baseline RMSSD may be a state-biomarker of depression and executive function impairment. Additionally, while baseline vagally mediated resting cardiac activity did not predict the outcome of depression, it may mediate executive function improvements following MST.