Multiple plasma phosphorylated tau assays are now commercially available for detection of Alzheimer's disease (AD) pathology, yet clinical laboratories lack a comprehensive comparative evaluation to guide implementation decisions. Diagnostic accuracy and analytical performance were assessed in a cohort of 273 participants with paired EDTA plasma and CSF specimens. CSF AD core biomarkers were used as the reference standard, and index tests included three plasma pTau217 assays by Roche, Fujirebio, and Meso Scale Discovery [MSD], and a pTau181 assay by Roche. Participants had a median age of 70 [IQR: 64-76] years, 42% were female and 60% were AD-positive. Diagnostic performance was statistically similar across all pTau217 assays (range: 0.88-0.89 area under the receiver operating characteristic curve [AUC]) with the pTau181 assay having significantly lower accuracy (AUC = 0.85). All assays were resistant to hemolysis, icterus, and lipemia. Automated assays (Roche, Fujirebio) showed superior analytical precision and freeze/thaw stability (≥6 cycles) compared to the manual MSD assay (2 cycles). Given that plasma pTau217 assays demonstrated high and comparable accuracy in this head-to-head comparison, their differences in analytical performance characteristics and general clinical laboratory suitability became the differentiating factors for clinical implementation. ### Competing Interest Statement This research was funded in part by a research grant from the Ministry of Health (Government of British Columbia) to MLD. In kind support (to institution) was provided in part by MSD (reagents), Roche Diagnostics (reagents), and Fujirebio via Phoenix Airmid (reagents and equipment). CH is supported in part by a Four-Year Doctoral Fellowship from University of British Columbia. OS, JRB, RS, LB, and CH declare no conflicts of interest. Outside of the submitted work, the authors report the following disclosures. AHB: Grants/contracts paid to institution from ICG Pharma, Alnylam, AriBio, Novo Nordisk, Cerevel, Anavex, the Canadian Consortium on Neurodegeneration in Aging, and CABHI; consulting fees and honoraria from Eli Lilly and Eisai (payments to professional corporation); volunteer board roles with the Consortium of Canadian Centres for Clinical Cognitive Research and the Canadian Neurological Society. JAP: Consulting fees and honoraria from Eisai and Eli Lilly. Volunteer board role with Canadian Colloquium on Dementia and scientific advisory committee for CLEAR. GRH: Grant funding from Biogen, Roche, Cassava Sciences, and Eisai; consulting for Biogen, Roche, Novo Nordisk, Eisai, and Eli Lilly; serves as President of the Consortium of Canadian Centres for Clinical Cognitive Research. PEL: Consulting for Eli Lilly and Eisai. HBN: Consulting for Eisai, and advisory boards for Biogen and Hoffmann-La Roche. MLD reports consulting for Canada Drug Agency, Siemens, Roche and Eisai, lecturing and educational activity fees from Eli Lilly and Roche, and role as co-chair for the Canadian Society of Clinical Chemists and Association for Diagnostics and Laboratory Medicine Guidance Document on Alzheimer Disease Biofluid Biomarkers. ### Funding Statement This study was funded in part by a research grant from the Ministry of Health (Government of British Columbia) to MLD. In kind support (to institution) was provided in part by MSD (reagents), Roche Diagnostics (reagents), and Fujirebio via Phoenix Airmid (reagents and equipment). CH is supported in part by a Four-Year Doctoral Fellowship from University of British Columbia. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the University of British Columbia and Providence Health Care Research Institute gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon reasonable request.

As the population ages, mild cognitive impairment (MCI) and dementia are increasingly prevalent. Patients, families, and healthcare systems will benefit from delaying progression of cognitive decline. Non-pharmacological interventions (NPIs) are safe, well-tolerated, and preferred by patients and have been studied in a broad body of literature. Despite this, few comprehensive guidelines exist on NPIs for early cognitive decline. We conducted a systematic review of the literature focused on NPI supported by the FINGER model and a review conducted by the AAIC Non-Pharmacological Interventions Professional Interest Area (Sikkes et al 2021). Inclusion criteria included meta-analysis or systematic review of randomized controlled trials enrolling patients ≥ 60 with MCI or dementia (MMSE >20 when provided). Included studies were published between 2014 - 2024, and outcomes assessed included cognition and/or function. Of 2,870 studies screened, 26 met inclusion criteria: exercise ( n  = 16), cognitive ( n  = 4), multicomponent ( n  = 5), and mindfulness ( n  = 1) interventions. Exercise, including dance, exergames, and mind-body showed improvement in global and cognitive sub-domains but benefit was not seen with walking alone. Cognitive interventions, including cognitive stimulation, mindfulness, and multicomponent interventions showed cognitive benefits. Only one study of virtual reality cognitive training improved functional status. Considerable heterogeneity including variable trial duration, multiple interventions studied, and inability to fully blind participants and researchers limit comparability and conclusions. NPIs benefit cognition in individuals with MCI and mild dementia. The most benefit was demonstrated with multi-domain interventions incorporating cognitive and exercise interventions, mindfulness, and some cognitive interventions. These interventions can be accessed through community or senior centres or integrated into clinic settings with multidisciplinary care teams. We recommend an individualized approach for each patient, which incorporates their interests, frailty, mobility, medical comorbidity, and level of function. Further research is needed to inform specific recommendations about how much cognitive or physical activity is optimal for improving cognition or function.

INTRODUCTION:In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. METHODS:The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. RESULTS:Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). DISCUSSION:AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing—used in medical care—impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. Patients with completed management questionnaires ( n = 142) had a median age of 64 (interquartile range: 59–69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (–52.0%) and detailed neuropsychological assessments (–63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and –50.0% in biomarker-positive and -negative cases, respectively). AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

Background Freezing of gait (FOG) is notoriously difficult to quantify, which has led to the use of multiple markers as outcomes for clinical trials. The instrumented timed up and go (TUG) and the many parameters that can be derived from it are commonly used as objective markers of FOG severity in clinical trials; however, it is unknown if they represent actual FOG severity. Objective To determine the specificity and responsiveness of objective surrogate markers of FOG severity commonly utilized in FOG studies. Methods Study design: We compared the specificity and responsiveness of commonly used markers in FOG clinical trials. Markers compared included velocity, step/stride length, step/stride length variability, TUG, and turn duration. Data was collected in four conditions (ON and OFF dopaminergic drugs, with and without a dual task). Unified Parkinson’s Disease Rating Scale (UPDRS) was administered in the ON and OFF states. Results Thirty-three subjects were recruited (17 PD subjects without FOG (PD-control) and 16 subjects with PD and dopa-responsive FOG PD-FOG). The UPDRS motor scores were 24.9 for the PD-control group in the ON state, 24.8 for the FOG group in the ON state, and 42.4 for the FOG group in the OFF state. Significant mean differences between the ON and OFF conditions were observed with all surrogate markers ( p < 0.01). However, only dual task turn duration and step variability showed trends toward significance when comparing PD-control and ON-FOG ( p = 0.08). Test–retest reliability was high (ICC > 0.90) for all markers except standard deviations. Step length variability was the only marker to show an area under the ROC curve analysis > 0.70 comparing ON-FOG vs. PD-control. Conclusions Multiple candidate surrogate markers for FOG severity showed responsiveness to levodopa challenge; however, most were not specific for FOG severity.

While previous studies have demonstrated the effect of Alzheimer’s disease (AD) CSF testing in changing diagnosis, we lack an understanding of how this testing affects clinical management. Therefore, we assessed changes in clinical management associated with AD CSF biomarker testing when ordered as part of routine clinical management. The ‘Investigating the Impact of Alzheimer’s Disease Diagnostics in British Columbia’ (IMPACT-AD BC) study (NCT05002699) is a longitudinal study examining the impact of AD CSF testing on clinical management, personal utility and health care economics in British Columbia, Canada. After AD CSF testing was ordered as part of routine care (where the clinical scenario met the appropriate use criteria), the patient and their physician were eligible to participate in the study. The primary outcome was the change in management (pre- v. post-biomarker results) in a composite measure including 1) AD drug therapy, 2) other relevant drug therapy, 3) other diagnostic procedures, and 4) referral or counselling. Participants (n = 129) had a median age of 63 (IQR:58-68); 49% were female. Cognitive impairment at baseline consisted of 7% with subjective cognitive impairment, 53% with mild cognitive impairment, and 40% with dementia. CSF biomarker profiles were consistent with an amyloid-beta pathology (i.e., A+) in 72% of cases. Changes in clinical management because of testing occurred in 83% of cases including: referrals and counseling (57%), imaging (47%) and other diagnostic procedures (e.g., neuropsychological testing) (42%), and use of AD drug therapies (40%). For those with a non-AD pre-biomarkers diagnosis, 42% were changed to AD post-biomarkers; for those with an AD pre-biomarkers diagnosis, 18% were changed to non-AD post-biomarkers. This study has revealed substantial changes in clinical management as a direct result of AD CSF biomarker testing in routine care. An understanding of the implications of biomarker testing will in turn help us: improve appropriate utilization, understand the broader impacts on persons living with dementia and on the health care system, and prepare for expanded use of this testing with the availability of disease-modifying therapeutics.

Background This investigation examined whether aspects of attention and executive functioning differed between Parkinson's Disease (PD) patients with freezing of gait (FOG) based on responsiveness to dopamine. We also explored association of cognition with FOG severity and gait metrics. Methods Fifty-four individuals with PD completed the study protocol: 17 without freezing (PDC), 23 with dopa-responsive FOG (RFOG), and 14 with dopa-unresponsive (URFOG). Standardized neuropsychological tests assessed attention (focused and sustained), psychomotor speed, and set-switching (time and errors). FOG severity was measured using the new FOG Questionnaire (nFOG-Q). Metrics from timed up and go (TUG) tasks were obtained while "on" and "off" dopamine, with and without dual cognitive tasks. Results After controlling for clinical and demographic factors, analysis of covariance revealed a significant between-group difference for set-switching errors; planned contrasts revealed increased set-switching errors in URFOG relative to RFOG and PD control groups. Groups were not different in other cognitive domains. FOG severity was modestly associated with set-switching errors in RFOG but not URFOG. TUG performances while "on" were associated with set-switching errors in PD controls, and with focused attention in RFOG. Conclusion PD patients with dopa-unresponsive FOG are more prone to set-switching errors than those who respond to treatment. Furthermore, executive function appears relevant to FOG severity only in patients who show dopamine response. Together, these findings suggest disruption of a common dopamine-mediated pathway for FOG and ability to monitor rules while alternating cognitive processes. Consideration of dopa-response could be useful in characterizing cohorts and treating FOG in PD.

IntroductionNeuropsychiatric symptoms (NPS) are common at all stages of Alzheimer disease (AD). Delusions in AD are associated with negative clinical consequences and may signal rapid disease progression. Hence, we sought to determine the prevalence of delusions in drug‐naïve (no cholinesterase inhibitor or neuroleptic medications) AD patients.MethodsIn this meta‐analysis, a search of the EMBASE, MEDLINE, and PsycINFO databases was performed. We selected studies reporting delusion prevalence measured by the Neuropsychiatric Inventory (NPI) in drug‐naïve AD patients. An aggregate delusion event rate with 95% confidence interval (CI) was calculated. The I2 statistic was used to assess the magnitude of between‐study heterogeneity. Single variable meta‐regressions allowed examination of the effect of moderating factors and heterogeneity. Quantitative measures were used to appraise for publication bias.ResultsWe identified 6 studies with 591 participants allowing calculation of the aggregate delusional prevalence rate. Irrespective of dementia severity, the aggregate event rate for delusions was 29.1% (95% CI: 20–41%; I2 = 84.59). No publication bias was observed.ConclusionThis meta‐analysis calculates a 29.1% prevalence rate of delusions in AD patients. There is a trend towards increasing delusion prevalence in concordance with increasing severity of dementia. Given delusions are associated with poorer outcomes, the obtained prevalence should motivate clinicians to screen carefully for delusions. Current literature limitations warrant future studies, with sub‐analyses on dementia severity, and other neurobiological factors known to influence the presence of delusions.

Question In patients who require procedural sedation (PS) in the emergency department (ED), does midazolam or haloperidol premedication reduce ketamine-induced recovery agitation? Methods Design Randomized placebo-controlled trial. ClinicalTrials.gov NCT02909465. Allocation {Concealed}*. Blinding Blinded (patients, clinicians, {data collectors, outcome adjudicators, data analysts, and data safety and monitoring committee}*). Follow-up period Until recovery after ketamine injection. Setting An ED in Iran. Patients 185 adults >18 years of age (mean age 38 y, 91% men) who needed PS in the ED. Exclusion criteria included study drug contraindication, acute respiratory infection or depression, intoxication, chronic psychiatric disease, or moderate to severe dementia. Intervention IV midazolam, 0.05 mg/kg, plus placebo-haloperidol (n =61), haloperidol, 5 mg, plus placebo-midazolam (n =61), or placebo-haloperidol plus placebo-midazolam (n =63), all administered 5 minutes before ketamine, 1 mg/kg. Outcomes Outcomes included maximum agitation (maximum Pittsburgh Agitation Scale [PAS] score [scale range 0 to 16]) and recovery agitation (Richmond AgitationSedation Scale [RASS]) 30 min after ketamine administration, recovery agitation (PAS score >0), clinically important recovery agitation (PAS score >3), and recovery duration. Patient follow-up 98%. Main results The results are in the Table. Conclusion In patients who require procedural sedation in the emergency department, midazolam or haloperidol premedication reduced ketamine-induced recovery agitation but increased recovery time. Midazolam or haloperidol vs placebo pretreatment before ketamine procedural sedation in the emergency department Outcomes Time (min) Difference (95% CI) Midazolam vs placebo Haloperidol vs placebo Richmond AgitationSedation Scale score 5 1 (1.47 to 0.53) 1 (1.52 to 0.48) 15 1 (2.08 to 0.08) 1 (2.05 to 0.05) 30 1 (1.96 to 0.04) 1 (3.29 to 0.71) Maximum PAS score 3 (4.72 to 1.27) 3 (4.75 to 1.25) Recovery time (min) 17 (9 to 25) 32 (25 to 39) Pretreatment vs placebo Event rates RRR (CI) NNT (CI) Recovery agitation Midazolam 25% vs 64% 61% (39 to 76) 3 (2 to 5) Haloperidol 20% vs 64% 69% (49 to 82) 3 (2 to 4) Clinically important recovery agitation** Midazolam 5.0% vs 26% 81% (43 to 94) 5 (3 to 12) Haloperidol 1.6% vs 26% 94% (65 to 99) 5 (3 to 8) PAS = Pittsburgh Agitation Scale; CI defined in Glossary. RRR, NNT, and CI calculated from event rates in article. Score range 5 (unarousable) to +4 (combative) (0 = alert and calm). Score range 0 (normal or absent behavior) to 16 (extreme agitated behavior). PAS score >0. No difference for midazolam vs haloperidol (relative risk increase 27%, CI 34 to 147). **PAS score >3. No difference for midazolam vs haloperidol (relative risk increase 205%, CI 55 to 2000). Commentary When used alone for ED PS, ketamine causes adverse recovery agitation in 10% to 20% of adults (1). Midazolam premedication has been shown to reduce this agitation (2). Haloperidol premedication in adults is novel but has been reported in children (3). The RCT by Akhlaghi and colleagues provides support for premedication with midazolam or haloperidol to reduce recovery agitation in adults sedated with ketamine. Most trials have used subjective physician perceptions or visual analog scales to measure agitation (2); the lack of an objective method for measuring recovery agitation has been a challenge for understanding the effectiveness of PS prevention interventions. Akhlaghi and colleagues used the PAS, a psychogeriatric score validated to measure agitation in dementia patients (4), to measure ketamine-induced recovery agitation. The higher-than-expected incidence of agitation (64%) in the trial might be a reflection of the new application of the scale to quantify PS recovery agitation. The validity and rationale for selecting the threshold of a score of 3 (out of a possible 4) in any of 4 domains for agitation is not clear. Patient psychological preparation and management of external stimuli have been suggested as alternatives to pharmacologic premedication (2) but were not used in this trial. Midazolam and haloperidol prolonged recovery time by 17 and 32 minutes, respectively. Clinicians need to recognize that the reduction in patient agitation comes with a prolonged recovery time, affecting ED patient flow and potentially worsening ED overcrowding.

PURPOSE:Evidence suggests anti-estrogen endocrine therapy (ET) is associated with adverse cognitive effects; however, findings are based on small samples and vary in the cognitive abilities affected. We conducted a meta-analysis to quantitatively synthesize the evidence.METHODS:Electronic databases were searched in November 2016. Fourteen studies totaling 911 BC patients on aromatase inhibitors (AIs) or tamoxifen (TAM) and 911 controls (i.e., non-cancer controls and BC controls not using ET) were included. Neuropsychological tests were categorized into six domains. Effect sizes were computed to compare (1) ET patients versus controls and (2) TAM patients versus AI patients.RESULTS:In cross-sectional comparisons, ET patients performed worse than control groups on verbal learning/memory, visual learning/memory, frontal executive function, and processing speed, but did not differ on psychomotor efficiency or visuospatial function. Subgroup analyses revealed that verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls. In other domains, ET patients and BC controls performed equivalently. Regarding change from pre-treatment performance, ET patients did not differ from controls on any domain. TAM and AI patients did not from one another differ overall; however, subgroup analyses indicated that TAM patients performed better than non-steroidal AI patients on several domains, but showed few performance differences relative to steroidal AI patients.CONCLUSIONS:Verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls, suggesting specific adverse effects on this domain. Additional studies assessing change from pre-treatment performance and differences between steroidal and non-steroidal AIs are warranted.

Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.

Background/objectives Evidence suggests that aerobic exercise may slow the progression of subcortical ischaemic vascular cognitive impairment (SIVCI) by modifying cardiovascular risk factors. Yet the economic consequences relating to aerobic training (AT) remain unknown. Therefore, our primary objective was to estimate the incremental cost per quality-adjusted life years (QALYs) gained of a thrice weekly AT intervention compared with usual care. Design Cost–utility analysis alongside a randomised trial. Setting Vancouver, British Columbia, Canada. Participants 70 adults (mean age of 74 years, 51% women) who meet the diagnostic criteria for mild SIVCI. Intervention A 6-month, thrice weekly, progressive aerobic exercise training programme compared with usual care (CON; comparator) with a follow-up assessment 6 months after formal cessation of aerobic exercise training. Measurements Healthcare resource usage was estimated over the 6-month intervention and 6-month follow-up period. Health status (using the EQ-5D-3L) at baseline and trial completion and 6-month follow-up was used to calculate QALYs. The incremental cost–utility ratio (cost per QALY gained) was calculated. Results QALYs were both modestly greater, indicating a health gain. Total healthcare costs (ie, 1791±1369 {2015 $CAD} at 6 months) were greater, indicating a greater cost for the thrice weekly AT group compared with CON. From the Canadian healthcare system perspective, the incremental cost–utility ratios for thrice weekly AT were cost-effective compared with CON, when using a willingness to pay threshold of $CAD 20 000 per QALY gained or higher. Conclusions AT represents an attractive and potentially cost-effective strategy for older adults with mild SIVCI. Trial registration number NCT01027858.

Presented herein is evidence for criterion, content, and convergent/discriminant validity of the NIMH-Provisional Diagnostic Criteria for depression of Alzheimer's Disease (PDC-dAD) that were formulated to address depression in Alzheimer's disease (AD). Using meta-analytic and systematic review methods, we examined criterion validity evidence in epidemiological and clinical studies comparing the PDC-dAD to Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), and International Classification of Disease (ICD 9) depression diagnostic criteria. We estimated prevalence of depression by PDC, DSM, and ICD with an omnibus event rate effect-size. We also examined diagnostic agreement between PDC and DSM. To gauge content validity, we reviewed rates of symptom endorsement for each diagnostic approach. Finally, we examined the PDC's relationship with assessment scales (global cognition, neuropsychiatric, and depression definition) for convergent validity evidence. The aggregate evidence supports the validity of the PDC-dAD. Our findings suggest that depression in AD differs from other depressive disorders including Major Depressive Disorder (MDD) in that dAD is more prevalent, with generally a milder presentation and with unique features not captured by the DSM. Although the PDC are the current standard for diagnosis of depression in AD, we identified the need for their further optimization based on predictive validity evidence.

Endocrine-based treatments are the mainstay of therapy for postmenopausal women with breast cancer; yet concern has been raised about potential adverse cognitive effects. We performed a systematic review of the published literature to evaluate whether endocrine-based treatments for breast cancer are associated with changes in cognitive domains and whether these effects are more pronounced with advanced age. An electronic database search was performed. Original investigations that examined the effects of endocrine treatment on cognitive function were identified. Data were abstracted and studies were assessed for risk of bias. A total of 21 unique studies (n = 2398) were identified. Ten were short-term (duration ≤ 2 years) and 11 were long-term (duration > 2 years). Nine (43 %) studies had a sample size ≤100 subjects; 9 (43 %) were longitudinal, with baseline measurement before treatment initiation. No studies were primary randomized clinical trials. While there was heterogeneity in the neuropsychological measures used, tests could be grouped into the cognitive domains that they assessed. Compared to breast cancer or healthy controls, endocrine therapy was associated with impaired performance on neuropsychological testing. No study explored the association between age and changes in cognitive performance. Overall, endocrine therapies were associated with greater cognitive deficits compared to surgical and healthy controls; yet, lack of randomized trial data and heterogeneity in design of many studies limited any definitive conclusions. Despite older women being at highest risk for the development of cognitive impairment, advanced age has not been adequately explored.

Objective: To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). Methods: This was a proof-of-concept single-blind randomized controlled trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimer's Disease Assessment Scale–Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT-25]), and activities of daily living (Alzheimer's Disease Cooperative Study–Activities of Daily Living [ADCS-ADL]). Results: Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS-Cog performance compared with the usual care plus education group (−1.71 point difference, 95% confidence interval [CI] −3.15 to −0.26, p = 0.02); however, this difference was not significant at the 6-month follow-up (−0.63 point difference, 95% CI −2.34 to 1.07, p = 0.46). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference, 95% CI 5.82 to 54.86, p = 0.02) and in diastolic blood pressure (−6.89 mm Hg difference, 95% CI −12.52 to −1.26, p = 0.02). Conclusions: This study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education. ClinicalTrials.gov identifier: NCT01027858. Classification of evidence: This study provides Class II evidence that for adults with mild SIVCI, an aerobic exercise program for 6 months results in a small, significant improvement in ADAS-Cog performance.

BACKGROUND:The assessment of quality of life is critical in ascertaining the benefit of interventions aimed to reduce morbidity among individuals with cognitive impairment. However, the assessment of quality of life is challenging in this population due to the uncertain validity of patient responses as cognitive function declines. Hence, we examined the level of agreement between patient and proxy assessments of health related quality of life (HRQoL) and wellbeing based on the domains that comprise each of these constructs.METHODS:Analysis of baseline data from 71 community-dwelling older adults with mild Vascular Cognitive Impairment (VCI) who participated in a six-month proof-of-concept single-blinded randomized trial. Level of agreement between patient and caregiver ratings of HRQoL (EQ-5D-3L) and wellbeing (ICECAP-O) were compared using raw agreement (%), intraclass correlation coefficient (ICC) and weighted Cohen's kappa statistic.RESULTS:Self-care (assessed via the EQ-5D-3L) demonstrated almost perfect raw agreement between the patient and caregiver ratings. Three domains (mobility, pain and anxiety) of the EQ-5D-3L demonstrated fair agreement between the patient and caregiver ratings. Two (attachment and control) of the five ICECAP-O domains demonstrated slight agreement. The ICC indicated good agreement for the EQ-5D-3L and poor agreement for the ICECAP-O.CONCLUSION:There is better patient-proxy agreement for the EQ-5D-3L compared with the ICECAP-O among individuals with mild VCI. These findings imply that the ICECAP-O may have limited clinical, research and policy related utility among individuals with mild VCI.TRIAL REGISTRATION:ClinicalTrials.gov NCT01027858.

Objective Systematic review of literature on patient-reported voice handicap following T1 glottic squamous cell carcinoma treatment using transoral laser microsurgery or radiation therapy.Data Sources PubMed, Web of Science, and Scopus (1997-2013).Review Methods These data sources were searched for papers reporting Voice Handicap Index (VHI) after treatment of early glottic carcinoma. Review and reference cross-checking were performed using a priori selection criteria. Study data were abstracted and publication quality categorized independently by 2 authors. Corresponding authors were contacted to maximize data for analysis. Meta-analysis was performed only with studies that included both treatment modalities, to reduce heterogeneity and maximize rigor; random effects modeling was used to pool results.Results Eighteen publications were identified that reported VHI data following surgery and radiotherapy for T1 glottic carcinoma. No studies were randomized. When studies that reported multiple T-stages or systematic treatment selection bias were excluded, 8 retrospective cohort studies describing 362 patients were suitable for meta-analysis. Follow-up time (mean, 47 months; range, 1-298 mo) and extent of surgical excision varied across studies. Six studies showed no VHI difference between treatment arms; 2 favored radiotherapy over surgery (1 of which reported transmuscular cordectomy for all surgical patients); and none favored surgery. Meta-analysis showed no significant difference in posttreatment VHI between radiotherapy and surgery (mean difference, -5.52; 95% confidence interval, -11.40, 0.36; heterogeneity I-2 = 61%, P = .01).Conclusion VHI scores were comparable following transoral laser microsurgery and radiation therapy for T1 glottic carcinoma in the current literature, suggesting no clinically significant difference in functional voice outcomes between treatment types.

Worldwide, Sub-cortical vascular ischaemia (SVCI) is the second most common etiology contributing to cognitive impairment among older adults. Yet, SVCI may be the most treatable form of cognitive impairment as many of its risk factors can be reduced with exercise. Nevertheless, few randomized controlled trials to date have specifically assessed the efficacy of exercise training on cognitive and brain outcomes in this high-risk group. Thus, we conducted a 6-month proof-of-concept randomized controlled trial of thrice-weekly aerobic exercise training (AE) among adults with mild SVCI. A sub-set of participants underwent MRI scanning; the focus of this analysis was to investigate the effect of AE on both white matter and grey matter in this sub-set. Seventy-one adults (56-96 years) with SVCI were recruited and randomized (1:1) to one of two experimental groups: 1) 3x/week AE or 2) usual care (UC). SVCI was confirmed by: 1) evidence of subcortical white matter lesions from neuroimaging (i.e., CT or MRI); 2) a score of less than 26 on the Montreal Cognitive Assessment (MoCA); and 3) clinical assessment by neurologist. Thirty participants (16 from AE and 14 from UC) completed 3T MRI scanning both at baseline and trial completion. Scans were analyzed using FSL Freesurfer. Compared with the control group, cortical white matter volume significantly increased in the AE group (p = .039). However, total grey matter volume significantly decreased in the AE group compared with the UC group (p= .043). A 6-month AE program significantly increased white matter volume in older adults diagnosed with VCI compared with the control group. However, future studies are need to confirm our current results.

The Clinical Meaningfulness in Alzheimer Disease Treatment (CLIMAT) scale has been designed to capture meaningful change in clinical trial and care settings. The baseline interview assesses Alzheimer Disease (AD) symptoms on two dimensions validated in previous work: severity of impairment, with patient and informant input, and impact of impairment, with patient input. Impact addresses the perceived personal-social importance of AD symptoms. Here we report on the empirically derived factor structure underlying patient and informant reports on the CLIMAT scale items. The sample comprised 97 participants with AD enrolled in a phase IV effectiveness study of cholinesterase inhibitors (ChEI) (BC Alzheimer's Drug Therapy Initiative), mean age 76.3 (SD=8.6), mean MMSE 23.8 (SD=6.3), 53% female. The majority of informants (75%) were spouses. Baseline patient and informant interviews were rated by clinicians on items in 4 domains: social (2), functional (3), cognitive (5) and affective (2) (total items=12). We computed descriptives and performed exploratory principal component analysis (PCA) with varimax rotation, on severity ratings based on patient and informant, and impact ratings based on patient. Factor loadings>0.5 were included in the interpretation. CLIMAT severity ratings: patients and informants described loss of independence, executive functioning and memory as most affected. Patient-reported severity was lower than that reported by informants, except for depressed mood and anxiety. Based on eigenvalues>1, 3-factor solutions were selected for both patient and informant severity ratings. Patient-rating factors were social engagement- mood, cognition-anxiety, and independence-executive functioning (65%-variance explained); informant-rating factors were function-cognition, social engagement, and mood-anxiety (72%-variance explained). CLIMAT impact ratings: patients described losses in independence and memory, depressed mood and anxiety as most impactful. A 3-factor solution was selected for impact ratings, with independence-mood-anxiety, social engagement and cognition as factors (65%-variance explained). In patient but not informant reports, affective symptoms are closely linked to social, cognitive and functional symptoms of AD. This suggests that there are important differences in how patients and informants perceive, and report on AD symptoms. These findings hold important implications for the CLIMAT interview domains, and in general, for the assessment of AD symptoms and treatment response.

OBJECTIVE: To compare prevalence rates of depression in AD by PDC-dAD and by other diagnostic and assessment approaches.