Nathan Herrmann

Background: Vascular mild cognitive impairment (vaMCI) is frequently accompanied by neuropsychiatric symptoms (NPS), particularly apathy, which are associated with white matter hyperintensities (WMH). N-acetylcysteine (NAC) combined with exercise may provide neuroprotective benefits. Objective: We hypothesized that baseline frontal and global WMH burden would moderate the neuropsychiatric response to NAC plus exercise. We further hypothesized that the strongest domain-specific effects would be observed for apathy and affective dysregulation. Methods: Participants with vaMCI were randomized to NAC (2400 mg daily) or placebo plus exercise for 6 months. WMH volumes were quantified using structural MRI. NPS were assessed using the Mild Behavioral Impairment Checklist (MBI-C) at baseline, 3 months, and 6 months. Negative binomial generalized linear mixed models examined WMH × time × treatment interactions. False discovery rate (FDR) correction was applied. Results: Fifty-one participants were included. Lower baseline frontal ( β = 0.229, SE = 0.070, FDR-adjusted p = 0.007) and global ( β = 0.258, SE = 0.080, FDR-adjusted p = 0.007) WMH volume was associated with greater reductions in NPS over 6 months in the NAC plus exercise group. This effect was driven by improvements in apathy (frontal: β = 0.186, SE = 0.076, FDR-adjusted p = 0.048; global: β = 0.207, SE = 0.089, FDR-adjusted p = 0.049). Conclusions: Baseline WMH burden moderates neuropsychiatric treatment response in vaMCI. These findings support the importance of optimizing care for cerebrovascular risk factors in this vulnerable population.

Objectives: To compare mental illness prevalence, and agreement between mental illness measures, in home care (HC) and long‐term care (LTC) using administrative definitions and Resident Assessment Instrument (RAI)‐diagnoses. Methods: Applying a common protocol to linked administrative‐RAI datasets in Alberta, Manitoba, and Ontario, Canada, we selected adults receiving HC or LTC between 2012 and 2023. Cross‐sectionally, we compared administrative definitions with RAI‐diagnoses (depression, anxiety, bipolar disorder and schizophrenia) using kappa, sensitivity, specificity, positive and negative predictive value. We examined discordance‐associated factors using multivariable logistic regression. Results: Depression was the most prevalent mental illness (administrative data, HC: 29%–34% of 493,895 people; LTC: 21%–51% of 357,117 people). Prevalence estimates were consistently lower using RAI‐diagnoses than administrative definitions. Agreement between data sources was moderate for depression ( k = 0.33–0.57) and anxiety disorders ( k = 0.35–0.63). Younger age, dementia, and more physician visits were associated with higher likelihood of discordance between data sources; male sex had a lower likelihood. Conclusion: While mental illness prevalence is high in HC and LTC populations, RAI‐based estimates are lower than administrative data estimates. Discordance between data sources differs by individual characteristics. Concurrent comparison of RAI‐diagnoses and administrative data to a gold standard clinical interview would clarify the optimal surveillance strategy.

Background: Limited epidemiologic data exists for mental illnesses among at-risk home care (HC) and residential long-term care (LTC) recipients. Objective: To estimate the annual prevalence (April 1, 2012-March 31, 2023) of various mental illnesses among HC and LTC populations (versus matched comparators) with and without dementia in the Canadian provinces of Ontario, Alberta, and Manitoba. Methods: Parallel repeated cross-sectional studies were conducted in each province using linked health administrative data. HC and LTC recipients aged ≥18 years were matched to comparators on demographics, dementia and comorbidity. Prevalence estimates were derived using validated case definitions for any mental illness, mood/anxiety disorders, depression and anxiety (with/without drug claims), schizophrenia, bipolar disorder and suicide attempt. Prevalence ratios (95% CIs) were estimated with modified Poisson regression models. Results: Included were 682,466 HC clients and 233,499 LTC residents. Mental illnesses were common in HC and LTC settings across all three provinces. Prevalence estimates were typically higher among care recipients versus matched comparators and among persons with versus without dementia. Up to 70% of HC clients and 80% of LTC residents with dementia had any mental illness; in both settings, 40% had mood/anxiety disorders, 4% bipolar disorders, and between 2%-6% schizophrenia. Suicide attempts were rare (0.5–0.6%). Prevalence varied by province and was higher for case algorithms including drug claims. Conclusions: The high prevalence of mental illness and its common co-occurrence with dementia in HC and LTC recipients illustrates the complexity and challenges of care in these populations and raises concerns about potential unmet mental health needs.

Background: Cognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions. Objective: To determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia. Methods: Nineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up. Results: In 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment ( β (SE) = 0.17(0.08) , p = 0.04, p _adj = 0.11, f ² = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up ( χ ² _LRT (3) = 24.9, p < 0.001). Conclusions: Lower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS. ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670 ; NCT02386670.

Objective: The Anticholinergic Drug Scale (ADS) is a commonly used measure of anticholinergic exposure. This study describes an expanded and revised version of the ADS (rADS) and its relationship with cultured cell‐based serum anticholinergic activity (cSAA) and cognitive measures.Study Participants: Adults aged 60 years and older with mild cognitive impairment (MCI), remitted major depressive disorder (rMDD), or both, participate in the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt‐MD) study.Study Design: Cross‐sectional investigation of data from the PACt‐MD study.Measures: The rADS includes ratings for 1047 distinct products, about twice as many as the originally published scale; previously published ratings were revised for 40 drugs. Total rADS scores were calculated as sums of ratings of all drugs taken by participants; cSAA was measured in the participants' sera; cognitive performance included measures of executive function, language, processing speed, verbal memory, visuospatial memory, working memory, and an overall composite score.Statistical Analysis: The relationship between rADS total scores and cSAA was examined using a Spearman rank correlation coefficient. Relationships between rADS total scores and cognitive performance measures were explored in multivariable linear regression models.Results: The sample included 310 participants (mean [standard deviation] age: 72 (6) years; 61.6% were women, and 81.6% had MCI [with or without rMDD]). Total rADS scores were positively correlated with cSAA (Spearman's correlation coefficient: 0.178, p = 0.0016). Total rADS scores were not significantly associated with cognitive performance.Conclusions: The revised scale is recommended as a replacement for the original ADS since it includes ratings for more drugs and was significantly, albeit weakly, associated with cSAA, similar to previous findings using the original ADS.

Objective: Changes in angiogenesis have been shown to contribute to cognitive decline and dementia. We aimed to identify angiogenesis blood markers associated with cognitive performance in older adults with mild cognitive impairment (MCI), remitted major depressive disorder (rMDD), or both (rMDD + MCI) who are at risk for dementia. Method: We analyzed data from participants with MCI, rMDD, or rMDD + MCI in the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression study. Elastic net regression was used to select variables associated with cognitive performance among 19 angiogenesis markers and 6 covariates. Linear regressions were used to determine which of the selected angiogenesis markers were associated with cognitive performance, controlling for the selected covariates. Significant angiogenesis markers were independently analyzed without other angiogenesis markers, controlling for covariates, with subgroup analyses in those with and without rMDD. Results: Angiogenin was the only selected marker associated with cognitive performance ( β = 0.28, P _adj = 0.03, f ² = .02) when controlling for other selected markers (endothelial cell-specific molecule 1, e-selectin, interleukin-33 [IL-33], oncostatin M, platelet-derived growth factor-AB, IL-33 receptor, and tissue inhibitor of metalloproteinases-1) and selected covariates (age, education, apolipoprotein E ε4 status, diagnosis, and cardiovascular risk factors). When independently analyzed, angiogenin remained positively associated with cognitive performance ( β = 0.21, P = 0.01, f ² =.02), controlling for the covariates. In subgroup analyses, angiogenin was also associated with cognition in rMDD and rMDD + MCI participants ( β =0.50, SE = 0.14, P < 0.001, f ² = 0.08) and in MCI-only participants ( β = 0.20, SE = 0.09 , P = 0.02, f ² = 0.02). Conclusion: The association of angiogenin with cognitive performance highlights a potentially novel biological pathway that could influence cognition in older adults at risk for dementia. Angiogenin may protect against cognitive decline, opening new avenues for innovative preventive, or therapeutic interventions.

Background: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer’s disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. Objective: To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. Method: Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. Results: Higher plasma NfL was correlated with worse MoCA scores at baseline ( β = −.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition ( b [SE] = −4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups ( F (1, 76) = 1.37, P = .245). Conclusion: Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.

Objective: Depression in later life is associated with a two-fold increased risk of dementia. It is not clear to what extent potentially modifiable risk factors account for this association. Method: Older adults (age 50 + ) with objective health measures ( n = 14,014) from the Canadian Longitudinal Study on Aging were followed for a mean duration of 35 months. Linear regression analyses were used to determine if clinically significant depression (Centre for Epidemiologic Studies Depression scale score (CESD) ≥ 10) was associated with global cognitive decline, assessed with a neuropsychological battery during follow-up, and if modifiable risk factors mediated this association. Results: Depression was associated with an excess of risk factors for cognitive decline including: vascular disease, hypertension, diabetes, apnoea during sleep, higher body mass index, smoking, physical inactivity and lack of social participation. In regression analyses depression remained independently associated with cognitive decline over time (beta −0.060, P = 0.038) as did cerebrovascular disease (beta −0.197, P < 0.001), HbA1C (beta −0.059, P < 0.001), visual impairment (beta −0.070, P = 0.007), hearing impairment (beta −0.098, P < 0.001) and physical inactivity (beta −0.075, P = 0.014). In mediation analyses, we found that cerebrovascular disease ( z = −3.525, P < 0.001), HbA1C ( z = −4.976, P < 0.001) and physical inactivity ( z = −3.998, P < 0.001) partially mediated the association between depression and cognitive decline. Conclusions: In this large sample of Canadian older adults incorporating several objective health measures, older adults with depression were at increased risk of cognitive decline and had an excess of potentially modifiable risk factors. Clinicians should pay particular attention to control of diabetes, physical inactivity and risk factors for cerebrovascular disease in older adults presenting with depression as they can contribute to accelerated cognitive decline and may be addressed during routine clinical care.