Tarek K. Rajji’s research while affiliated with University of Texas Southwestern Medical Center and other places

Introduction Mild Behavioral Impairment (MBI) is characterized by later‐life emergent and persistent neuropsychiatric symptoms (NPS) in older adults without dementia, serving as a potential precursor to various forms of dementia. This study explores the association between NPS and functional connectivity (FC) of the default mode network (DMN), executive control network (ECN), and salience network (SN) across three cohorts: mild cognitive impairment due to AD (MCI), cerebrovascular disease (CVD), and Parkinson's disease (PD). Additionally, the effect of CNS medication on NPS‐FC associations was explored. Methods Participants were recruited from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). NPS were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q). We used dual regression to generate subject‐specific whole‐brain FC maps of the DMN, ECN, and SN. Using permutation testing we examined the association between NPS scores and FC maps at baseline ( n = 349) and over a 2‐year period ( n = 225), controlling for age, sex, and years of education. A post‐hoc linear model was used to assess the effect of CNS medication on each significant NPI‐FC association within each group. Results In the MCI group ( n = 73), baseline disturbed nighttime behavior was positively correlated with functional connectivity (FC) between the anterior sensorimotor network. Longitudinally ( n = 46), appetite changes were positively associated with FC between the anterior SN and fusiform gyrus. Disinhibition and apathy correlated with FC between the posterior SN and DMN. In the CVD group ( n = 144), baseline anxiety was negatively associated with FC within the DMN and between the right ECN and DMN in the left hippocampus. Longitudinally ( n = 99), agitation/aggression changes were negatively associated with FC between the right ECN and left anterior cerebellum. Irritability, the most common symptom in both MCI and CVD, did not have identifiable neural correlates, possibly due to its complexity or analysis limitations. In the PD group ( n = 132), baseline disturbed nighttime behavior was positively associated with FC between the right ECN and DMN in the precuneus and left ECN and fusiform gyrus. Longitudinally ( n = 80), changes in nighttime behavior correlated with FC between the left ECN and DMN in the precuneus. CNS medications had no effect on NPI‐FC associations in the MCI group. In the CVD group, the absence of CNS medications was linked to decreased right ECN FC. In the PD group, Parkinson's medications changed the direction of the NPI night‐time score‐FC correlation at both baseline and the 2‐year assessment, with higher scores associated with reduced left ECN FC in medicated individuals. Conclusions In conclusion, our study highlights the critical role of the DMN, ECN, and SN in processing neuropsychiatric symptoms (NPS) across MCI, CVD, and PD populations. We found significant associations between NPS and functional connectivity (FC) within and between these networks. MCI and PD showed positive associations with FC, particularly for disturbed nighttime behavior, while CVD exhibited negative associations, notably with anxiety and agitation. Although irritability was common in both MCI and CVD groups, its neural correlates remain unclear, emphasizing the need for further investigation. These findings support existing literature and pave the way for targeted therapeutic approaches, such as brain stimulation, to alleviate NPS. Additionally, the complex role of CNS medications in modulating NPS and FC warrants further investigation.

Background: The COVID-19 pandemic has greatly increased the burden on the healthcare system, especially tertiary healthcare settings, such as hospitals. Hospitalization require a great amount of resources and cost, and often require patient follow-up and continued support to the patient once they are discharged. Older adults, a rapidly growing population that makes up a large proportion of Canadians has more hospitalizations, longer length of hospital stay and higher cost associated with hospitalizations. Older adults who comprised 14% of the Canadian population in 2011 occupied 40% of acute hospital care beds (1). Moreover, there is an essential need to support older adults post-discharge with different levels of support as they are more likely to be readmitted to the hospital and have decline in their activities of daily living (2). In Canada 12% of older adults discharged from the hospital are readmitted within 30 days (3). The use of digital interventions may be an innovative approach to tackle the limited healthcare resources including staffing shortages. This systematic review will identify points where digital health technologies can create innovative solutions to support integrative care at the community level in order to fill an ongoing gap in post-discharge follow-up and continuity of care Methods: Pubmed, Scopus and Web of Science were used for this systematic review. The following keywords were used (Digital OR Virtual OR Tele*) AND (management) AND (discharge) AND (Geriatric*). A total of 435 articles were identified in this search. Results: This is an ongoing study, results will be available in January 2024. Discussion: This systematic review will provide an overview of the different types of digital health technologies being used to follow up with older adults post-hospital discharge, the components that have been successfully implemented and barriers. Successful digital health technologies may reduce the resources and personnel required, reduce rehospitalizations and improve the continuity of care for older adults. References: https://www.cihi.ca/en/dementia-in-canada/dementia-care-across-the-health-system/dementia-in-hospitals Boyd CM, Landefeld CS, Counsell SR, Palmer RM, Fortinsky RH, Kresevic D, Burant C, Covinsky KE. Recovery of activities of daily living in older adults after hospitalization for acute medical illness. Journal of the American Geriatrics Society. 2008 Dec;56(12):2171-9. Gruneir A, Fung K, Fischer HD, Bronskill SE, Panjwani D, Bell CM, Dhalla I, Rochon PA, Anderson G. Care setting and 30-day hospital readmissions among older adults: a population-based cohort study. Cmaj. 2018 Sep 24;190(38):E1124-33.

Citalopram is effective in treating agitation in Alzheimer’s dementia (AD), but it is associated with cognitive and cardiac risks, likely due to its R-enantiomer. Escitalopram, the S-enantiomer, may be an alternative. In this double-masked randomized (1:1) placebo-controlled trial, we assessed the efficacy and safety of escitalopram in treating agitation in AD after failure of a psychosocial intervention (PSI). Assessments occurred at enrollment, post-PSI (baseline) and at 3, 6, 9 and 12 weeks post-baseline. Settings were 27 community-based centers. The target randomization sample was 392 participants. Participants were adults with AD, a Mini-Mental State Examination Telephone score of 3–20 and significant agitation. PSI non-responders received escitalopram (up to 15 mg per day) or placebo for 12 weeks while continuing PSI. The outcome was the proportion of participants with clinically significant improvement in agitation from baseline at 12 weeks. In total, 173 participants were randomized (84 escitalopram versus 89 placebo; mean ± s.d. age = 78.4 ± 8.7 years; 90 men (52.0%); 127 White (73.4%)). The unadjusted risk difference at 12 weeks was 0.08 (95% confidence interval: −0.21, 0.06). Drug-related QT interval prolongation was observed. Although the randomized sample was smaller than planned, escitalopram was not effective in treating agitation in AD and was associated with cardiac conduction delays. Clinicians need to be cautious in recommending escitalopram as an alternative to citalopram for this condition. ClincialTrials.gov identifier: NCT03108846.

Background and objectives: Plasma biomarkers of Alzheimer disease (AD), neuroinflammation, and neurodegeneration are increasingly being used in clinical trials for diagnosis and monitoring of dementia. However, their association with longitudinal structural brain MRI changes, an important outcome measure across neurodegenerative and cerebrovascular diseases, is less known. We investigated how baseline plasma biomarkers reflect MRI markers of progression over time in patients with neurodegenerative and cerebrovascular diseases. Methods: This longitudinal cohort study included patients from the Ontario Neurodegenerative Disease Research Initiative diagnosed with AD or mild cognitive impairment (AD/MCI), Parkinson disease (PD), frontotemporal dementia spectrum disorders (FTD), or cerebrovascular disease (CVD), followed annually for 2 years. Recruitment took place at specialized university-based dementia, movement disorders, and/or stroke clinics in the province of ON, Canada. MRI outcomes included markers of cerebral atrophy (ventricular CSF and regional gray matter volumes) and of small vessel disease pathology (white matter hyperintensity [WMH], perivascular spaces, and lacunar volumes). Hemorrhagic markers at baseline were also included. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau181 and tau217 (p-tau181, p-tau217), and β-amyloid (Aβ42/40) were quantified from blood samples collected at baseline using Simoa and used as predictors in linear mixed models adjusted for time (months), age, sex, apolipoprotein E (APOE)-ε4 carrier status, kidney function, vascular risk factors, microtubule-associated protein tau (MAPT) diplotypes, waist-hip circumference ratio, and disease duration. Results: We analyzed 1,240 MRIs from 473 patients (age: 69.2 ± 7.4 [range: 49-87]; 32.8% women). Elevated baseline levels of GFAP, NfL, p-tau181, and p-tau217, and to a lesser extent decreased levels of Aβ42/40, were significantly associated with more cerebral atrophy and WMH burden at baseline (|B| = 0.02 to 1.69, p = 0.044 to <0.001) and with progression over time (|B| = 0.001 to 0.028, p = 0.049 to <0.001) in the pooled disease-agnostic group. Within disease-specific cohorts, GFAP and NfL were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, PD, FTD, or CVD. P-tau181 and p-tau217 were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, CVD, PD-MCI, or PD-dementia. Discussion: Selected plasma biomarkers seem useful as prognosis and monitoring tools of longitudinal imaging changes within real-world populations of neurodegenerative and/or cerebrovascular diseases, and provide insight into overlap across diseases in shared pathologic burden.

Agitation, a common dementia symptom often arising from untreated pain, lacks comprehensive research on its connection with opioids prescribed for long-term pain. This study investigated the relationship between opioid use and agitation in dementia patients. Participants (n = 188) were categorized into opioid, acetaminophen PRN, or no-pain medication groups. Despite higher reported pain levels in the opioid group, no significant differences in agitation were observed among the groups. In conclusion, opioid use for pain management in older adults with dementia did not significantly impact agitation, emphasizing the ongoing importance of proper pain management in improving dementia care and addressing agitation in this population.

Background Drug development in Alzheimer’s disease (AD) over the past two decades has had high rates of failure. Novel trial designs, such as adaptive designs, have the potential to improve the efficiency of drug development in AD. Objective To evaluate the design characteristics, temporal trends, and differences in design between sponsor types in phase II trials of investigational agents in AD. Methods Phase I/II, II, and II/III trials for AD with drug or other biological interventions registered from December 1996 to December 2021 in ClinicalTrials.gov were included. Descriptive statistics were used to summarize trial characteristics. Linear, logistic, and multinomial regression models assessed temporal trends and differences between sponsor types in design characteristics. Results Of N = 474 trials identified, randomized parallel group design was the most common design (72%). Only 12 trials (2.5%) used an adaptive design; adaptive features included early stopping rules, model-based dose-finding, adaptive treatment arm selection, and response adaptive randomization. The use of non-randomized parallel-group and open-label single arm designs increased over time. No temporal trend in the use of adaptive design was identified. Trials sponsored by industry only were more likely to use a randomized parallel-group design and have a larger estimated sample size than trials with other sponsor types. Conclusion Our systematic review showed that very few phase II trials in AD used an adaptive trial design. Innovation and implementation of novel trial designs in AD trials can accelerate the drug development process.

[This corrects the article DOI: 10.1371/journal.pone.0277408.].

Background Late-life depression (LLD) is often accompanied by cognitive impairment, which may persist despite antidepressant treatment. Repetitive transcranial magnetic stimulation (rTMS) is an efficacious treatment for depression, with potential benefits on cognitive functioning. However, research on cognitive effects is inconclusive, relatively sparse in LLD, and predominantly focused on group-level cognitive changes. This study aimed to explore individual-level cognitive changes following rTMS treatment in patients with LLD. Method Data were analyzed from 153 patients with LLD from the FOUR-D study (ClinicalTrials.gov identifier: NCT02998580) who received bilateral standard rTMS or theta burst stimulation (TBS) targeting the dorsolateral prefrontal cortex (DLPFC). Cognitive function was assessed pre- and post-treatment using measures of executive function, information processing speed, and learning and memory. Reliable change indices, adjusted for practice effects and test-retest reliability, were employed to evaluate individual-level cognitive changes. Chi-square tests examined if proportions of cognitive improvers differed from expected proportions. Results Cognitive performance from baseline to end of treatment remained stable for most patients. Reliably improved performance was observed in 0.0% to 20.0% of participants across cognitive measures, while worsened performance was observed in 0.0% to 2.7%. A small but significant proportion (20.0%) of participants showed improvement in verbal learning. Conclusions Bilateral standard rTMS or TBS of the DLPFC in LLD yielded no substantial cognitive enhancing effects, although a small proportion showed improved verbal learning after treatment. Importantly, both interventions were cognitively safe with relatively stable performance across time. Future research is needed to explore approaches to enhance the cognitive benefits of standard rTMS and TBS in patients with LLD.

Background Neuropsychiatric symptoms (NPS) constitute a major challenge for patients with Alzheimer’s disease (AD). We have recently demonstrated that in AD, overall NPS burden is significantly associated with patient function. However, few studies have examined the relationship between specific symptom clusters with neurological biomarkers. Therefore, we identified NPS clusters in AD and explored their association with structural neuroimaging markers. Method Participants with AD (N = 111) were included from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). NPS were assessed using the neuropsychiatric inventory questionnaire (NPI‐Q), and symptom clusters were identified through exploratory factor analysis. The Semi‐Automatic Brain Region Extraction (SABRE) pipeline was used to compute regional cortical thickness and subcortical volumes using participant MRI data. We then evaluated correlations between symptom clusters with subcortical volumes and regional cortical thickness. Result Factor analysis identified four symptom clusters explaining 62% of the variance. These were labeled as “behavioral” (disinhibition, irritability, motor disturbance, and agitation), “psychotic” (hallucinations, delusions, and euphoria), “neurovegetative” (apathy and appetite), and “affective” (depression, anxiety, nighttime behavior) clusters. The psychotic cluster was associated with increased cortical thickness in bilateral frontal regions, the left inferior parietal lobe (r=0.23, p=0.02), and with left anterior cingulate volumes (r=0.21, p=0.03). The neurovegetative cluster was associated with reductions in volume among bilateral frontal and right‐sided temporal and parietal regions. The affective cluster was associated with increased left anterior cingulate volume (r=0.21, p=0.03). Conclusion NPS symptom clusters in AD separate into behavioral, psychotic, neurovegetative, and affective dimensions. These symptom groups demonstrate unique associations with neuroimaging markers.

Background N‐acetyl‐aspartate (NAA) and myo‐inositol (mI) are neurometabolites reflecting neuronal viability and astrocyte activity, respectively. These can be quantified in vivo using proton magnetic resonance spectroscopy (1H‐MRS). Previous studies have suggested that these metabolites could serve as biomarkers for Alzheimer’s disease dementia (AD). NAA and mI levels were compared in the dorsolateral prefrontal cortex (DLPFC) between AD and cognitively healthy control participants to assess for significant differences, assess if NAA/mI ratio can distinguish the two groups, and to explore the relationship between metabolites and cognition. Method Participants with AD and HCs over 55 years old were included. Bilateral NAA and mI levels were quantified in the DLPFC using 3T proton magnetic resonance spectroscopy (point‐resolved spectroscopy, echo time=35ms). NAA and mI levels were estimated using LCmodel version 6.3 and reported in H2O ratios i.e. NAA/ H2O or mI/H2O. Result The study included 64 participants, 41 with AD (mean (SD) age = 75.2 (7.2) years, females = 58.5%), and 23 HC (age = 72.2 (7.7) years, females = 60.1%). Bilateral NAA levels in the DLPFC were lower in AD vs. HC, (t(62)=‐2.5, p =0.02); however, mI levels in the DLPFC did not differ between the two groups t(62)=1.0, p=0.35. NAA/mI ratio was lower in AD vs. healthy (t(62)= ‐2.368, p =0.02). The NAA/mI ratio at a cut off value of 1.69 showed 59% sensitivity and 87% specificity at distinguishing AD from HC. NAA levels were associated positively with global cognition. Conclusion DLPFC NAA is decreased in AD and is associated with cognition. NAA/mI ratio shows good specificity in distinguishing AD from the control group, suggesting its role in complementing other biomarkers in ascertaining AD. Future studies should prospectively evaluate the clinical utility of NAA/mI ratio as a biomarker in AD.