Journal of Alzheimer's Disease - Volume 86, issue 4

Authors: Saari, Toni | Koivisto, Anne | Hintsa, Taina | Hänninen, Tuomo | Hallikainen, Ilona

Article Type: Review Article

Abstract: Neuropsychiatric symptoms cause a significant burden to individuals with neurocognitive disorders and their families. Insights into the clinical associations, neurobiology, and treatment of these symptoms depend on informant questionnaires, such as the commonly used Neuropsychiatric Inventory (NPI). As with any scale, the utility of the NPI relies on its psychometric properties, but the NPI faces unique challenges related to its skip-question and scoring formats. In this narrative review, we examined the psychometric properties of the NPI in a framework including properties pertinent to construct validation, and health-related outcome measurement in general. We found that aspects such as test-retest and inter-rater …reliability are major strengths of the NPI in addition to its flexible and relatively quick administration. These properties are desired in clinical trials. However, the reported properties appear to cover only some of the generally examined psychometric properties, representing perhaps necessary but insufficient reliability and validity evidence for the NPI. The psychometric data seem to have significant gaps, in part because small sample sizes in the relevant studies have precluded more comprehensive analyses. Regarding construct validity, only one study has examined structural validity with the NPI subquestions. Measurement error was not assessed in the reviewed studies. For future validation, we recommend using data from all subquestions, collecting larger samples, paying specific attention to construct validity and formulating hypotheses a priori . Because the NPI is an outcome measure of interest in clinical trials, examining measurement error could be of practical importance. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, measurement, Neuropsychiatric Inventory, neuropsychiatric symptoms, reliability, validity

DOI: 10.3233/JAD-200739

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1485-1499, 2022

Authors: Choi, Hyunjung | Lee, Dongjoon | Mook-Jung, Inhee

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the most common neurodegenerative disorder, is accompanied by cognitive impairment and shows representative pathological features, including senile plaques and neurofibrillary tangles in the brain. Recent evidence suggests that several systemic changes outside the brain are associated with AD and may contribute to its pathogenesis. Among the factors that induce systemic changes in AD, the gut microbiota is increasingly drawing attention. Modulation of gut microbiome, along with continuous attempts to remove pathogenic proteins directly from the brain, is a viable strategy to cure AD. Seeking a holistic understanding of the pathways throughout the body that can affect the …pathogenesis, rather than regarding AD solely as a brain disease, may be key to successful therapy. In this review, we focus on the role of the gut microbiota in causing systemic manifestations of AD. The review integrates recently emerging concepts and provides potential mechanisms about the involvement of the gut-brain axis in AD, ranging from gut permeability and inflammation to bacterial translocation and cross-seeding. Show more

Keywords: Alzheimer’s disease, gut-brain axis, gut microbiota, systemic inflammation

DOI: 10.3233/JAD-215235

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1501-1526, 2022

Authors: Tu, Jennifer Young | Jin, Grace | Chen, Jen-Hau | Chen, Yen-Ching

Article Type: Systematic Review

Abstract: Background: As the demand for dementia care grows rapidly worldwide, heavy “caregiver burden” has been associated with stress and depression. Even so, standard metrics for interdisciplinary research of caregiver burden are limited. Objective: The objective of the present review is to recommend valid, reliable, and comprehensive self-report instruments of caregiver burden. Methods: A systematic review was performed using four databases, searched in April 2021. Articles that established or evaluated self-report instruments for dementia caregiver burden were included, while studies that involved non-dementia caregivers or did not clearly define caregiver burden were excluded. Established guidelines for reliability …and agreement studies were used to assess quality and risk of bias. Assessments of self-report instruments were made based on reliability, validity, feasibility, and quality of psychometric evaluations, and comparative evaluations were presented in visual form using radar graphs. Results: Search terms yielded 1,720 articles, and 40 were included in the systematic review after excluding those of low quality. Based on the results of these studies, we recommend the Zarit Burden Interview, Screen for Caregiver Burden, Caregiver Burden Interview, and Burden Scale for Family Caregivers, due to their validity, reliability, and inclusion of multiple subjective and objective dimensions of burden. Conclusion: Targeting specific sources of caregiver burden can help prevent negative outcomes for both dementia patients and caregivers. Future studies should apply self-report instruments to measure and address caregiver burden longitudinally. Show more

Keywords: Alzheimer’s disease, caregiver burden, caregivers, dementia, geriatric psychiatry, psychometrics

DOI: 10.3233/JAD-215082

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1527-1543, 2022

Authors: Parker, Ashleigh F. | Ohlhauser, Lisa | Scarapicchia, Vanessa | Smart, Colette M. | Szoeke, Cassandra | Gawryluk, Jodie R.

Article Type: Systematic Review

Abstract: Background: Individuals with subjective cognitive decline (SCD) are hypothesized to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (AD), although more research is needed on this topic. Given that treatment approaches may be most effective pre-clinically, a primary objective of emerging research is to identify biological markers of SCD using neuroimaging methods. Objective: The current review aimed to comprehensively present the neuroimaging studies on SCD to date. Methods: PubMed and PsycINFO databases were searched for neuroimaging studies of individuals with SCD. Quality assessments were completed using the Appraisal tool for Cross-Sectional …Studies. Results: In total, 62 neuroimaging studies investigating differences between participants with SCD and healthy controls were identified. Specifically, the number of studies were as follows: 36 MRI, 6 PET, 8 MRI/PET, 4 EEG, 7 MEG, and 1 SPECT. Across neuroimaging modalities, 48 of the 62 included studies revealed significant differences in brain structure and/or function between groups. Conclusion: Neuroimaging methods can identify differences between healthy controls and individuals with SCD. However, inconsistent results were found within and between neuroimaging modalities. Discrepancies across studies may be best accounted for by methodological differences, notably variable criteria for SCD, and differences in participant characteristics and risk factors for AD. Clinic based recruitment and cross-sectional study design were common and may bias the literature. Future neuroimaging investigations of SCD should consistently incorporate the standardized research criteria for SCD (as recommended by the SCD-Initiative), include more details of their SCD sample and their symptoms, and examine groups longitudinally. Show more

Keywords: Healthy controls, neuroimaging, subjective cognitive decline, systematic review

DOI: 10.3233/JAD-215249

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1545-1567, 2022

Authors: Colverson, Aaron J. | Trifilio, Erin | Williamson, John B.

Article Type: Review Article

Abstract: Background: Music-based interventions may help to alleviate neuropsychiatric symptoms of dementia and promote prosocial interactions between individuals living with dementia and their caregivers. However, current literature does not combine these evidence bases toward explanation of how music-based interventions may alleviate symptoms and promote prosocial interactions. Objective: We conducted a scoping review to address the following question: what do the evidence bases suggest toward how music therapy or music-based therapeutic interventions might promote prosocial interactions between individuals living with dementia and their caregivers? Methods: In this review we focused on: 1) quantitative and qualitative evidence of music-based …therapies promoting prosocial behaviors in individuals living with dementia, and 2) potential neurobehavioral mechanisms associated with the processes involved with how music may promote prosocial interactions. Databases included PubMed, EBSCOhost’s CINAHL and PsycINFO, Cochrane Library (sub-search conducted using ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), Web of Science, clinicaltrials.gov, ProQuest’s Biological Science Collection, the Journal of Music Therapy, Nordic Journal of Music Therapy , and Google Scholar. Results: Sixteen original research studies were included for evidence synthesis. This scoping review reveals the need to define and clarify mechanisms of prosocial interactions between individuals living with dementia and their caregivers considering biological and social factors. These mechanisms may include dynamic interactions between preserved brain regions associated with music-evoked autobiographical memory recall and shifts from negative to positive mood states. Conclusion: Defining and clarifying how and to what extent music may promote prosocial behaviors using well-designed and well-controlled mixed-methods studies may positively influence the design of interventions to promote prosocial interactions with caregivers. Show more

Keywords: Alzheimer’s disease, caregiver distress, dementia, mood, music, social factors

DOI: 10.3233/JAD-215199

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1569-1588, 2022

Authors: Ho, Bo-Lin | Hsieh, Sun-Wung | Chou, Ping-Song | Yang, Yuan-Han

Article Type: Systematic Review

Abstract: Background: Patients with atrial fibrillation (AF) carry higher risks of cognitive consequences and psychological burden. An optimal anticoagulant therapy would be expected to better preserve neuropsychological function in addition to effective prevention of stroke and systemic thromboembolism. Objective: The aim of this review is to explore the effects of the non-vitamin K antagonist oral anticoagulant (NOAC) dabigatran, a direct thrombin inhibitor, on cognitive and psychological function as well as dementia pathogenesis. Methods: We performed a comprehensive search of PubMed/Medline for all types of relevant articles using a combination of dabigatran and associated keywords updated to August …31, 2021. All titles and abstracts were screened for eligibility, and potentially relevant papers were collected for inclusion. Results: The pooled results demonstrated neutral to positive impacts of dabigatran on cognitive and psychological outcomes, including laboratory results in animal models of Alzheimer’s disease, and reduced incidences of anxiety/depression and dementia for AF patients. Dabigatran also exhibited better therapeutic profiles than warfarin in preclinical and observational research. Conclusion: Given limited strength of evidence from heterogeneous studies, our review proposed modest beneficial effects of dabigatran on neuropsychological function. Further clinical trials are warranted to affirm the pleiotropic protective effects of NOACs on dementia treatment. Show more

Keywords: Anticoagulant, atrial fibrillation, cognitive, dabigatran, dementia, psychological function

DOI: 10.3233/JAD-215513

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1589-1601, 2022

Authors: Jacobs, Heidi I.L. | O’Donnell, Adrienne | Satizabal, Claudia L. | Lois, Cristina | Kojis, Daniel | Hanseeuw, Bernard J. | Thibault, Emma | Sanchez, Justin S. | Buckley, Rachel F. | Yang, Qiong | DeCarli, Charles | Killiany, Ron | Sargurupremraj, Muralidharan | Sperling, Reisa A. | Johnson, Keith A. | Beiser, Alexa S. | Seshadri, Sudha

Article Type: Short Communication

Abstract: The brainstem is among the first regions to accumulate Alzheimer’s disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-β or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

Keywords: Aging, amyloid, brainstem, tau

DOI: 10.3233/JAD-215372

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1603-1609, 2022

Authors: Krishna-K, Kumar | Behnisch, Thomas | Sajikumar, Sreedharan

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) is characterized by memory and cognitive deficits that in part are related to a diminished ability to activity-dependent synaptic plasticity. In AD, an attenuated long-term potentiation has been correlated with a deficit of synaptic plasticity-relevant proteins and protein turnover. The ubiquitin-proteasome system (UPS) critically regulates the protein turnover and contributes to dynamic changes of the protein milieu within synapses. In AD, UPS aberration has been implicated in inadequate proteostasis and synaptic malfunction. However, here we show that the inhibition of proteasome-mediated protein degradation by MG132 or lactacystin restored an impaired activity-dependent synaptic plasticity in an AD-like mouse …model. In this whole-cell voltage-clamp study, we provided evidence that an amelioration of long-term plasticity by modulating UPS activity in pyramidal neurons. Show more

Keywords: Alzheimer’s disease, hippocampus, lactacystin, long-term potentiation, MG132, protein degradation, proteostasis, synaptic plasticity, ubiquitin-proteasome system

DOI: 10.3233/JAD-215718

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1611-1616, 2022

Authors: Koncz, Rebecca | Wen, Wei | Makkar, Steve R. | Lam, Ben C.P. | Crawford, John D. | Rowe, Christopher C. | Sachdev, Perminder | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (SVD) and Alzheimer’s disease pathology, namely amyloid-β (Aβ) deposition, commonly co-occur. Exactly how they interact remains uncertain. Objective: Using participants from the Alzheimer’s Disease Neuroimaging Initiative (n  = 216; mean age 73.29±7.08 years, 91 (42.1%) females), we examined whether the presence of vascular risk factors and/or baseline cerebral SVD was related to a greater burden of Aβ cross-sectionally, and at 24 months follow-up. Method: Amyloid burden, assessed using 18 F-florbetapir PET, was quantified as the global standardized uptake value ratio (SUVR). Multimodal imaging was used to strengthen the quantification of baseline SVD …as a composite variable, which included white matter hyperintensity volume using MRI, and peak width of skeletonized mean diffusivity using diffusion tensor imaging. Structural equation modeling was used to analyze the associations between demographic factors, Apolipoprotein E ɛ4 carrier status, vascular risk factors, SVD burden and cerebral amyloid. Results: SVD burden had a direct association with Aβ burden cross-sectionally (coeff. = 0.229, p  = 0.004), and an indirect effect over time (indirect coeff. = 0.235, p  = 0.004). Of the vascular risk factors, a history of hypertension (coeff. = 0.094, p  = 0.032) and a lower fasting glucose at baseline (coeff. = –0.027, p  = 0.014) had a direct effect on Aβ burden at 24 months, but only the direct effect of glucose persisted after regularization. Conclusion: While Aβ and SVD burden have an association cross-sectionally, SVD does not appear to directly influence the accumulation of Aβ longitudinally. Glucose regulation may be an important modifiable risk factor for Aβ accrual over time. Show more

Keywords: Amyloid, cerebral small vessel disease, hypertension, peak width of skeletonized mean diffusivity, positron emission tomography, white matter hyperintensities

DOI: 10.3233/JAD-210358

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1617-1628, 2022

Authors: Ghani, Zartashia | Saha, Sanjib | Jarl, Johan | Andersson, Martin | Berglund, Johan Sanmartin | Anderberg, Peter

Article Type: Research Article

Abstract: Background: A randomized controlled trial of the SMART4MD tablet application was conducted for persons with mild cognitive impairment (PwMCI) and their informal caregivers to improve or maintain quality of life. Objective: The objective was to conduct economic evaluation of SMART4MD compared to standard care in Sweden from a healthcare provider perspective based on a 6-month follow-up period. Methods: Three hundred forty-five dyads were enrolled: 173 dyads in the intervention group and 172 in standard care. The primary outcome measures for PwMCI and informal caregivers were quality-adjusted life years (QALY). The results are presented as incremental cost-effectiveness …ratios, and confidence intervals are calculated using non-parametric bootstrap procedure. Results: For PwMCI, the mean difference in total costs between intervention and standard care was € 12 (95% CI: –2090 to 2115) (US$ = € 1.19) and the mean QALY change was –0.004 (95% CI: –0.009 to 0.002). For informal caregivers, the cost difference was – € 539 (95% CI: –2624 to 1545) and 0.003 (95% CI: –0.002 to 0.008) for QALY. The difference in cost and QALY for PwMCI and informal caregivers combined was –€ 527 (95% CI: –3621 to 2568) and –0.001 (95% CI: –0.008 to 0.006). Although generally insignificant differences, this indicates that SMART4MD, compared to standard care was: 1) more costly and less effective for PwMCI, 2) less costly and more effective for informal caregivers, and 3) less costly and less effective for PwMCI and informal caregivers combined. Conclusion: The cost-effectiveness of SMART4MD over 6 months is inconclusive, although the intervention might be more beneficial for informal caregivers than PwMCI Show more

Keywords: Carer, cost-effectiveness, economic evaluation, elderly, memory, mHealth, mild cognitive impairment, mild dementia, mobile application, smartphone

DOI: 10.3233/JAD-215013

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1629-1641, 2022