Journal of Alzheimer's Disease - Volume 81, issue 4

Authors: Waller, Michael | Buckley, Rachel F. | Masters, Colin L. | Nona, Francis R. | Eades, Sandra J. | Dobson, Annette J.

Article Type: Research Article

Abstract: Background: The prevalence of dementia is generally reported to be higher among Indigenous peoples. Objective: The rates and coding of dementia mortality were compared between Indigenous and non-Indigenous Australians. Methods: De-identified individual records on causes of death for all people aged 40 years or more who died in Australia between 2006 and 2014 (n  = 1,233,084) were used. There were 185,237 records with International Classification of Diseases, Tenth Revision , codes for dementia (Alzheimer’s Disease, vascular dementia, or unspecified dementia) as the underlying cause of death or mentioned elsewhere on the death certificate. Death rates were compared …using Poisson regression. Logistic regression was used to assess whether dementia was more likely to be classified as ‘unspecified’ type in Indigenous Australians. Results: The rates of death with dementia were 57% higher in Indigenous Australians, compared to non-Indigenous, relative rate (RR) 1.57, 95% confidence interval (CI) (1.48, 1.66), p  < 0.0001. This excess of deaths was highest at ages below 75 (RRs > 2, test for interaction p  < 0.0001), and among men (test for interaction p  < 0.0001). When the underreporting of Indigenous status on the death certificate was taken into account the relative rate increased to 2.17, 95% CI (2.07, 2.29). Indigenous Australians were also more likely to have their dementia coded as ‘unspecified’ on their death certificate (Odds Ratio 1.92, 95% CI (1.66, 2.21), p  < 0.0001), compared to the non-Indigenous group. Conclusion: This epidemiological analysis based on population level mortality data demonstrates the higher dementia-related mortality rate for Indigenous Australians especially at younger ages. Show more

Keywords: Alzheimer’s disease, dementia, Indigenous, mortality, population-level studies, rural, unspecified dementia, vascular dementia

DOI: 10.3233/JAD-201175

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1589-1599, 2021

Authors: Kobayashi, Nobuyuki | Shinagawa, Shunichiro | Nagata, Tomoyuki | Tagai, Kenji | Shimada, Kazuya | Ishii, Azusa | Oka, Naomi | Shigeta, Masahiro | Kondo, Kazuhiro

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) cause a heavy burden for both patient and caregivers. These symptoms are diverse, and their mechanism is still unclear. Agitation is the most common and difficult to treat among BPSD. In recent years, while changes in DNA methylation levels have been receiving attention as a biomarker of aging and dementia, associations with BPSD have not been examined. Objective: Focusing on agitation, the objective of the present study was to identify a region where changes in DNA methylation levels are associated with agitation. Methods: Using genome-wide DNA methylation analysis …data for 7 dementia subjects with agitation, 5 dementia subjects without agitation, and 4 normal elderly controls, we determined a signaling pathway in the WNT5A gene promoter region to be associated with agitation. Based on this result, we measured DNA methylation levels in this region for 26 dementia subjects with agitation and 82 dementia subjects without agitation by means of methylation-sensitive high-resolution melting (MS-HRM) analysis. Results: The WNT5A DNA methylation level in dementia subjects with agitation was significantly lower than in those without agitation (p  = 0.001). Changes in WNT5A DNA methylation levels were not influenced by age, sex, body mass index, APOE ɛ4, medication, or inflammatory cytokines. Conclusion: Our results suggested an association of agitation with Wnt signaling, in particular with changes in WNT5A DNA methylation levels, which could be a potentially useful biomarker for predicting the appearance of agitation. It may contribute to the elucidation of the mechanism of BPSD. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, DNA methylation, epigenetics, Wnt signaling pathway, WNT5A

DOI: 10.3233/JAD-210078

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1601-1611, 2021

Authors: Almkvist, Ove | Brüggen, Katharina | Nordberg, Agneta

Article Type: Research Article

Abstract: Background: The effect of regional brain amyloid-β (Aβ) pathology on specific cognitive functions is incompletely known. Objective: The relationship between Aβ and cognitive functions was investigated in this cross-sectional multicenter study of memory clinic patients. Methods: The participants were patients diagnosed with Alzheimer’s disease (AD, n  = 83), mild cognitive impairment (MCI, n  = 60), and healthy controls (HC, n  = 32), who had been scanned by 11 C-PiB PET in 13 brain regions of both hemispheres and who had been assessed by cognitive tests covering seven domains. Results: Hierarchic multiple regression analyses were performed on each …cognitive test as dependent variable, controlling for demographic characteristics and APOE status (block 1) and PiB measures in 13 brain regions (block 2) as independent variables. The model was highly significant for each cognitive test and most strongly for tests of episodic memory (learning and retention) versus PiB in putamen, visuospatially demanding tests (processing and retention) versus the occipital lobe, semantic fluency versus the parietal lobe, attention versus posterior gyrus cinguli, and executive function versus nucleus accumbens. In addition, education had a positively and APOE status a negatively significant effect on cognitive tests. Conclusion: Five subcortical and cortical regions with Aβ pathology are differentially associated with cognitive functions and stages of disease in memory clinic patients. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive functions, mild cognitive impairment, pittsburgh compound-B (PiB), positron emission tomography, regional Aβ pathology

DOI: 10.3233/JAD-201612

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1613-1624, 2021

Authors: Hunter, Matthew B. | Jenkins, Natalie | Dolan, Clare | Pullen, Hannah | Ritchie, Craig | Muniz-Terrera, Graciela

Article Type: Research Article

Abstract: Background: Telephone and videoconference administration of cognitive tests introduce additional sources of variance compared to in-person testing. Reviews of test-retest reliability have included mixed neurocognitive and psychiatric populations with limited consideration of methodological and statistical contributions. Objective: We reviewed reliability estimates from comparison studies of older adults with and without dementia, considering test-retest analyses and study methods. Methods: Medline, Embase, PsycINFO, and Web of Science were systematically searched from 1 January 2000 to 9 June 2020 for original articles comparing telephone or videoconference administered cognitive instruments to in-person administration in older adults with and without dementia …or mild cognitive impairment. Results: Of 4,125 articles, 23 were included: 11 telephone (N = 2 dementia cohorts) and 12 videoconference (N = 4 dementia cohorts). Telephone administered subtest scores trended in the same direction as in-person with comparable means. Person-level data were scarce. Data on dementia was only available for MMSE, with resulting subtle modality bias. MMSE, SMMSE, Letter Fluency, and HVLT-R in healthy to mild-moderate Alzheimer’s disease were particularly reliable for videoconference administration. Other tests show promise but require more observations and comprehensive analyses. Most studies used high-speed stable videoconferencing hardware resulting in a lack of ecological validity for home administration. Conclusion: Remote administration is often consistent with in-person administration but variable and limited at the person/test level. Improved statistical design and inclusion of dementia related cohorts in telephone studies is recommended. Reliability evidence is stronger for videoconferencing but with limited applicability to home administration and severe dementia. Improved reporting of administrative procedures is recommended. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, neuropsychological assessment, telehealth, telemedicine, teleneuropsychology

DOI: 10.3233/JAD-210088

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1625-1647, 2021

Authors: Hannestad, Jonas | Duclos, Tiffanie | Chao, Whitney | Koborsi, Katie | Klutzaritz, Vicki | Beck, Brian | Patel, Ashok K. | Scott, James | Thein, Stephen G. | Cummings, Jeffrey L. | Kay, Gary | Braithwaite, Steven | Nikolich, Karoly

Article Type: Research Article

Abstract: Background: The plasma fraction GRF6019 shows multiple benefits on brain aging in mice, including enhanced cognition, neurogenesis, and synaptic density, as well as reduced neuroinflammation. Objective: To evaluate the safety, tolerability, and preliminary efficacy of GRF6019 in patients with severe Alzheimer’s disease (AD). Methods: A phase II, double-blind, placebo-controlled study in patients with severe AD (Mini-Mental State Examination score 0–10). Patients were randomized 2 : 1 to GRF6019 (N = 18) or placebo (N = 8) and received daily 250 mL intravenous infusions over 5 days. The primary endpoints were the rates of adverse events (AEs) and the tolerability of GRF6019 as assessed …by the number of patients completing the study. Change from baseline in cognitive and functional assessments was also evaluated. Results: All patients completed 100%of study visits and infusions. The rate of AEs was similar in the GRF6019 (8/18 patients [44.4%]) and placebo (3/8 patients [37.5%]) groups, and there were no deaths or serious AEs. The most common AEs considered related to treatment were mild, transient changes in blood pressure in the GRF6019 group (hypotension: 2 patients [11.1%]; hypertension: 1 patient [5.6%]); there were no related AEs in the placebo group. The trial was not powered to detect statistically significant differences between treatment groups. At the end of the study, patients in both treatment groups remained stable or improved on all cognitive and functional endpoints. Conclusion: GRF6019 demonstrated excellent safety, feasibility, and tolerability. Future trials designed to characterize the potential functional benefits of GRF6019 and related plasma fractions in severe AD are warranted. Show more

Keywords: Aging, Alzheimer’s disease, blood proteins, dementia, plasma, randomized controlled trial

DOI: 10.3233/JAD-210011

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1649-1662, 2021

Authors: Subotic, Arsenije | McCreary, Cheryl R. | Saad, Feryal | Nguyen, Amanda | Alvarez-Veronesi, Ana | Zwiers, Angela M. | Charlton, Anna | Beaudin, Andrew E. | Ismail, Zahinoor | Pike, G. Bruce | Smith, Eric E.

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood. Objective: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA. Methods: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements …were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region. Results: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) –0.047 mm, 95% confidence interval (CI) –0.088, –0.005, p  = 0.03), and lower in AD compared to CAA (MD –0.104 mm, 95% CI –0.165, –0.043, p  = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD –0.07 mm, 95% CI –0.13 to –0.01, p  = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2  = 0.10; p  = 0.05) and higher white matter hyperintensity volume (R2  = 0.09, p  = 0.04). Conclusion: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cortical thickness, cognition, MRI, neurodegeneration

DOI: 10.3233/JAD-210138

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1663-1671, 2021

Authors: Du, Yan | Dennis, Brittany | Liu, Jia | Meyer, Kylie | Siddiqui, Nazish | Lopez, Katrina | White, Carole | Myneni, Sahiti | Gonzales, Mitzi | Wang, Jing

Article Type: Research Article

Abstract: Background: As the population rapidly ages, a growing number of families are engaging in care for individuals living with Alzheimer’s disease and related dementias (ADRD). The perceived challenges and burdens that face informal caregivers are enormous. Objective: The objective of this study was to 1) explore from the family caregivers’ perspective, the daily lives of individuals living with ADRD, and the challenges family caregivers encounter when caring for a family member with ADRD; and 2) to develop a comprehensive model with the endeavor to improve care for individuals with ADRD and their family caregivers. Methods: Posts …were extracted from the ALZConnected online caregiving forum in May 2019. Guided by a triangular model focused on Caregiver, Individual with ADRD , and Context of Care, two researchers independently analyzed 654 posts with a combination of deductive and inductive thematic analysis approach. Researchers all agreed on finalized codes and themes. Results: Thematic analysis resulted in four themes: Individual with ADRD , Caregiver, Dynamic between Caregiver and Individual with ADRD, and Context of Care . The most frequently discussed topics among caregivers were informational and emotional support for caregivers, and the capabilities and functioning of individuals with ADRD. Conclusion: Online forums provide a valuable platform for caregivers to support each other informationally and emotionally, share care strategies, and navigate caregiving burdens. An expanded model was derived to support a comprehensive and dynamic approach to improve care for both caregivers and individuals with ADRD. The unique nature of the caregiver forum data is worthy of further data mining using a novel analysis approach. Show more

Keywords: Alzheimer’s disease, caregiver, dementia, peer group, quality of life, support, technology

DOI: 10.3233/JAD-210167

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1673-1684, 2021

Authors: Ji, Mu-huo | He, Xue | Shen, Jin-chun | Yang, Jian-jun

Article Type: Research Article

Abstract: Background: Accumulating evidence has demonstrated that aging is associated with an exaggerated response to surgical trauma together with cognitive impairments. This has significant implications for the development of clinical phenotype such as perioperative neurocognitive disorders (PND), which is a common complication following surgery, especially for the elderly. However, the mechanism by which aging brain is vulnerable to surgical trauma remains to be elucidated. Objective: To test whether age-related alterations in hippocampal network activities contribute to increased risk of PND following surgery. Methods: Thirty-two adult and seventy-two aged male C57BL/6 mice undergone sevoflurane anesthesia and exploratory laparotomy …were used to mimic human abdominal surgery. For the interventional study, mice were treated with minocycline. Behavioral tests were performed post-surgery with open field, novel object recognition and fear conditioning tests, respectively. The brain tissues were then harvested and subjected to biochemistry studies. Local field potential (LFP) recording was performed in another separate experiment. Results: Aged mice displayed signs of neuroinflammation, as reflected by significantly increased proinflammatory mediators in the hippocampus. Also, aged mice displayed persistently decreased oscillation activities under different conditions, both before and after surgery. Further correlation analysis suggested that theta power was positively associated with time with novel object, while γ oscillation activity was positively associated with freezing time to context. Of note, downregulation of neuroinflammation by microglia inhibitor minocycline reversed some of these abnormities. Conclusion: Our study highlights that age-related hippocampal oscillation dysregulation increases the risk of PND incidence, which might provide diagnostic/prognostic biomarkers for PND and possible other neurodegenerative diseases. Show more

Keywords: Aging, cognitive function, inflammation, microglia, oscillation

DOI: 10.3233/JAD-201590

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1685-1699, 2021

Authors: Xu, Wei | Tan, Chen-Chen | Zou, Juan-Juan | Cao, Xi-Peng | Tan, Lan | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: It is suggested that not all individuals with elevated Aβ will develop dementia or cognitive impairment. Environment or lifestyle might modulate the association of amyloid pathology with cognition. Insomnia is a risk factor of cognitive disorders including Alzheimer’s disease. Objective: To investigate if insomnia moderated the relationship between amyloid-β (Aβ) and longitudinal cognitive performance in non-demented elders. Methods: A total of 385 Alzheimer’s Disease Neuroimaging Initiative participants (mean age = 73 years, 48% females) who completed 4 + neuropsychological evaluations and a [18 F] florbetapir positron emission tomography scan were followed up to 8 years. Linear mixed-effects regression models …were used to examine the interactions effect between insomnia and Aβ on longitudinal cognitive sores, including four domains (memory [MEM], executive function [EF], language [LAN], and visuospatial function [VS]). Results: The Aβ-positive status (A +) but not insomnia independently predicted faster cognitive decline in all domains. Furthermore, the relationship between Aβ and cognitive decline was moderated by insomnia (MEM: χ 2  = 4.05, p  = 0.044, EF: χ 2  = 4.38, p  = 0.036, LAN: χ 2  = 4.56, p  = 0.033, and VS: χ 2  = 4.12, p  = 0.042). Individuals with both elevated Aβ and insomnia experienced faster cognitive decline than those with only elevated Aβ or insomnia. Conclusion: These data reinforced the values of insomnia management in preventing dementia, possibly by interacting Aβ metabolism. Future efforts are warranted to determine whether sleep improvement will postpone the onset of dementia, specifically among populations in stages of preclinical or prodromal AD. Show more

Keywords: Amyloid-β , cognition, insomnia, interaction, longitudinal

DOI: 10.3233/JAD-201582

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1701-1710, 2021

Authors: Bangen, Katherine J. | Thomas, Kelsey R. | Sanchez, Danielle L. | Edmonds, Emily C. | Weigand, Alexandra J. | Delano-Wood, Lisa | Bondi, Mark W. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer’s disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease. Objective: To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume. Method: 147 Alzheimer’s Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI …examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models. Results: Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ɛ4 positivity, cerebrospinal fluid p-tau/Aβ ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories. Conclusion: Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both Show more

Keywords: Aging, Alzheimer’s disease, cognition, entorhinal cortex regional blood flow, magnetic resonance imaging, neuropsychology, perfusion, white matter hyperintensities

DOI: 10.3233/JAD-201474

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1711-1725, 2021