Journal of Alzheimer's Disease - Volume 83, issue 3

Authors: Morris, Robert | Umeukeje, Gibret | Bu, Kun | Cheng, Feng

Article Type: Research Article

Abstract: Background: Pneumonia is an inflammatory condition induced by infection of the lungs and is frequently a cause of morbidity and mortality among patients with Alzheimer’s disease (AD). Some studies have shown an association between acetylcholinesterase inhibitor use and elevated pneumonia risk. Objective: The purpose of this study was to perform a comparative analysis of the number of reported pneumonia cases in individuals prescribed rivastigmine relative to the number of reported cases by patients using other therapeutics including over-the-counter drugs and other AD therapeutics, as reported to the FDA Adverse Event Reporting System (FAERS) database. Methods: A …disproportionality analysis was conducted to investigate the association between using rivastigmine and risk of pneumonia. Age, gender, dosage, temporality, and geographic distribution of reported cases were also assessed. Results: Patients prescribed rivastigmine were more likely to report pneumonia as an adverse event than many drugs except galantamine. Males were found to be 46% more likely than females to report pneumonia as an adverse event while likelihood of pneumonia diagnosis increases 3–5-fold in patients older than 65 years of age. Conclusion: The observed elevated frequency of aspiration pneumonia in patients prescribed rivastigmine may be due to an induced cholinergic crisis that is selective for the medulla oblongata, resulting in gastrointestinal distress, impaired swallowing, heightened salivation, and labored breathing. The observed elevated frequency of infectious pneumonia in patients prescribed rivastigmine may also be linked to overstimulation of neurons in the medulla oblongata and downstream suppression of localized inflammatory responses. Show more

Keywords: Acetylcholine, acetylcholinesterase inhibitors, Alzheimer’s disease, aspiration pneumonia, medulla oblongata, rivastigmine, FAERS

DOI: 10.3233/JAD-210662

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1061-1071, 2021

Authors: Kuźma, Elżbieta | Littlejohns, Thomas J. | Khawaja, Anthony P. | Llewellyn, David J. | Ukoumunne, Obioha C. | Thiem, Ulrich

Article Type: Research Article

Abstract: Background: Visual impairment and eye diseases have been associated with dementia, though with mixed findings and often in cross-sectional studies. Objective: To identify prospective studies investigating associations between visual impairment or common eye diseases and risk of all-cause dementia or key dementia subtypes. Methods: We searched Medline, PsycINFO, and Embase from inception to January 2020. We also conducted backward and forward citation searches of included studies and set up alerts to identify studies published after the search date. Random-effects meta-analysis was used to combine adjusted estimates across studies. Results: Thirty studies met our eligibility …criteria. For visual impairment, pooled estimates indicated an increased risk of all-cause dementia (37,705 participants, 3,415 cases, risk ratio [RR] = 1.38, 95% confidence interval [CI]: 1.19–1.59, I2  = 28.6%). Pooled estimates also suggested an increased dementia risk associated with cataract (6,659 participants, 1,312 cases, hazard ratio [HR] = 1.17, 95% CI: 1.00–1.38, I2  = 0.0%) and diabetic retinopathy (43,658 participants, 7,060 cases, HR = 1.34, 95% CI: 1.11–1.61, I2  = 63.9%), respectively. There was no evidence of an association between glaucoma (175,357 participants, 44,144 cases, HR = 0.97, 95% CI: 0.90–1.04, I2  = 51.5%) or age-related macular degeneration (7,800,692 participants, > 2,559 cases, HR = 1.15, 95% CI: 0.88–1.50, I2  = 91.0%) and risk of dementia, respectively. Conclusion: As visual impairment, cataract, and diabetic retinopathy are associated with an increased likelihood of developing dementia, early diagnosis may help identify those at risk of dementia. Given most causes of visual impairment are treatable or preventable, the potential for dementia prevention warrants further investigation. Show more

Keywords: Alzheimer’s disease, dementia, eye diseases, prospective studies, vision disorders

DOI: 10.3233/JAD-210250

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1073-1087, 2021

Authors: Scarth, Morgan | Rissanen, Ina | Scholten, Rob J.P.M. | Geerlings, Mirjam I.

Article Type: Research Article

Abstract: Background: Early identification of Alzheimer’s disease (AD) may be extremely beneficial for delaying disease progression. Subjective cognitive decline (SCD) may be an early indicator of AD pathology. Not all individuals with SCD will eventually develop AD, making it critical to identify biomarkers during the SCD stage which indicate likely clinical progression. Objective: The present review aims to summarize available data on structural MRI and cerebrospinal fluid (CSF) biomarkers and their association with clinical progression to mild cognitive impairment (MCI) or AD in people with SCD. Methods: Database searches were conducted using Embase and PubMed until June …2020. Longitudinal studies assessing biomarkers in individuals with SCD and assessing clinical progression to MCI/AD were included. Two assessors performed data extraction and assessed the risk of bias in the included studies. Data were synthesized narratively. Results: An initial search identified 1,065 papers; after screening and review 14 studies were included. Sample size of the included studies ranged from 28–674, mean age was 60.0–68.6 years, and 10.2%–52%of participants converted to MCI/AD. Lower levels of CSF Aβ42 were consistently associated with clinical progression. Combination measures identifying an AD-like profile of Aβ42 and tau levels were strongly associated with clinical progression. Biomarkers identified with structural MRI were less conclusive, as some studies found significant associations while others did not. Conclusion: Biomarkers may be able to predict clinical progression in those with cognitive complaints. Aβ42 , or combinations of Aβ42 and tau may be useful biomarkers in identifying individuals with SCD who will progress to MCI/AD. Show more

Keywords: Amyloid, biomarkers, cognitive decline, dementia, magnetic resonance imaging, subjective cognitive decline

DOI: 10.3233/JAD-210218

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1089-1111, 2021

Authors: Siqueira, Luciana Domett | Celes, Ana Paula M. | Santos, Hellin Dos | Ferreira, Sergio T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by progressive cognitive decline. Considerable evidence supports an important role of amyloid-β oligomers (AβOs) in the pathogenesis of AD, including the induction of aberrant glial activation and memory impairment. Objective: We have investigated the protective actions of a nutritional formulation, denoted AZ formulation, on glial activation and memory deficits induced by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Methods: Two-month-old male mice were treated orally with AZ formulation or isocaloric placebo for 30 consecutive days. Microglial and astrocytic activation …were analyzed by immunohistochemistry in the hippocampus 10 days after i.c.v. infusion of AβOs (n  = 5 mice per experimental condition). Memory loss was assessed by the novel object recognition (NOR) test (n  = 6–10 mice per experimental condition). Results: Oral treatment with the AZ formulation prevented hippocampal microglial and astrocytic activation induced by i.c.v. infusion of AβOs. The AZ formulation further protected mice from AβO-induced memory impairment. Conclusion: Results suggest that administration of the AZ formulation may comprise a promising preventative and non-pharmacological strategy to reduce brain inflammation and attenuate memory impairment in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , astrocytes, memory, microglia, non-pharmacological approaches

DOI: 10.3233/JAD-210139

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1113-1124, 2021

Authors: Rehan, Sana | Giroud, Nathalie | Al-Yawer, Faisal | Wittich, Walter | Phillips, Natalie

Article Type: Research Article

Abstract: Background: Visual impairment is associated with deficits in cognitive function and risk for cognitive decline and Alzheimer’s disease (AD). Objective: The purpose of this study was to characterize the degree of visual impairment and explore the association thereof with cortical atrophy in brain regions associated with visual processing in individuals with (or at risk for) AD. Methods: Using the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) dataset, we analyzed vision and brain imaging data from three diagnostic groups: individuals with subjective cognitive decline (SCD; N  = 35), mild cognitive impairment (MCI; N  = 74), and mild AD (N … = 30). We used ANCOVAs to determine whether performance on reading acuity and contrast sensitivity tests differed across diagnostic groups. Hierarchical regression analyses were applied to determine whether visual performance predicted gray matter volume for vision-related regions of interest above and beyond group membership. Results: The AD group performed significantly worse on reading acuity (F(2,138) = 4.12, p  < 0.01, ω2  = 0.04) compared to the SCD group and on contrast sensitivity (F(2,138) = 7.6, p  < 0.01, ω2  = 0.09) compared to the SCD and MCI groups, which did not differ from each other. Visual performance was associated with volume in some vision-related structures beyond clinical diagnosis. Conclusion: Our findings demonstrate poor visual performance in AD and that both group membership and visual performance are predictors of cortical pathology, consistent with the idea that atrophy in visual areas and pathways contributes to the functional vision deficits observed in AD. Show more

Keywords: Alzheimer’s disease, brain imaging, cognitive decline, mild cognitive impairment, subjective cognitive decline, visual impairment

DOI: 10.3233/JAD-201521

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1125-1148, 2021

Authors: Wimo, Anders | Belger, Mark | Bon, Jaka | Jessen, Frank | Dumas, Annette | Kramberger, Milica G. | Jamilis, Laura | Johansson, Gunilla | Rodrigo Salas, Adrián | Rodríguez Gómez, Octavio | Sannemann, Lena | Stoekenbroek, Malou | Gurruchaga Telleria, Miren | Valero, Sergi | Vermunt, Lisa | Waterink, Lisa | Winblad, Bengt | Visser, Peter Jelle | Zwan, Marissa | Boada, Mercè | Escher, Claus | Müller, Theresa | Bogdanovic, Nenad | Andersen, Pia | Spulber, Gabriela | Sundström, Maria | Westman, Eric | Ferreira, Daniel | Jelic, Vesna | Haglund, Anders | Stomrud, Erik | Nelvig, Anders | Saha, Samir | Petek, Davorina | Serné, Erik

Article Type: Research Article

Abstract: Background: For care planning and support, under-detection and late diagnosis of Alzheimer’s disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer’s Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation. Objective: To make a cost-consequence analysis of MOPEAD. Methods: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the …cost per true-positive case (TP) of AD from the screened population. Results: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was €3,115 with the web-approach, €2,722 with the Open-House, €1,530 in primary care, and €1,190 by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists. There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP. Conclusion: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications. Show more

Keywords: Alzheimer’s disease, cost-consequence analysis, cost analysis, costs, dementia, diagnosis, diagnostic work-up, screening

DOI: 10.3233/JAD-210303

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1149-1159, 2021

Authors: Fote, Gianna | Wu, Jie | Mapstone, Mark | Macciardi, Fabio | Fiandaca, Massimo S. | Federoff, Howard J.

Article Type: Research Article

Abstract: Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer’s disease (AD) and in AD patient plasma samples. Objective: This study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (n  = 138). Methods: Specimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods. Results: Total plasma SM levels were not significantly affected by age or cognitive status. However, one metabolite that has been elevated in manifest AD in several recent studies, SM OHC14:1, was reduced significantly in pre-clinical AD and …MCI relative to normal controls. Conclusion: We recommend additional comprehensive plasma lipidomics in experimental and clinical biospecimens related to LOAD that might advance the utility of plasma sphingomyelin levels in molecular phenotyping and interpretations of pathobiological mechanisms. Show more

Keywords: Alzheimer’s disease, metabolomics, plasma, sphingolipids, sphingomyelin

DOI: 10.3233/JAD-200871

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1161-1171, 2021

Authors: Schild, Ann-Katrin | Volk, Jenny | Scharfenberg, Daniel | Schuermann, Katrin | Meiberth, Dix | Onur, Oezguer A. | Jessen, Frank | Maier, Franziska

Article Type: Research Article

Abstract: Background: Social cognition (SC) is a core criterion for neurocognitive disorders. However, findings in patients with amnestic mild cognitive impairment (aMCI) and dementia of the Alzheimer type (DAT) are inconsistent. Objective: We report assessments of emotion recognition (ER), affective and cognitive theory of mind (ToM) in young (YC) and older controls (OC) compared to aMCI and DAT. Methods: 28 aMCI, 30 DAT, 30 YC, and 29 OC received tests of SC and a comprehensive neuropsychological assessment. Analysis of covariance was used to determine group differences. Multiple regression models were applied to identify predictors for each SC …task. Results: In controls, OC performed worse in ER and both ToM tasks compared to YC except for one subtest. No significant differences were found between OC and patients concerning ER and affective ToM. In cognitive ToM, differences between OC and patients depended on content and cognitive load with significant impairment in DAT compared to OC. A cognitive composite score predicted SC in OC, but not in patients. Associations of SC with single cognitive domains were found in all groups with language and complex attention as best predictors. Not all variance of SC performance was explained by variance in cognitive domains. Conclusion: Lower performance on SC tasks in OC versus YC was confirmed, although not all tasks were equally affected. With progressive cognitive impairment, cognitive ToM is more impaired than ER or affective ToM. SC seems to be at least partly independent of other cognitive domains, justifying its inclusion in batteries for dementia diagnostic. Show more

Keywords: Amnestic mild cognitive impairment, dementia of the Alzheimer type, emotion recognition, social cognition, theory of mind

DOI: 10.3233/JAD-201126

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1173-1186, 2021

Authors: Jiang, Ziying | Han, Xiaolei | Wang, Yongxiang | Hou, Tingting | Cong, Lin | Tang, Shi | Han, Xiaodong | Ngandu, Tiia | Kivipelto, Miia | Winblad, Bengt | Launer, Lenore J. | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Evidence has emerged that anemia is associated with dementia, but data on the relationships of red blood cell distribution width (RDW) with dementia and cognitive function in older adults are sparse. Objective: We sought to investigate the associations of RDW with dementia and global cognitive performance among rural-dwelling Chinese older adults and further to examine their associations by anemia status. Methods: This population-based cross-sectional study included 5,115 participants (age≥65 years, 57.0%women) in the baseline examination (March-September 2018) of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-CHINA). We collected data through face-to-face …interviews, clinical examinations, and laboratory tests. Global cognitive function was evaluated using the Mini-Mental State Examination (MMSE). We defined dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) following the respective international criteria. Data were analyzed using multinomial logistic and general linear regression models. Results: Of all participants, 300 were diagnosed with dementia, including 195 with AD and 95 VaD. The multiple-adjusted odds ratio of dementia associated with quartiles of RDW were 1.45 (95%CI: 0.87–2.44), 1.00 (reference), 1.77 (1.07–2.93), and 2.28 (1.40–3.72). Similar J-shaped patterns existed for the association of RDW with odds ratio of AD and VaD. Anemia was not significantly associated with dementia. The J-shaped associations of RDW with dementia and subtypes were statistically evident only among participants without anemia. There was an inverted J-shaped relationship between RDW quartiles and β-coefficients of MMSE score. Conclusion: There is a J-shaped association between RDW level and likelihood of dementias among rural-dwelling Chinese older adults, especially among people without anemia. Show more

Keywords: Alzheimer’s disease, anemia dementia, elderly, population-based study, red cell distribution width

DOI: 10.3233/JAD-210517

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1187-1198, 2021

Authors: Sakurai, Keita | Kaneda, Daita | Uchida, Yuto | Inui, Shohei | Bundo, Masahiko | Akagi, Akio | Nihashi, Takashi | Kimura, Yasuyuki | Kato, Takashi | Ito, Kengo | Ohashi, Wataru | Hashizume, Yoshio

Article Type: Research Article

Abstract: Background: The differentiation of idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative diseases such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is often challenging because of their non-specific symptoms. Therefore, various neuroradiological markers other than ventriculomegaly have been proposed. Despite the utility of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) for the appropriate selection of shunt surgery candidates, the specificity and neuropathology of this finding have not been sufficiently evaluated. Objective: Investigation of the clinicopathological features and comparison of the neuroradiological findings between DESH with postmortem neuropathological diagnoses (pDESH) and clinically-diagnosed iNPH (ciNPH) patients are the main purposes …of this study. Method: In addition to the retrospective evaluation of clinicopathological information, quantitative, semiquantitative, and qualitative magnetic resonance imaging (MRI) indices were compared between pathologically-investigated 10 patients with pDESH and 10 patients with ciNPH Results: Excluding one patient with multiple cerebral infarctions, the postmortem neuropathological diagnoses of the pathologically-investigated patients were mainly neurodegenerative diseases (five AD, one DLB with AD pathologies, one DLB, one argyrophilic grain disease, and one Huntington’s disease). In addition to the common neuroradiological features Conclusion: Hippocampal atrophy and deformation with temporal horn enlargement seem to be characteristic neuroradiological findings of long-standing severely demented patients with DESH and neurodegenerative diseases, mainly advanced-stage AD. Show more

Keywords: Disproportionately enlarged subarachnoid-space hydrocephalus, hippocampal atrophy, hippocampal deformation, idiopathic normal pressure hydrocephalus, magnetic resonance imaging, temporal horn enlargement

DOI: 10.3233/JAD-210535

Citation: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1199-1209, 2021