Journal of Alzheimer's Disease - Volume 79, issue 1

Authors: Tuena, Cosimo | Mancuso, Valentina | Stramba-Badiale, Chiara | Pedroli, Elisa | Stramba-Badiale, Marco | Riva, Giuseppe | Repetto, Claudia

Article Type: Research Article

Abstract: Background: Spatial navigation is the ability to estimate one’s position on the basis of environmental and self-motion cues. Spatial memory is the cognitive substrate underlying navigation and relies on two different reference frames: egocentric and allocentric. These spatial frames are prone to decline with aging and impairment is even more pronounced in Alzheimer’s disease (AD) or in mild cognitive impairment (MCI). Objective: To conduct a systematic review of experimental studies investigating which MCI population and tasks are used to evaluate spatial memory and how allocentric and egocentric deficits are impaired in MCI after navigation. Methods: PRISMA …and PICO guidelines were applied to carry out the systematic search. Down and Black checklist was used to assess methodological quality. Results: Our results showed that amnestic MCI and AD pathology are the most investigated typologies; both egocentric and allocentric memory are impaired in MCI individuals, and MCI due to AD biomarkers has specific encoding and retrieval impairments; secondly, spatial navigation is principally investigated with the hidden goal task (virtual and real-world version), and among studies involving virtual reality, the privileged setting consists of non-immersive technology; thirdly, despite subtle differences, real-world and virtual versions showed good overlap for the assessment of MCI spatial memory. Conclusion: Considering that MCI is a subclinical entity with potential risk for conversion to dementia, investigating spatial memory deficits with navigation tasks might be crucial to make accurate diagnosis and rehabilitation. Show more

Keywords: Alzheimer’s disease, embodiment, mild cognitive impairment, navigation, spatial memory, virtual reality

DOI: 10.3233/JAD-201017

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 95-116, 2021

Authors: Du, Mengtian | Andersen, Stacy L. | Schupf, Nicole | Feitosa, Mary F. | Barker, Megan S. | Perls, Thomas T. | Sebastiani, Paola

Article Type: Research Article

Abstract: Background: The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. Objective: To test whether APOE genotype is associated with change of cognitive function in older adults. Methods: We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or …>1935), and the number of copies of ɛ 2 or ɛ 4 alleles. Results: Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOE ɛ 4 allele on Logical Memory. Participants carrying at least one copy of the ɛ 4 allele had lower scores in both immediate (–0.31 points, 95% CI: –0.57, –0.05) and delayed (–0.37 points, 95% CI: –0.64, –0.10) recall comparing to non-ɛ 4 allele carriers. We did not detect any significant longitudinal effect of the ɛ 4 allele. There was no cross-sectional or longitudinal effect of the ɛ 2 allele. Conclusion: The APOE ɛ 4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOE ɛ 2 allele was not significantly associated with any of the cognitive test scores. Show more

Keywords: APOE, cognition, longevity, longitudinal studies

DOI: 10.3233/JAD-201113

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 117-125, 2021

Authors: Femminella, Grazia Daniela | Harold, Denise | Scott, James | Williams, Julie | Edison, Paul | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer’s disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects. Objective: The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls. Methods: AD biomarkers ([18 F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the …ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes. Results: Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism. Conclusion: Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively. Show more

Keywords: Alzheimer’s disease, biomarkers, genetic risk, polygenic score, SNPs

DOI: 10.3233/JAD-200578

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 127-139, 2021

Authors: Yang, Bing | Yang, Siyuan | Zhang, Yunmei | Liu, Wentao | Gan, Yao | Li, Yaling | Jiang, Dengbi | Luo, Yetao | Zhao, Qinghua

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) experience various stressors that negatively impact well-being. Most studies have, however, small effect size and are limited by the experiences of severe patients. Therefore, we conducted a single-blind, randomized controlled trial, which has included patients at different stages. Objective: The stressor-oriented multicomponent program was designed as an intervention for AD patients to enhance well-being. Methods: Patients were randomly assigned to control or SOUL-P conditions according to disease severity. The SOUL-P group received 15 intensive sessions over 6 months and 6 maintenance sessions over a 6-month follow-up by a multidisciplinary team …comprising psychologists, occupational therapists, and community nurses. The control group received a similar number of sessions by community nurses. Stress-related outcomes (primary stressors and well-being outcomes) were obtained from in-person baseline and follow-up interviews conducted at 6- and 12-months post-baseline. A treatment compliance survey was conducted at the intervention endpoint for patients. Results: Of the 863 patients screened, 218 (25.3%) were eligible. At 6 months, compared to controls, SOUL-P patients had improved quality of life (QoL) (p  < 0.001; Cohen d  = 0.56), depression (p  = 0.020; Cohen d  = –0.33), neurobehavioral symptoms (p  = 0.034; Cohen d  = –0.30), perceived stress (p  = 0.030; Cohen d  = –0.31), and family conflict (p  = 0.026; Cohen d  = –0.32). QoL, depression, perceived stress, and family conflict were still significantly different at 12 months. Most patients were satisfied with SOUL-P, while caregivers in the SOUL-P group reported overloading tasks. Conclusion: SOUL-P may reduce perceived stress and improve psychological outcomes in AD patients. Stressor-based interventions, patient-oriented goals, and a multidisciplinary team are essential features for a successful SOUL-P. Show more

Keywords: Alzheimer’s disease, multidisciplinary intervention, perceived stress, quality of life, stress-oriented

DOI: 10.3233/JAD-200652

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 141-152, 2021

Authors: Ylä-Herttuala, Salla | Hakulinen, Mikko | Poutiainen, Pekka | Laitinen, Tiina M. | Koivisto, Anne M. | Remes, Anne M. | Hallikainen, Merja | Lehtola, Juha-Matti | Saari, Toni | Korhonen, Ville | Könönen, Mervi | Vanninen, Ritva | Mussalo, Hanna | Laitinen, Tomi | Mervaala, Esa

Article Type: Research Article

Abstract: Background: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer’s disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-β (Aβ) burden and severe OSA in middle-aged patients. Objective: Examine the possible presence of cortical Aβ accumulation in middle-aged patients with severe OSA. Methods: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30 h–1 ). Known etiological factors for possible Aβ accumulation were used as exclusion criteria. Aβ uptake was studied with [11 C]-PiB-PET, glucose metabolism with [18 …F]-FDG-PET, and structural imaging with 3.0T MRI. Results: When analyzed individually, in [11 C]-PiB-PET a substantial number (∼32%) of the patients exhibited statistically significant evidence of increased cortical Aβ uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18 F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology. Conclusion: Increased [11 C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aβ uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aβ clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction. Show more

Keywords: Alzheimer’s disease, amyloid, PET, sleep apnea

DOI: 10.3233/JAD-200736

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 153-161, 2021

Authors: van Waalwijk van Doorn, Linda J.C. | Ghafoorian, Mohsen | van Leijsen, Esther M.C. | Claassen, Jurgen A.H.R. | Arighi, Andrea | Bozzali, Marco | Cannas, Jorge | Cavedo, Enrica | Eusebi, Paolo | Farotti, Lucia | Fenoglio, Chiara | Fortea, Juan | Frisoni, Giovanni B. | Galimberti, Daniela | Greco, Viviana | Herukka, Sanna-Kaisa | Liu, Yawu | Lleó, Alberto | de Mendonça, Alexandre | Nobili, Flavio M. | Parnetti, Lucilla | Picco, Agnese | Pikkarainen, Maria | Salvadori, Nicola | Scarpini, Elio | Soininen, Hilkka | Tarducci, Roberto | Urbani, Andrea | Vilaplana, Eduard | Meulenbroek, Olga | Platel, Bram | Verbeek, Marcel M. | Kuiperij, H. Bea

Article Type: Research Article

Abstract: Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42 ), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer’s disease (AD). However, CSF biomarker levels can be affected by confounding factors. Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated …segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. Results: A small, negative association of CSF Aβ42 , but not p -tau and t -tau, levels with WMH volume was observed in the AD (r 2  = 0.084, p  = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r 2  = 0.105, p  = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, magnetic resonance imaging, tau proteins, white matter hyperintensities, white matter lesions

DOI: 10.3233/JAD-200496

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 163-175, 2021

Authors: Koychev, Ivan | Jansen, Katrin | Dette, Alina | Shi, Liu | Holling, Heinz

Article Type: Research Article

Abstract: Background: The Amyloid Tau Neurodegeneration (ATN) framework was proposed to define the biological state underpinning Alzheimer’s disease (AD). Blood-based biomarkers offer a scalable alternative to the costly and invasive currently available biomarkers. Objective: In this meta-analysis we sought to assess the diagnostic performance of plasma amyloid (Aβ40 , Aβ42 , Aβ42/40 ratio), tangle (p-tau181), and neurodegeneration (total tau [t-tau], neurofilament light [NfL]) biomarkers. Methods: Electronic databases were screened for studies reporting biomarker concentrations for AD and control cohorts. Biomarker performance was examined by random-effect meta-analyses based on the ratio between biomarker concentrations in patients and …controls. Results: 83 studies published between 1996 and 2020 were included in the analyses. Aβ42/40 ratio as well as Aβ42 discriminated AD patients from controls when using novel platforms such as immunomagnetic reduction (IMR). We found significant differences in ptau-181 concentration for studies based on single molecule array (Simoa), but not for studies based on IMR or ELISA. T-tau was significantly different between AD patients and control in IMR and Simoa but not in ELISA-based studies. In contrast, NfL differentiated between groups across platforms. Exosome studies showed strong separation between patients and controls for Aβ42 , t-tau, and p-tau181. Conclusion: Currently available assays for sampling plasma ATN biomarkers appear to differentiate between AD patients and controls. Novel assay methodologies have given the field a significant boost for testing these biomarkers, such as IMR for Aβ, Simoa for p-tau181. Enriching samples through extracellular vesicles shows promise but requires further validation. Show more

Keywords: Alzheimer’s disease, ATN framework, diagnosis, fluid biomarkers, meta-analysis

DOI: 10.3233/JAD-200900

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 177-195, 2021

Authors: Becker, Sara | Boettinger, Olga | Sulzer, Patricia | Hobert, Markus A. | Brockmann, Kathrin | Maetzler, Walter | Berg, Daniela | Liepelt-Scarfone, Inga | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Instrumental activities of daily living (IADL) impairment can begin in mild cognitive impairment (MCI), and is the core criteria for diagnosing dementia in both Alzheimer’s (AD) and Parkinson’s (PD) diseases. The Functional Activities Questionnaire (FAQ) has high discriminative power for dementia and MCI in older age populations, but is influenced by demographic factors. It is currently unclear whether the FAQ is suitable for assessing cognitive-associated IADL in non-demented PD patients, as motor disorders may affect ratings. Objective: To compare IADL profiles in MCI patients with PD (PD-MCI) and AD (AD-MCI) and to verify the discriminative ability of …the FAQ for MCI in patients with (PD-MCI) and without (AD-MCI) additional motor impairment. Methods: Data of 42 patients each of PD-MCI, AD-MCI, PD cognitively normal (PD-CN), and healthy controls (HC), matched according to age, gender, education, and global cognitive impairment were analyzed. ANCOVA and binary regressions were used to examine the relationship between the FAQ scores and groups. FAQ cut-offs for PD-MCI (versus PD-NC) and AD-MCI (versus HC) were separately identified using receiver operating characteristic analyses. Results: FAQ total score did not differentiate between MCI groups. PD-MCI subjects had greater difficulties with tax records and traveling while AD-MCI individuals were more impaired in managing finances and remembering appointments. Classification accuracy of the FAQ was good for diagnosing AD-MCI (69%, cut-off ≥1) compared to HC, and sufficient for differentiating PD-MCI (38.1%, cut-off ≥3) from PD-CN. Conclusion: The FAQ task profiles and classification accuracy differed between MCI related to PD and AD. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognitive dysfunction, dementia, mild cognitive impairment, Parkinson’s disease

DOI: 10.3233/JAD-200256

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 197-209, 2021

Authors: Vittal Rao, Haripriya | Bihaqi, Syed Waseem | Iannucci, Jaclyn | Sen, Abhik | Grammas, Paula

Article Type: Research Article

Abstract: Background: Diabetes is one of the strongest disease-related risk factors for Alzheimer’s disease (AD). In diabetics, hyperglycemia-induced microvascular complications are the major cause of end-organ injury, contributing to morbidity and mortality. Microvascular pathology is also an important and early feature of AD. The cerebral microvasculature may be a point of convergence of both diseases. Several lines of evidence also implicate thrombin in AD as well as in diabetes. Objective: Our objective was to investigate the role of thrombin in glucose-induced brain microvascular endothelial injury. Methods: Cultured Human brain microvascular endothelial cells (HBMVECs) were treated with 30 mM …glucose±100 nM thrombin and±250 nM Dabigatran or inhibitors of PAR1, p38MAPK, MMP2, or MMP9. Cytotoxicity and thrombin activity assays on supernatants and western blotting for protein expression in lysates were performed. Results: reatment of HBMVECs with 30 mM glucose increased thrombin activity and expression of inflammatory proteins TNFα , IL-6, and MMPs 2 and 9; this elevation was reduced by the thrombin inhibitor dabigatran. Direct treatment of brain endothelial cells with thrombin upregulated p38MAPK and CREB, and induced TNFα , IL6, MMP2, and MMP9 as well as oxidative stress proteins NOX4 and iNOS. Inhibition of thrombin, thrombin receptor PAR1 or p38MAPK decrease expression of inflammatory and oxidative stress proteins, implying that thrombin may play a central role in glucose-induced endothelial injury. Conclusion: Since preventing brain endothelial injury would preserve blood-brain barrier integrity, prevent neuroinflammation, and retain intact functioning of the neurovascular unit, inhibiting thrombin, or its downstream signaling effectors, could be a therapeutic strategy for mitigating diabetes-induced dementia. Show more

Keywords: Alzheimer’s disease, diabetes, glucose, hyperglycemia, inflammation, NADHP oxidase, nitric oxide synthase, oxidative stress, p38 MAPK, thrombin

DOI: 10.3233/JAD-200658

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 211-224, 2021

Authors: Rådestig, Maya Arvidsson | Skoog, Johan | Zetterberg, Henrik | Kern, Jürgen | Zettergren, Anna | Sacuiu, Simona | Waern, Margda | Wetterberg, Hanna | Blennow, Kaj | Skoog, Ingmar | Kern, Silke

Article Type: Research Article

Abstract: Background: We have previously shown that older adults with preclinical Alzheimer’s disease (AD) pathology in cerebrospinal fluid (CSF) had slightly worse performance in Mini-Mental State Examination (MMSE) than participants without preclinical AD pathology. Objective: We therefore aimed to compare performance on neurocognitive tests in a population-based sample of 70-year-olds with and without CSF AD pathology. Methods: The sample was derived from the population-based Gothenburg H70 Birth Cohort Studies in Sweden. Participants (n  = 316, 70 years old) underwent comprehensive cognitive examinations, and CSF Aβ-42 , Aβ-40 , T-tau, and P-tau concentrations were measured. Participants were classified according …to the ATN system, and according to their Clinical Dementia Rating (CDR) score. Cognitive performance was examined in the CSF amyloid, tau, and neurodegeneration (ATN) categories. Results: Among participants with CDR 0 (n  = 259), those with amyloid (A+) and/or tau pathology (T+, N+) showed similar performance on most cognitive tests compared to participants with A-T-N-. Participants with A-T-N+ performed worse in memory (Supra span (p  = 0.003), object Delayed (p  = 0.042) and Immediate recall (p  = 0.033)). Among participants with CDR 0.5 (n  = 57), those with amyloid pathology (A+) scored worse in category fluency (p  = 0.003). Conclusion: Cognitively normal participants with amyloid and/or tau pathology performed similarly to those without any biomarker evidence of preclinical AD in most cognitive domains, with the exception of slightly poorer memory performance in A-T-N+. Our study suggests that preclinical AD biomarkers are altered before cognitive decline. Show more

Keywords: Biomarkers in early Alzheimer’s disease, cerebrospinal fluid, cognition, population-based

DOI: 10.3233/JAD-200751

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 225-235, 2021