Journal of Alzheimer's Disease - Volume 90, issue 1

Authors: Latgé-Tovar, Sofia | Bertrand, Elodie | Cosentino, Stephanie | Dourado, Marcia C.N. | Laks, Jerson | Landeira-Fernandez, Jesus | Morris, Robin G. | Mograbi, Daniel C.

Article Type: Research Article

Abstract: Background: Impaired awareness of ability is common in dementia and has important clinical implications. Evidence from different clinical groups has shown that awareness can vary according to whether evaluation refers to self or other performance. Objective: The present study aimed to investigate awareness for self- and other-performance in Alzheimer’s disease (AD) patients, exploring if results vary according to cognitive domain of the tasks. It was hypothesized that, particularly for memory tasks, AD patients would be inaccurate in relation to self-but not other-performance. Methods: Twenty-two mild to moderate AD patients and twenty-two healthy older adults participated. Two …tasks, with reaction time and working memory tasks, were carried out, and each had a success and a failure condition. Participants were asked to estimate their own performance, as well as the performance of another person they observed. Awareness of performance was measured comparing participant estimations of performance with actual performance. Results: For both the reaction time and working memory tasks, results indicate that participants from both groups overestimated the performance in the failure condition and underestimated the performance in the success condition. They tended to overestimate more the performance of the other person compared to themselves. Additionally, for the working memory task, AD patients tended to overestimate more performances compared to controls. Conclusion: Findings suggest that the AD and control groups present the same pattern, with attribution of better performance to another person. For the AD group, the pattern of response was different for memory tasks, which may suggest domain-specific limited awareness. Show more

Keywords: Alzheimer’s disease, awareness, dementia, metacognition, perspective-taking

DOI: 10.3233/JAD-220453

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 283-294, 2022

Authors: Ota, Miho | Sato, Noriko | Nakaya, Moto | Shigemoto, Yoko | Kimura, Yukio | Chiba, Emiko | Yokoi, Yuma | Tsukamoto, Tadashi | Matsuda, Hiroshi

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) and tau protein accumulation in the brain is thought to be one of the causes of Alzheimer’s disease (AD). Recent study found that the glymphatic system was waste drainage system in the brain and promoting the elimination of Aβ and tau protein. Objective: We evaluated the relationships between the glymphatic system activity and the Aβ and tau protein deposition. Methods: Subjects were 21 patients with AD and 36 healthy subjects who underwent diffusion tensor imaging (DTI) scan and the positron emission tomography (PET) using with the Aβ tracer: 11 C-PiB and the tau/inflammatory …tracer: 18 F-THK5351. We computed diffusion tensor image analysis along the perivascular space (DTI-ALPS) index as the proxy of glymphatic system activity, and estimated the relationships between the DTI-ALPS index and Aβ and tau protein/inflammatory deposition. Results: We found significant negative correlations between DTI-ALPS index and the standard uptake value ratio (SUVR) of 11 C-PiB in the bilateral temporal and left parietal cortices and left posterior cingulate gyrus in all subjects. Further, we detected significant negative correlations between DTI-ALPS index and the SUVR of 18 F-THK5351 in the bilateral temporal cortices and right parietal cortex in all participants, too. Conclusion: Our data suggested that DTI-ALPS index was a good biomarker for the evaluation of Aβ and tau deposition and neuroinflammation, and this marker might be effective to estimate the glymphatic system activity. Show more

Keywords: Diffusion tensor image analysis along the perivascular space (DTI-ALPS), positron emission tomography, 11C-PiB, 18F-THK5351

DOI: 10.3233/JAD-220534

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 295-303, 2022

Authors: Yeh, Wei-Chih | Hsu, Chung-Yao | Li, Kuan-Ying | Chien, Ching-Fang | Huang, Ling-Chun | Yang, Yuan-Han

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia. Aging is a risk factor for both AD and seizures. Subclinical epileptiform discharge (SED) has no evident clinical manifestation in patients with AD. Therefore, SED is liable to be overlooked in these patients since electroencephalography is not routinely performed in clinical settings. Previous studies about the association between SED and AD have yielded inconsistent results. Objective: The current study aimed to evaluate the prevalence of SED and its effect on AD severity and clinical outcomes. Methods: Patients with AD from Kaohsiung Municipal Ta-tung Hospital were …included in this study. International 10–20 system scalp electroencephalography for 13 minutes was performed to detect SED. Clinical outcomes of patients with and without SED were assessed by neuropsychological tests [Cognitive Abilities Screening Instrument (CASI), Mini-Mental State Examination (MMSE), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)]. Results: 288 patients (mean age 80.5 years, 60.4% female) were enrolled in this study. Fifty-seven (19.8%) out of 288 patients with AD had SED. The prevalence of SED increased with the severity of cognitive impairment. Compared with patients without SED, those with SED showed significantly greater decline in CASI (–9.32 versus –3.52 points, p  = 0.0001) and MMSE (–2.52 versus –1.12 points, p  = 0.0042) scores in one year. Conclusion: SED may play a significant role in AD progression and is a potential therapeutic target. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, electroencephalography, mental status and dementia tests, neuropsychological tests

DOI: 10.3233/JAD-220567

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 305-312, 2022

Authors: Loewenstein, David A. | Curiel Cid, Rosie E. | Kitaigorodsky, Marcela | Ortega, Alexandra | Hincapie, Diana | Zheng, D. Diane | Amaya, Alexandra | Gallardo, Liz | Manso, Leslie | Sosa, Jaylene | Crocco, Elizabeth A.

Article Type: Research Article

Abstract: Background: Susceptibility to proactive semantic interference (PSI) and the inability to ameliorate these difficulties with one additional learning trial have repeatedly been implicated as early features of incipient Alzheimer’s disease (AD). Unfortunately, persistent failure to recover from PSI (frPSI) after repeated learning trials, are not captured by existing memory measures, or been examined in pre-mild cognitive impairment (PreMCI). Objective: A novel Cognitive Stress Test (CST) was employed to measure the impact of PSI, initial failure to recover from PSI and persistent effects of PSI, despite multiple learning trials of the new to-be-remembered material (pfrPSI). We hypothesized that PSI …deficits on the CST would persist in both PreMCI and amnestic MCI (aMCI) groups over repeated learning trials when compared to cognitively unimpaired (CU) older adults. Methods: One hundred fifty older adults (69 CU, 31 PreMCI, and 50 aMCI) underwent a standardized clinical and neuropsychological evaluation. The CST was independent of diagnostic classification. Results: Even after adjusting for strength of initial learning, aMCI and PreMCI groups demonstrated greater persistent PSI (pfrPSI) relative to the CU group despite repeated learning trials of List B. Further, the aMCI group made a higher number of semantic intrusion errors relative to the PreMCI and CU groups on all List B Cued Recall trials. Conclusion: Persistent PSI appears to be a common feature of aMCI and PreMCI. The possible theoretical mechanisms and empirical implications of these new findings are discussed. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, persistent semantic interference, proactive semantic interference

DOI: 10.3233/JAD-220348

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 313-322, 2022

Authors: Thomas, Kelsey R. | Bangen, Katherine J. | Weigand, Alexandra J. | Ortiz, Gema | Walker, Kayla S. | Salmon, David P. | Bondi, Mark W. | Edmonds, Emily C.

Article Type: Research Article

Abstract: Background: There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer’s disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults. Objective: We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of ≤129 across subgroups. Methods: Hierarchical cluster analysis was conducted on individual baseline neuropsychological test scores from …365 CU participants in the UCSD Shiley-Marcos Alzheimer’s Disease Research Center longitudinal cohort. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score ≤129, by cluster group. Results: Cluster analysis identified 5 groups: All-Average (n  = 139), Low-Visuospatial (n  = 46), Low-Executive (n  = 51), Low-Memory/Language (n  = 83), and Low-All Domains (n  = 46). Subgroups had unique demographic and clinical characteristics. Rates of progression to MCI/dementia or to DRS ≤129 were faster for all subgroups (Low-All Domains progressed the fastest > Low Memory/Language≥Low-Visuospatial and Low-Executive) relative to the All-Average subgroup. Conclusion: Faster progression in the Low-Visuospatial, Low-Executive, and Low-Memory/Language groups compared to the All-Average group suggests that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. Use of comprehensive neuropsychological test batteries that assess several domains may be a key first step toward an individualized approach to early detection and fewer missed opportunities for early intervention. Show more

Keywords: Alzheimer’s disease, cognitive phenotypes, heterogeneity, subtle cognitive decline

DOI: 10.3233/JAD-220684

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 323-331, 2022

Authors: Sturchio, Andrea | Dwivedi, Alok K. | Malm, Tarja | Wood, Matthew J.A. | Cilia, Roberto | Sharma, Jennifer S. | Hill, Emily J. | Schneider, Lon S. | Graff-Radford, Neill R. | Mori, Hiroshi | Nübling, Georg | El Andaloussi, Samir | Svenningsson, Per | Ezzat, Kariem | Espay, Alberto J.

Article Type: Research Article

Abstract: Background: In amyloid-positive individuals at risk for Alzheimer’s disease (AD), high soluble 42-amino acid amyloid-β (Aβ42 ) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. Objective: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer’s disease (AD)-causing mutations (APP , PSEN1 , or PSEN2 ) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). Methods: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal …cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. Results: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19–0.67; p  = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68–0.96; p  = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. Conclusion: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations. Show more

Keywords: Alzheimer’s disease, amyloid-β , atrophy, cognition, FDG-PET

DOI: 10.3233/JAD-220808

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 333-348, 2022

Authors: Wei, Shan | Dang, Liangjun | Gao, Fan | Wang, Jingyi | Wang, Jin | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Abnormal blood lipids are associated with cognitive impairment and amyloid-β (Aβ) deposition in the brain. However, the effects of statins on Alzheimer’s disease (AD) have not been determined. Objective: Considering that plasma Aβ are related to Aβ deposition in the brain, we investigated the effects of simvastatin on plasma Aβ transport. Methods: This was a randomized, double-blind, placebo-controlled trial. One hundred and twenty patients with hyperlipidemia were randomly assigned to receive 40 mg of simvastatin per day or matching placebo for 12 weeks (sixty patients per group). Plasma Aβ, sLRP1, sRAGE, and lipid levels were measured …at baseline and at the 6-week and 12-week visits. Results: The ITT database ultimately included 108 participants (placebo group: n  = 53; simvastatin group: n  = 55) and 64 (59.3%) were women, ranging in age from 45 to 75 years (mean 57.2±6.9 years). Multiple linear regression analysis showed that, after 12 weeks of follow-up, compared with the placebo group, Δ Aβ42 levels (the change of Aβ42 levels from baseline at week 12) increased more and Δ sRAGE levels decreased more in the simvastatin group (Aβ42 : β= 5.823, p  = 0.040; sRAGE: β= –72.012, p  = 0.031), and a significant negative association was found between Δ Aβ42 and Δ sRAGE levels (β= –0.115, p  = 0.045). In addition, generalized estimation equation analysis showed that triglycerides levels were negatively correlated with Aβ40 (β= –16.79, p  = 0.023), Aβ42 (β= –6.10, p  = 0.001), and sRAGE (β= –51.16, p  = 0.003). Conclusion: Daily oral simvastatin (40 mg/day) in patients with hyperlipidemia for 12 weeks can significantly increase plasma Aβ42 levels compared with placebo, which was associated with reduced triglycerides and sRAGE levels, indicating that statins may affect plasma Aβ transport. Show more

Keywords: Alzheimer’s disease, hyperlipidemia, plasma amyloid-β, simvastatin, soluble low-density lipoprotein receptor-related protein-1, soluble receptor of advanced glycation end products

DOI: 10.3233/JAD-220240

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 349-362, 2022

Authors: Bolsewig, Katharina | Hok-A-Hin, Yanaika S. | Sepe, Federica N. | Boonkamp, Lynn | Jacobs, Dirk | Bellomo, Giovanni | Paoletti, Federico Paolini | Vanmechelen, Eugeen | Teunissen, Charlotte E. | Parnetti, Lucilla | Willemse, Eline A. J.

Article Type: Research Article

Abstract: Background: The differential diagnosis of frontotemporal dementia (FTD) is still a challenging task due to its symptomatic overlap with other neurological diseases and the lack of biofluid-based biomarkers. Objective: To investigate the diagnostic potential of a combination of novel biomarkers in cerebrospinal fluid (CSF) and blood. Methods: We included 135 patients from the Center for Memory Disturbances, University of Perugia, with the diagnoses FTD (n  = 37), mild cognitive impairment due to Alzheimer’s disease (MCI-AD, n  = 47), Lewy body dementia (PDD/DLB, n  = 22), and cognitively unimpaired patients as controls (OND, n  = 29). Biomarker levels of neuronal pentraxin-2 …(NPTX2), neuronal pentraxin receptor, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were measured in CSF, as well as NfL and GFAP in serum. We assessed biomarker differences by analysis of covariance and generalized linear models (GLM). We performed receiver operating characteristics analyses and Spearman correlation to determine biomarker associations. Results: CSF NPTX2 and serum GFAP levels varied most between diagnostic groups. The combination of CSF NPTX2, serum NfL and serum GFAP differentiated FTD from the other groups with good accuracy (FTD versus MCI-AD: area under the curve (AUC) [95% CI] = 0.89 [0.81–0.96]; FTD versus PDD/DLB: AUC = 0.82 [0.71–0.93]; FTD versus OND: AUC = 0.80 [0.70–0.91]). CSF NPTX2 and serum GFAP correlated positively only in PDD/DLB (ρ = 0.56, p  < 0.05). NPTX2 and serum NfL did not correlate in any of the diagnostic groups. Serum GFAP and serum NfL correlated positively in all groups (ρ = 0.47–0.74, p  < 0.05). Conclusion: We show the combined potential of CSF NPTX2, serum NfL, and serum GFAP to differentiate FTD from other neurodegenerative disorders. Show more

Keywords: Biomarker, differential diagnosis, frontotemporal dementia, glial fibrillary acidic protein, neurofilament light, NPTX2, NPTXR

DOI: 10.3233/JAD-220318

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 363-380, 2022

Authors: van Harten, Thijs W. | Heijmans, Anne | van Rooden, Sanneke | Wermer, Marieke J.H. | van Osch, Matthias J.P. | Kuijf, Hugo J. | van Veluw, Susanne J. | Greenberg, Steven M. | van Buchem, Mark A. | van der Grond, Jeroen | van Walderveen, Marianne A.A.

Article Type: Research Article

Abstract: Background: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer’s disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer’s disease. So far, DMVs have not been evaluated in CAA. Objective: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. Methods: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n  = 8), symptomatic D-CAA mutation carriers (n  = 8), and controls …(n  = 25). Hemorrhagic MRI markers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. Results: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA. Conclusion: This study indicates that vascular amyloid-β deposition does not affect DMV parameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA. Show more

Keywords: Cerebral small vessel disease, cerebral veins, hereditary cerebral amyloid angiopathy, magnetic resonance imaging

DOI: 10.3233/JAD-220354

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 381-388, 2022

Authors: Fu, Jingzhu | Zhu, Yun | Sun, Yue | Liu, Qian | Duan, Huilian | Huang, Ling | Zhou, Dezheng | Wang, Zehao | Zhao, Jing | Li, Zhenshu | Du, Yue | Liu, Huan | Ma, Fei | Chen, Yongjie | Sun, Changqing | Wang, Guangshun | Li, Wen | Huang, Guowei

Article Type: Research Article

Abstract: Background: The high cost, limited availability, and perceived invasiveness of amyloid PET and cerebrospinal fluid biomarkers limit their use for the diagnosis of Alzheimer’s disease. Objective: The present study aimed to assess the associations of mild cognitive impairment (MCI) with circulating amyloid-β (Aβ), methionine circulating metabolites (MCMs), and their downstream products, and to develop a nomogram based on these easily accessible blood indexes for the individualized prediction of MCI risk in older adults. Methods: In this nested case-control study, we recruited 74 MCI patients and, for each, 3 matched controls (n  = 222) within the context of …the Tianjin Elderly Nutrition and Cognition (TENC) cohort, a population-based prospective study in China. Concentrations of Aβ, MCMs, and their circulating downstream factors (i.e., leukocyte telomere length and inflammatory cytokines) were evaluated in fasting blood sample using standard procedures. We constructed a nomogram for MCI harnessed multivariable logistic models incorporating variables selected in the Lasso regression. Results: Among the many biomarkers examined, the final prediction nomogram retained only 3 factors: Aβ42 /Aβ40 ratio, Hcy, and SAM/SAH ratio. The model achieved favorable discrimination, with a C-statistic of 0.75 (95% confidence interval 0.69–0.81) in internal validation after adjustment of optimism. The calibration accuracy was satisfactory; the Brier score of the model was 0.161 in internal validation after adjustment of optimism. Conclusion: his study presents an individualized prediction nomogram incorporating only three blood biomarkers (i.e., Aβ42 /Aβ40 ratio, Hcy, and SAM/SAH ratio), which can be conveniently utilized to facilitate early identification and the development of high-risk prevention strategies for MCI in older adults. Show more

Keywords: Inflammatory factor, leukocyte telomere length, methionine circulating metabolites, mild cognitive impairment, nested case-control study, older adult, plasma amyloid-β, predictive model

DOI: 10.3233/JAD-220373

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 389-404, 2022