Journal of Alzheimer's Disease - Volume 89, issue 2

Authors: Kong, Yu | Chen, Zhongyun | Wang, Xue | Wang, Wenjiao | Zhang, Jing

Article Type: Research Article

Abstract: Background: Creutzfeldt-Jakob disease (CJD) can be difficult to distinguish clinically from some non-prion neurological diseases. Previous studies have reported markedly increased levels of α -synuclein in cerebrospinal fluid (CSF) of CJD patients, indicating that it is a potential diagnostic biomarker. Objective: The aim of this study was to assess the diagnostic power of CSF α -synuclein in discriminating CJD from non-prion disorders. Methods: The Ovid MEDLINE, Cochrane, and Embase databases were searched for articles published on or before February 25, 2022, using the search term (prion diseases OR Creutzfeldt-Jakob syndrome) AND (synuclein OR α -synuclein). The …difference in CSF α -synuclein levels between CJD and non-prion diseases was calculated using random-effects models (I2  > 50%) or fixed-effects models (I2  < 50%) in terms of standardized mean difference (SMD) and 95% confidence interval (CI). The publication bias was estimated using funnel plots and the Egger’s test. Results: Ten studies were included in this study. The concentrations of CSF α -synuclein were significantly higher in CJD patients compared to total non-prion controls (SMD = 1.98, 95% CI 1.60 to 2.36, p  < 0.00001), tauopathies (SMD = 1.34, 95% CI 0.99 to 1.68, p  < 0.00001), synucleinopathies (SMD = 1.78, 95% CI 1.11 to 2.44, p  < 0.00001), or Alzheimer’s (SMD = 1.14, 95% CI 0.95 to 1.33, p  < 0.00001). CSF α -synuclein could distinguish CJD from non-prion diseases with overall sensitivity of 89% (95% CI 80–95%), specificity of 92% (95% CI 86–95%), and AUC of 0.96 (95% CI: 0.94–0.97). Conclusion: CSF α -synuclein has excellent diagnostic value in discriminating CJD from non-prion neurological diseases. Given the high heterogeneity among the included studies, further studies are needed to confirm its clinical utility. Show more

Keywords: α-synuclein, Creutzfeldt-Jakob disease, CSF biomarkers, meta-analysis, systematic review

DOI: 10.3233/JAD-220425

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 493-503, 2022

Authors: Yao, Weina | Zhang, Xiao | Zhao, Hui | Xu, Yun | Bai, Feng

Article Type: Research Article

Abstract: Objective: Background: Plasma neurofilament light chain (NFL) is a recognized biomarker for Alzheimer’s disease (AD) and inflammation. Intrinsically organized default mode network core subsystem and frontoparietal network (FPN) and their interactions support complex cognitive function. The present study investigated the inflammatory effect on cognitive integrity via plasma NFL coupling internetwork interactions in AD. Objective: Objective: This study investigates the hypothesis that inflammation-related plasma NFL could affect the interactions of the core subsystem and FPN, which leads to the aggravation of the clinical symptoms of AD-spectrum patients. Objective: Methods: A total of 112 AD-spectrum …participants underwent complete resting-state fMRI, neuropsychological tests, and plasma NFL at baseline (n  = 112) and after approximately 17 months of follow-up (n  = 112). The specific intersystem changes in the core subsystem and FPN were calculated and compared across groups. Then, the classifications of different AD-spectrum groups were analyzed using the association of plasma NFL and the changed intersystem interacting regions. Finally, mediation analysis was applied to investigate the significance of plasma NFL coupling networks on cognitive impairments in these subjects. Objective: Results: Discrimination of disease-related interactions of the core subsystem and FPN was found in AD-spectrum patients, which was the neural circuit fundamental to plasma NFL disrupting cognitive integrity. Furthermore, the clinical significance of plasma NFL coupling networks on AD identification and monitoring cognitive impairments were revealed in these subjects. Conclusion: The characteristic change in inflammation-related plasma NFL coupled with brain internetwork interactions could be used as a potential observation indicator in the progression of AD patients. Show more

Keywords: Alzheimer’s disease, cognitive integrity, core subsystem, frontoparietal network, plasma neurofilament light chain

DOI: 10.3233/JAD-220475

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 505-518, 2022

Authors: Li, Chenxi | Li, Youjun | Wu, Jianqian | Wu, Min | Peng, Fang | Chao, Qiuling

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is considered to be a transitional stage between Alzheimer’s disease (AD) and normal cognitive state because it has the same clinical symptoms as AD but with lower severity. Studies have confirmed that patients with aMCI are more likely to develop to AD. Although studies on resting state functional connectivity have revealed the abnormal organization of brain networks, the dynamic changes of the functional connectivity across the scans have been ignored. Objective: Dynamic functional connectivity is a novel method to reveal the temporal variation of brain networks. This paper aimed to investigate the …dynamic characteristics of brain functional connectivity in the early and late phases of aMCI. Methods: Based on the “triple network” model, we used the sliding time window approach to construct dynamical functional networks and then analyzed the dynamic characteristics of the functional connectivity across the entire scan. Results: The results showed that patients with aMCI had longer dwell times in weaker network connection than in the strong network. The transitions between different states become more frequent, and the stability of the patient’s brain core network deteriorates. This study also found the correlation between the altered dynamic properties of the core functional networks and the patient’s clinical Mini-Mental State Examination assessment scale sores. Conclusion: This study revealed that the characteristics of dynamic functional networks constructed by the core cognitive networks varied in distinct ways at different stages of aMCI, which could provide a new idea for exploring the neuro-mechanisms of neurological disorders. Show more

Keywords: Amnestic mild cognitive impairment, dynamic functional connectivity network, temporal variability, triple network

DOI: 10.3233/JAD-220282

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 519-533, 2022

Authors: Caprioglio, Camilla | Garibotto, Valentina | Jessen, Frank | Frölich, Lutz | Allali, Gilles | Assal, Frédéric | Frisoni, Giovanni B. | Altomare, Daniele

Article Type: Research Article

Abstract: Background: Recent advances occurred in the field of Alzheimer’s disease (AD) biomarkers and the introduction of a research framework grounded on a biomarker-based definition of AD might have fostered an increased clinical use of AD biomarkers. For this reason, an up-to-date depiction of the clinical use of AD biomarkers is needed. Objective: To investigate the clinical use of the main AD biomarkers in patients with mild cognitive impairment (MCI) by examining the beliefs and preferences of professionals (clinicians and biomarker experts) of the European Alzheimer’s Disease Consortium (EADC). Methods: 150 professionals filled in an online survey …from May to September 2020. The investigated biomarkers were medial temporal lobe atrophy score (MTA) on structural MRI, typical AD (i.e., temporoparietal and posterior cingulate) hypometabolism on FDG-PET, CSF (Aβ42 , p-tau, t-tau), amyloid-PET and tau-PET. Results: The frequency of responders reporting a frequent-to-constant use of MTA (77%) is higher than that of those reporting a frequent-to-constant use of the other AD biomarkers (i.e., CSF: 45%, p  = 0.014; FDG-PET: 32%, p  < 0.001; amyloid-PET: 8%, p  < 0.001; and tau-PET: 2%, p  < 0.001). CSF is considered the most valuable biomarker in terms of additional diagnostic value, followed by amyloid-PET, tau-PET, and typical AD hypometabolism on FDG-PET. Conclusion: AD biomarkers are widely used across European memory clinics with a clinical research background for the diagnosis of MCI. Overall, we observed that CSF is currently considered as the most useful biomarker, followed by amyloid-PET. Show more

Keywords: Alzheimer’s disease, amyloid-PET, APOE , biomarkers, cerebrospinal fluid, clinical use, FDG-PET, magnetic resonance imaging, mild cognitive impairment, tau-PET

DOI: 10.3233/JAD-220333

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 535-551, 2022

Authors: Lai, Po-Yu | Wang, Wen-Fu | Chang, Ming-Che | Jhang, Kai-Ming

Article Type: Research Article

Abstract: Background: The global population with dementia is growing rapidly. Dementia patients have been included in the services of the long-term care Act 2.0, supported by Taiwan’s government since 2017. Community aging care centers are extensively established, which are places providing social connections and group physical and cognitive training programs for elderly people. Objective: To elucidate the efficacy of community aging care centers on cognitive function in people with dementia. Methods: A total of 1,277 patients with dementia diagnosed at the Changhua Christian Hospital outpatient departments were enrolled. A total of 113 patients who used community aging …care centers and 452 subjects matched for age, education, and initial score of clinical dementia rating scale sum of boxes (CDR-SOB) control group were analyzed. The primary outcome was the change in CDR-SOB scores before and after utilization of community aging care centers. Results: The mean annual change of CDR-SOB scores were 1.72±2.97, 1.08±2.36, and 1.04±3.64 in control, Community Service Centers for Dementia, and community elderly stations, respectively, after about 1.5 years follow-up. Patients with dementia using community aging care centers had significantly less progression in CDR-SOB scores than those in the control group (–0.65; 95% CI: –1.27, –0.03; p  = 0.041). Using one more day of community aging care centers per week significantly promotes 0.16 points of CDR-SOB decline (–0.16, 95% CI: –0.31; –0.00; p  = 0.045). Conclusion: Community aging care centers, based on the long-term care Act 2.0 in Taiwan, were effective in delaying the decline in global function in people living with dementia. Show more

Keywords: Cognitive dysfunction, community care, dementia, long-term care

DOI: 10.3233/JAD-220372

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 553-562, 2022

Authors: Hoffmann, Coles M. | Nianogo, Roch A. | Yaffe, Kristine | Rosenwohl-Mack, Amy | Carrasco, Anna | Barnes, Deborah E.

Article Type: Research Article

Abstract: Background: We recently estimated that 36.9% of Alzheimer’s disease and related dementias (ADRD) cases in the US may be attributable to modifiable risk factors, but it is not known whether national estimates generalize to specific states or regions. Objective: To compare national estimates of modifiable risk factors of ADRD to California, overall and by sex and race/ethnicity, and to estimate number of cases potentially preventable by reducing the prevalence of key risk factors by 25%. Methods: Adults ≥18 years who participated in the Behavioral Risk Factor Surveillance Survey in California (n  = 9,836) and the US (n … = 378,615). We calculated population attributable risks (PARs) for eight risk factors (physical inactivity, current smoking, depression, low education, diabetes mellitus, midlife obesity, midlife hypertension, and hearing loss) and compared estimates in California and the U.S. Results: In California, overall, 28.9% of ADRD cases were potentially attributable to the combination of risk factors, compared to 36.9% in the U.S. The top three risk factors were the same in California and the U.S., although their relative importance differed (low education [CA:14.9%; U.S.:11.7% ], midlife obesity [CA:14.9%; U.S.:17.7% ], and physical inactivity [CA:10.3%; U.S.:11.8% ]). The number of ADRD cases attributable to the combined risk factors was 199,246 in California and 2,287,683 in the U.S. If the combined risk factors were reduced by 25%, we could potentially prevent more than 40,000 cases in California and 445,000 cases in the U.S. Conclusion: Our findings highlight the importance of examining risk factors of ADRD regionally, and within sex and race/ethnic groups to tailor dementia risk reduction strategies. Show more

Keywords: Alzheimer’s disease, dementia, public health, prevention, risk factors

DOI: 10.3233/JAD-220278

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 563-570, 2022

Authors: Canario, Edgar | Chen, Donna | Han, Ying | Niu, Haijing | Biswal, Bharat

Article Type: Research Article

Abstract: Background: A minimum spanning tree (MST) is a unique efficient network comprising the necessary connections needed to connect all regions in a network while retaining the lowest possible cost of connection weight. Objective: This study aimed to utilize functional near-infrared spectroscopy (fNIRS) to analyze brain activity in different regions and then construct MST-based regions to characterize the brain topologies of participants with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and normal controls (NC). Methods: A 46 channel fNIRS setup was used on all participants, with correlation being calculated for each channel pair. An MST was constructed …from the resulting correlation matrix, from which graph theory measures were calculated. The average number of connections within a lobe in the left versus right hemisphere was calculated to identify which lobes displayed and abnormal amount of connectivity. Results: Compared to those in the MCI group, the AD group showed a less integrated network structure, with a higher characteristic path length, but lower leaf fraction, maximum degree, and degree divergence. The AD group also showed a higher number of connections in the frontal lobe within the left hemisphere and a lower number between hemispheric frontal lobes as compared to MCI. Conclusion: These results indicate a deviation in network structure and connectivity within patient groups that is consistent with the theory of dysconnectivity for AD. Additionally, the AD group showed strong correlations between the Hamilton depression rating scale and different graph metrics, suggesting a link between network organization and the recurrence of depression in AD. Show more

Keywords: Amyloid, cognitive decline, depression, functional neuroimaging

DOI: 10.3233/JAD-215573

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 571-581, 2022

Authors: Cao, Qiao-Ling | Sun, Yan | Hu, Hao | Wang, Zuo-teng | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The links between cerebral small vessel disease (CSVD) burden and neuropsychiatric symptoms (NPS) have not been fully studied. Objective: We aimed to explore the associations of the CSVD burden with Neuropsychiatric Inventory (NPI) total scores and its subsyndromes in the elderly without dementia. Methods: We investigated 630 non-demented participants from the Alzheimer’s Disease Neuroimaging Initiative. All of them had NPI assessments and 3 Tesla MRI scans at baseline and 616 had longitudinal NPI assessments during the follow-up. Linear mixed-effects models were used to investigate the cross-sectional and longitudinal associations of CSVD burden with NPI total …scores and its subsyndromes. Results: Higher CSVD burden longitudinally predicted more serious neuropsychiatric symptoms, including NPS (p  < 0.0001), hyperactivity (p  = 0.0006), affective symptoms (p  = 0.0091), and apathy (p  < 0.0001) in the total participants. Lacunar infarcts (LIs), white matter hyperactivities (WMHs), and cerebral microbleeds (CMBs) might play important roles in the occurrence of NPS, since they were longitudinally associated with specific neuropsychiatric subsyndromes. LIs contributed to hyperactivity (p  = 0.0092), psychosis (p  = 0.0402), affective symptoms (p  = 0.0156), and apathy (p  < 0.0001). WMHs were associated with hyperactivity (p  = 0.0377) and apathy (p  = 0.0343). However, CMBs were only related to apathy (p  = 0.0141). Conclusion: CSVD burden was associated with multiple neuropsychiatric symptoms, suggesting the importance of monitoring and controlling vascular risk factors. Different markers of CSVD were associated with specific subsyndromes of NPS, suggesting that different markers tended to occur in different encephalic regions. Show more

Keywords: Alzheimer’s Disease Neuroimaging Initiative, cerebral small vessel disease burden, neuropsychiatric subsyndrome, non-demented elders

DOI: 10.3233/JAD-220128

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 583-592, 2022

Authors: Liu, Zi-Yue | Zhai, Fei-Fei | Han, Fei | Li, Ming-Li | Zhou, Lixin | Ni, Jun | Yao, Ming | Zhang, Shu-Yang | Cui, Li-Ying | Jin, Zheng-Yu | Zhu, Yi-Cheng

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in the elderly population. Exploring patterns of white matter damage at the microstructural level would give important indications for the underlying mechanisms. Objective: To investigate the spatial patterns of white matter microstructure and structural network alternations in relation to different cognition domains Methods: Participants from the community-based Shunyi Study were included to investigate the association between white matter measurements and cognition cross-sectionally, via both global and local analysis. Cognitive functions were assessed using digit span, trail making test (TMT)-A/B, Fuld object Memory, and 12-Word Philadelphia Verbal Learning Test (PVLT). White matter …measurements including fractional anisotropy (FA), mean diffusivity (MD), and structural network parameters were calculated based on diffusion tensor imaging. Results: Of the 943 participants included, the mean (SD) age was 55.8 (9.1) years, and the mean (SD) education level was 6.7 (3.2) years. We found the whole set of cognitive measurements was related to diffused white matter microstructural integrity damage and lower global efficiency. Poor executive functions (TMTA/B complete time) were related to lower FA and higher MD predominantly on the anterior white matter skeleton, while verbal memory loss (PVLT test scores) was related to sub-network dysconnectivity in the midline and the right temporal lobe. Conclusion: The anterior brain is dominantly involved in executive dysfunction, while midline and right temporal brain disconnection are more prominent in verbal memory loss. Global and regional disruption of white matter integrity and network connectivity is the anatomical basis of the cognitive impairment in the aging population. Show more

Keywords: Aging, cognitive function, diffuse tensor imaging, white matter network

DOI: 10.3233/JAD-220191

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 593-603, 2022

Authors: Contini, Cristina | Serrao, Simone | Manconi, Barbara | Olianas, Alessandra | Iavarone, Federica | Bizzarro, Alessandra | Masullo, Carlo | Castagnola, Massimo | Messana, Irene | Diaz, Giacomo | Cabras, Tiziana

Article Type: Research Article

Abstract: Background: Aging is a risk factor for several pathologies as Alzheimer’s disease (AD). Great interest exists, therefore, in discovering diagnostic biomarkers and indicators discriminating biological aging and health status. To this aim, omic investigations of biological matrices, as saliva, whose sampling is easy and non-invasive, offer great potential. Objective: Investigate the salivary proteome through a statistical comparison of the proteomic data by several approaches to highlight quali-/quantitative variations associated specifically either to aging or to AD occurrence, and, thus, able to classify the subjects. Methods: Salivary proteomic data of healthy controls under-70 (adults) and over-70 (elderly) …years old, and over-70 AD patients, obtained by liquid chromatography/mass spectrometry, were analyzed by multiple Mann-Whitney test, Kendall correlation, and Random-Forest (RF) analysis. Results: Almost all the investigated proteins/peptides significantly decreased in relation to aging in elderly subjects, with or without AD, in comparison with adults. AD subjects exhibited the highest levels of α-defensins, thymosin β4, cystatin B, S100A8 and A9. Correlation tests also highlighted age/disease associated differences. RF analysis individuated quali-/quantitative variations in 20 components, as oxidized S100A8 and S100A9, α-defensin 3, P-B peptide, able to classify with great accuracy the subjects into the three groups. Conclusion: The findings demonstrated a strong change of the salivary protein profile in relation to the aging. Potential biomarkers candidates of AD were individuated in peptides/proteins involved in antimicrobial defense, innate immune system, inflammation, and in oxidative stress. RF analysis revealed the feasibility of the salivary proteome to discriminate groups of subjects based on age and health status. Show more

Keywords: Aging, α-defensins, Alzheimer’s disease, RF analysis, salivary proteome, S100A8, S100A9, thymosin β4

DOI: 10.3233/JAD-220246

Citation: Journal of Alzheimer's Disease, vol. 89, no. 2, pp. 605-622, 2022