Journal of Alzheimer's Disease - Volume 88, issue 1

Authors: Liang, Yajun | Gao, Ya | Wang, Rui | Grande, Giulia | Monastero, Roberto | Dong, Yanhong | Jiang, Xin | Lv, Peiyuan | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: The potential impact of migraine on cognitive aging among older adults remains controversial. Objective: To examine the relationship of migraine and subtypes with cognitive decline and dementia in an older Swedish population. Methods: This population-based study included 3,069 participants (age ≥ 60 years) from the Swedish National study on Aging and Care in Kungsholmen, Stockholm. Baseline examination was conducted in 2001–2004, and participants were followed every 3 or 6 years until 2013–2016. Data were collected through face-to-face interviews, clinical examinations, laboratory tests, and linkage with registers. Global cognitive function was measured with the Mini-Mental State …Examination (MMSE). Dementia was diagnosed according to the DSM-IV criteria. Migraine and subtypes were defined following the international classification system. Data were analyzed using logistic regression, Cox regression, and linear mixed-effects models. Results: At baseline, 305 participants were defined with non-migraine headache and 352 with migraine. The cross-sectional analysis showed that the multivariable-adjusted odds ratio (95% confidence interval) of prevalent dementia was 0.49 (0.20–1.21) for migraine and 0.66 (0.26–1.66) for migraine without aura. The longitudinal analysis showed that the multivariable-adjusted hazard ratios of incident dementia associated with migraine and subtypes ranged 0.68–0.89 (p  > 0.05). Furthermore, migraine and subtypes were not significantly associated with either baseline MMSE score or MMSE changes during follow-ups (p  > 0.05). The nonsignificant associations did not vary substantially by age, APOE ɛ 4 allele, cerebrovascular disease, and antimigraine treatment (p for interactions > 0.05). Conclusion: This study shows no evidence supporting the associations of migraine and its subtypes with cognitive decline and dementia among older adults. Show more

Keywords: Cognitive aging, dementia, headache, migraine, population-based study

DOI: 10.3233/JAD-220013

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 263-271, 2022

Authors: Zhang, Xingxing | Guan, Qing | Li, Yingjia | Zhang, Jianfeng | Zhu, Wanlin | Luo, Yuejia | Zhang, Haobo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: BOLD signals in the gray matter (GM) and white matter (WM) are tightly coupled. However, our understanding of the cross-tissue functional network in Alzheimer’s disease (AD) is limited. Objective: We investigated the changes of cross-tissue functional connectivity (FC) metrics for the GM regions susceptible to AD damage. Methods: For each GM region in the default mode (DMN) and limbic networks, we obtained its low-order static FC with any WM region, and the high-order static FC between any two WM regions based on their FC pattern similarity with multiple GM regions. The dynamic and directional properties …of cross-tissue FC were then acquired, specifically for the regional pairs whose low- or high-order static FCs showed significant differences between AD and normal control (NC). Moreover, these cross-tissue FC metrics were correlated with voxel-based GM volumes and MMSE in all participants. Results: Compared to NC, AD patients showed decreased low-order static FCs between the intra-hemispheric GM-WM pairs (right ITG-right fornix ; left MoFG-left posterior corona radiata ), and increased low-order static, dynamic, and directional FCs between the inter-hemispheric GM-WM pairs (right MTG-left superior/posterior corona radiata ). The high-order static and directional FCs between the left cingulate bundle -left tapetum were increased in AD, based on their FCs with the GMs of DMN. Those decreased and increased cross-tissue FC metrics in AD had opposite correlations with memory-related GM volumes and MMSE (positive for the decreased and negative for the increased). Conclusion: Cross-tissue FC metrics showed opposite changes in AD, possibly as useful neuroimaging biomarkers to reflect neurodegenerative and compensatory mechanisms. Show more

Keywords: Alzheimer’s disease, directional, dynamic, functional connectivity, gray matter, high-order, static, white matter

DOI: 10.3233/JAD-215649

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 273-290, 2022

Authors: Contador, Israel | Alzola, Patricia | Bermejo-Pareja, Félix | del Ser, Teodoro | Llamas-Velasco, Sara | Fernández-Calvo, Bernardino | Benito-León, Julián

Article Type: Research Article

Abstract: Background: A protective effect of education on cognitive decline after stroke has been claimed, but evidence from prospective population-based cohorts is very limited. The differential role of literacy and education on dementia after stroke remains unexplored. Objective: This research addresses the role of education and literacy in dementia incidence after stroke and transient ischemic attack (TIA). Methods: 131 participants with stroke or TIA were identified within the population-based NEDICES study (N  = 5,278 persons). Participants were fully assessed at baseline (1994–1995) and incident dementia diagnosis was made by expert neurologists (DSM-IV criteria) after a mean follow-up of …3.4 years. Adjusted Cox regression analyses were applied to test the association between education, literacy, and dementia risk. Results: Within the 131 subjects with stroke or TIA, 19 (14%) developed dementia at follow-up. The Cox’s regression model (age and sex adjusted) showed that low education (HR = 3.48, 95% CI = 1.28, 9.42, p  = 0.014) and literacy (HR = 3.16, 95% CI = 1.08, 9.22, p  = 0.035) were significantly associated with a higher dementia risk. Low education was also associated with dementia when main confounders (i.e., cognitive/functional performance) were considered in the Cox’s model. However, after including stroke recurrence, only low/null literacy (versus education) remained as significant predictor of dementia. Finally, low/null literacy showed an effect over-and-above education on dementia risk when both factors were introduced in the adjusted Cox’s regression. Conclusion: These findings underline the importance of literacy to estimate cognitive decline after stroke in low-educated populations. Show more

Keywords: Cognitive reserve, illiteracy, low education, stroke, transient ischemic attack

DOI: 10.3233/JAD-220109

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 291-299, 2022

Authors: Yeung, Michael K. | Lee, Tsz-lok | Chan, Agnes S.

Article Type: Research Article

Abstract: Background: Identifying individuals at increased risks for developing Alzheimer’s disease (AD) is crucial for early intervention. Memory complaints are associated with brain abnormalities characteristic of AD in cognitively normal older people. However, the utility of memory complaints for predicting mild cognitive impairment (MCI) or AD onset remains controversial, likely due to the heterogeneous nature of this construct. Objective: We investigated whether prefrontal oxygenation changes measured by functional near-infrared spectroscopy (fNIRS) during an arduous cognitive task, previously shown to be associated with the AD syndrome, could differentiate memory abilities among individuals with memory complaints. Episodic memory performance was adopted …as a proxy for MCI/AD risks since it has been shown to predict AD progression across stages. Methods: Thirty-six adults self-reporting memory complaints in the absence of memory impairment completed a verbal list learning test and underwent a digit n -back paradigm with an easy (0-back) and a difficult (2-back) condition. K-means clustering was applied to empirically derive memory complaint subgroups based on fNIRS-based prefrontal oxygenation changes during the effortful 2-back task. Results: Cluster analysis revealed two subgroups characterized by high (n  = 12) and low (n  = 24) bilateral prefrontal activation during the 2-back but not a 0-back task. The low activation group was significantly less accurate across the n -back task and recalled significantly fewer words on the verbal memory test compared to the high activation group. Conclusion: fNIRS may have the potential to differentiate verbal memory abilities in individuals with self-reported memory complaints. Show more

Keywords: Episodic memory, fNIRS, k-means, memory complaints, n-back, prefrontal cortex

DOI: 10.3233/JAD-220130

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 301-310, 2022

Authors: Wittfeld, Katharina | Raman, Mekala R. | Conner, Sarah C. | Aslam, Asra | Teumer, Alexander | Nauck, Matthias | Hosten, Norbert | Habes, Mohamad | DeCarli, Charles | Vasan, Ramachandran S. | Beiser, Alexa S. | Himali, Jayandra J. | Seshadri, Sudha | Grabe, Hans J. | Satizabal, Claudia L.

Article Type: Research Article

Abstract: Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer’s disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer’s disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. Methods: We included participants from the Framingham Heart Study (n  = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n  = 674, mean age …50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], –0.05 [–0.09, –0.02], p  = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p  = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife. Show more

Keywords: Alzheimer’s disease endophenotype, C-reactive protein, cohort study, epidemiology, hippocampus, insulin-like growth factor, neuroimaging, white matter hyperintensity

DOI: 10.3233/JAD-220356

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 311-322, 2022

Authors: Blujus, Jenna Katherine | Korthauer, Laura Elizabeth | Awe, Elizabeth | Frahmand, Marijam | Driscoll, Ira

Article Type: Research Article

Abstract: Background: Disease-modifying treatments for Alzheimer’s disease (AD) may be more successful if interventions occur early, prior to significant neurodegeneration and subsequent to the onset of clinical symptoms, potentially during middle age. Polymorphisms within BDNF , COMT , and KIBRA have been implicated in AD and relate to episodic memory and executive functioning, two domains that decline early in AD. Objective: The purpose of the current study was to use an endophenotype approach to examine in healthy, non-demented middle-aged adults the association between polymorphisms in BDNF , COMT , and KIBRA and functional connectivity within networks related …to episodic memory and executive function (i.e., default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN)). Methods: Resting state networks were identified using independent component analysis and spatial maps with associated time courses were extracted using a dual regression approach. Results: Functional connectivity within the DMN was associated with polymorphisms in BDNF (rs11030096, rs1491850) and KIBRA (rs1030182, rs6555791, rs6555802) (p s < 0.05), ECN connectivity was associated with polymorphisms in KIBRA (rs10475878, rs6555791) (p s < 0.05), and FPN connectivity was associated with KIBRA rs6555791 (p  < 0.05). There were no COMT -related differences in functional connectivity of any of the three networks investigated (p s > 0.05). Conclusion: Our study demonstrates that in middle age, polymorphisms in BDNF and KIBRA are associated with altered functional connectivity in networks that are affected early in AD. Future preclinical work should consider these polymorphisms to further elucidate their role in pathological aging and to aid in the identification of biomarkers. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, endophenotypes, functional neuroimaging, genetic polymorphism, middle aged

DOI: 10.3233/JAD-215477

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 323-334, 2022

Authors: Agger, Mikkel Pejstrup | Carstensen, Marcus Schultz | Henney, Mark Alexander | Hansen, Luna Skytte | Baandrup, Anders Ohlhues | Nguyen, Mai | Petersen, Paul Michael | Madsen, Kristoffer Hougaard | Kjær, Troels Wesenberg

Article Type: Research Article

Abstract: Background: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted. Objective: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous …light (CON) and 40 Hz stroboscopic light (STROBE). Methods: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next. Results: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14). Conclusion: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker. Show more

Keywords: 40 Hz, Alzheimer’s disease, electroencephalograph, functional MRI, gamma entrainment, GENUS, invisible spectral flicker, light-based neurostimulation, steady state visually evoked potentials

DOI: 10.3233/JAD-220081

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 335-344, 2022

Authors: Wolfova, Katrin | Creese, Byron | Aarsland, Dag | Ismail, Zahinoor | Corbett, Anne | Ballard, Clive | Hampshire, Adam | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied. Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort. Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, …spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models. Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p  = 0.001) and social inappropriateness (12% versus 15%; p  < 0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36%; p  < 0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females. Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier. Show more

Keywords: Behavioral symptoms, cognition, dementia, gender differences, sex differences

DOI: 10.3233/JAD-220040

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 345-355, 2022

Authors: Zhang, Kaixia | Ma, Xiaoying | Zhang, Rui | Liu, Zanchao | Jiang, Lei | Qin, Yushi | Zhang, Di | Tian, Pei | Gao, ZhaoYu | Zhang, Nan | Shi, Zhongli | Xu, Shunjiang

Article Type: Research Article

Abstract: Background: The interactions between environmental factors and genetic variants have been implicated in the pathogenesis of Alzheimer’s disease (AD). The altered gut microbiota (GM) and vitamin D deficiency are closely associated with the higher risk of AD. Objective: This study was performed to evaluate whether the crosstalk between GM and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) or vitamin D binding protein (VDBP) have a link with the risk of amnestic mild cognitive impairment (aMCI) in the Chinese elderly population. Methods: A total of 171 aMCI patients and 261 cognitive normal controls (NC) were …enrolled in this study. Six tag SNPs of VDR and VDBP were genotyped by PCR-RFLP. The serum levels of vitamin D, Aβ1-42 , and p-tau (181P) were determined by using of ELISA kits. The alterations in the GM were analyzed by full-length 16S ribosomal RNA (rRNA) gene sequencing. Results: The frequencies of AG genotype and A allele of VDR rs1544410 in aMCI group were significantly higher than that in NC group (genotype: p  = 0.002, allele: p  = 0.003). Patients with aMCI showed an abnormal GM composition compared with NC group. Interestingly, significant differences in GM composition were found between aMCI and NC group among individuals with AG genotype, as well as between individuals with AG and GG genotype of VDR rs1544410 among patients with aMCI. Conclusion: These results implicated that the crosstalk between gut microflora and vitamin D receptor variants are associated with the risk of aMCI in Chinese elderly population. Show more

Keywords: Amnestic mild cognitive impairment, full-length 16S rRNA sequencing, gut microbiota, single nucleotide polymorphisms, vitamin D receptor

DOI: 10.3233/JAD-220101

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 357-373, 2022

Authors: Cheng, Yuan | Jian, Jie-Ming | He, Chen-Yang | Ren, Jun-Rong | Xu, Man-Yu | Jin, Wang-Sheng | Tan, Cheng-Rong | Zeng, Gui-Hua | Shen, Ying-Ying | Chen, Dong-Wan | Li, Hui-Yun | Yi, Xu | Zhang, Yuan | Zeng, Fan | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. Objective: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-β (Aβ) and tau in the plasma and cerebrospinal fluid (CSF). Methods: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The …levels of FABP1 in plasma, and Aβ and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aβ levels. Results: The level of plasma FABP1 was significantly elevated in the AD group (p  = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aβ42 (AUC = 0.6794, p  = 0.0071) and FABP1/t-tau (AUC = 0.7168, p  = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aβ42 , Aβ40 , and t-tau, both FABP1/Aβ42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ42 had the highest diagnostic value (AUC = 0.8075, p  < 0.0001). Conclusion: These findings indicate that FABP1 may play a role in AD pathogenesis and be worthy of further investigation in the future. Show more

Keywords: Alzheimer’s disease, amyloid-β, liver-type fatty acid-binding protein, tau

DOI: 10.3233/JAD-220126

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 375-383, 2022