Journal of Alzheimer's Disease - Volume 88, issue 2

Authors: Kuriyama, Nagato | Koyama, Teruhide | Ozaki, Etsuko | Saito, Satoshi | Ihara, Masafumi | Matsui, Daisuke | Watanabe, Isao | Kondo, Masaki | Marunaka, Yoshinori | Takada, Akihiro | Akazawa, Kentaro | Tomida, Satomi | Nagamitsu, Reo | Miyatani, Fumitaro | Miyake, Masahiro | Nakano, Eri | Kobayashi, Daiki | Watanabe, Yoshiyuki | Mizuno, Shigeto | Maekawa, Mizuho | Yoshida, Tamami | Nukaya, Yukiko | Mizuno, Toshiki | Yamada, Kei | Uehara, Ritei

Article Type: Research Article

Abstract: Background: Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored. Objective: We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment. Methods: In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain …MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (< 0.65 nmol/L) or high (≥0.65 nmol/L). Results: The mean MR-proADM level was 0.515±0.127 nmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (p  < 0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; p  < 0.05). Conclusion: High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients. Show more

Keywords: Adrenomedullin, biomarkers, cerebral small vessel diseases, cognitive dysfunction, magnetic resonance imaging, peptides

DOI: 10.3233/JAD-220195

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 731-741, 2022

Authors: Haehner, Antje | Chen, Ben | Espin, Melanie | Haussmann, Robert | Matthes, Claudia | Desser, Dmitriy | Loessner, Lorenz | Brandt, Moritz D. | Donix, Markus | Hummel, Thomas

Article Type: Research Article

Abstract: Background: The olfactory system is affected early in Alzheimer’s disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear. Objective: The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients. …Methods: A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period. Results: After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus; the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL; the change of cortical thickness of entorhinal cortex was positively associated with change of executive function. Conclusion: Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy. Show more

Keywords: Cortical thickness, hippocampus, mild cognitive impairment, olfactory bulb, olfactory training

DOI: 10.3233/JAD-220248

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 743-755, 2022

Authors: Pyun, Jung-Min | Park, Young Ho | Kim, SangYun

Article Type: Research Article

Abstract: Background: Although thyroid dysfunction has been considered as a cause of reversible cognitive impairment, association between subclinical hypothyroidism and cognitive impairment is controversial. Objective: We compared cognitive profiles of patients in an euthyroid or subclinical hypothyroid (sHypo) state, as well as their disease progression from mild cognitive impairment (MCI) to dementia within 3 years. Methods: We included 2,181 patients in a euthyroid and 284 in a sHypo state over 60 years of age who underwent an extensive cognitive assessment at Seoul National University Bundang Hospital but were not prescribed levothyroxine, methimazole, carbimazole, or propylthiouracil. After propensity …score matching for age, sex, and education level, 1,118 patients in a euthyroid and 283 patients in a sHypo state were included. Attention, language, memory, visuocontructive, and executive functions were compared between the groups using Student’s t -test or the Mann-Whitney U test. To investigate the association between disease progression and subclinical hypothyroidism, a Cox regression analyses was performed in 379 patients with MCI. Patients with thyroid-stimulating hormone levels over 10 mlU/L was classified as the “sHypo10”, and hazard ratios for sHypo or sHypo10 were assessed. Results: There was no difference in attention, language, memory, visuoconstructive, and executive functions between the patient groups. Progression from MCI to dementia was not associated with sHypo or sHypo10. Conclusion: There was no difference in cognitive profile between euthyroid and sHypo patients, and no association between subclinical hypothyroidism and disease progression. This might suggest a clue of strategies regarding hormone therapy in subclinical hypothyroidism with cognitive impairment. Show more

Keywords: cognition, dementia, mild cognitive impairment, subclinical hypothyroidism

DOI: 10.3233/JAD-220302

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 757-762, 2022

Authors: Zhu, Liu-Ying | Shi, Lin | Luo, Yishan | Leung, Jason | Kwok, Timothy

Article Type: Research Article

Abstract: Background: Structural magnetic resonance imaging markers predicting symptomatic progression at the individual level can be highly beneficial for early intervention and treatment planning for Alzheimer’s disease (AD). However, the correlation between baseline MRI findings and AD progression has not been fully established. Objective: To explore the correlation between baseline MRI findings and AD progression. Methods: Brain volumetric measures were applied to differentiate the patients at risk of fast deterioration in AD. We included 194 AD patients with a 24-month follow-up: 65 slow decliners, 63 normal decliners, and 66 fast decliners categorized by changes in Alzheimer’s Disease …Assessment Scale-Cognitive Subscale (ADAS-Cog). ANOVA analyses were used to identify baseline brain atrophy between groups. Logistic regressions were further performed to explore the relative merits of AD resemblance structural atrophy index (AD-RAI) and individual regional volumetric measures in prediction of disease progression. Results: Atrophy in the temporal and insular lobes was associated with fast cognitive decline over 24 months. Smaller volumes of temporal and insular lobes in the left but not the right brain were associated with fast cognitive decline. Baseline AD-RAI predicted fast versus slow progression of cognitive decline (odds ratio 3.025 (95% CI: 1.064–8.600), high versus low, AUC 0.771). Moreover, AD-RAI was significantly lower among slow decliners when compared with normal decliners (p  = 0.039). Conclusion: AD-RAI on MRI showed potential in identifying clinical AD patients at risk of accelerated cognitive decline. Show more

Keywords: Alzheimer’s disease, atrophy index, automated brain volumetry, progression

DOI: 10.3233/JAD-215189

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 763-769, 2022

Authors: Ma, Xiaowei | Zhang, Yizhou | Gou, Dongyun | Ma, Jingle | Du, Juan | Wang, Chang | Li, Sha | Cui, Huixian

Article Type: Research Article

Abstract: Background: The activation of microglia and neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD), but the exact roles of microglia and the underlying mechanisms remain unclear. Objective: To clarify how the metabolic reprogramming of microglia induce by amyloid-β (Aβ)1-42 to affect the release of proinflammatory cytokines in AD. Methods: MTS assay was used to detect the viability of BV2 cells treated with different concentrations of Aβ1-42 for different periods of time. The expression levels of proinflammatory cytokines were determined by qRT-PCR and western blot assay in BV2 cells and hippocampus of …mice. RNA sequencing was applied to evaluate the gene expression profiles in response to HK2 knockdown in BV2 cells treated with Aβ1-42 . Results: Low concentrations of Aβ1-42 increased the viability of BV2 cells and promoted the release of proinflammatory cytokines, and this process is accompanied by increased glycolysis. Inhibition of glycolysis significantly downregulated the release of proinflammatory cytokines in BV2 cells and hippocampus of mice treated with Aβ1-42 . The results of RNA sequencing revealed the expression of chemokine ligand 2 (Cxcl2) and ephrin receptor tyrosine kinase A2 (EphA2) were significantly downregulated when knocked down HK2 in BV2 cells. Subsequently, the expression of proinflammatory cytokines was downregulated in BV2 cell after knocking down EphA2. Conclusion: This study demonstrated that EphA2/p38 MAPK pathway is involved the release of proinflammatory cytokines in microglia induced by Aβ1-42 in AD, which is accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis. Show more

Keywords: Alzheimer’s disease, EphA2, glycolysis, metabolic reprogramming, microglia, p38 MAPK

DOI: 10.3233/JAD-220227

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 771-785, 2022

Authors: Harper, Jordan D. | Fan, Kang-Hsien | Aslam, M. Muaaz | Snitz, Beth E. | DeKosky, Steven T. | Lopez, Oscar L. | Feingold, Eleanor | Kamboh, M. Ilyas

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for. Objective: The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above. Methods: We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects. Results: The established association …of APOE* 4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) = 2.22; p  = 9.36E-14) and was stronger in females (OR = 2.72; p  = 1.74E-10) than in males (OR = 1.88; p  = 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711 /rs148377161 (OR = 3.31; p  = 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/ rs140076909 on chromosome 1 (OR = 4.51; p  = 3.72E-08) and the other approaching GWS near ncRNA LOC105375138/ rs117803234 on chromosome 7 (OR = 3.76; p  = 6.93E-08). Conclusion: The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD. Show more

Keywords: Alzheimer’s disease, genome-wide association study (GWAS), incident dementia, non-coding RNA genes

DOI: 10.3233/JAD-220293

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 787-798, 2022

Article Type: Correction

DOI: 10.3233/JAD-229007

Citation: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 799-799, 2022