Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Horvath, Alexandra | Quinlan, Patrick | Eckerström, Carl | Åberg, N. David | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: Serum insulin-like growth factor-I (IGF-I) has shown some association with hippocampal volume in healthy subjects, but this relation has not been investigated in stable mild cognitive impairment (sMCI) or Alzheimer’s disease (AD). Objective: At a single memory clinic, we investigated whether serum IGF-I was associated with baseline magnetic resonance imaging (MRI)-estimated brain volumes and longitudinal alterations, defined as annualized changes, up to 6 years of follow-up. Methods: A prospective study of patients with sMCI (n  = 110) and AD (n  = 60). Brain regions included the hippocampus and amygdala as well as the temporal, parietal, frontal, and …occipital lobes, respectively. Results: Serum IGF-I was statistically similar in sMCI and AD patients (112 versus 123 ng/mL, p  = 0.31). In sMCI, serum IGF-I correlated positively with all baseline MRI variables except for the occipital lobe, and there was also a positive correlation between serum IGF-I and the annualized change in hippocampal volume (r  _ s = 0.32, p  = 0.02). Furthermore, sMCI patients having serum IGF-I above the median had lower annual loss of hippocampal volume than those with IGF-I below the median (p  = 0.02). In contrast, in AD patients, IGF-I did not associate with baseline levels or annualized changes in brain volumes. Conclusion: In sMCI patients, our results suggest that IGF-I exerted neuroprotective effects on the brain, thereby maintaining hippocampal volume. In AD, serum IGF-I did not associate with brain volumes, indicating that IGF-I could not induce neuroprotection in this disease. This supports the notion of IGF-I resistance in AD. Show more

Keywords: Alzheimer’s disease, brain region volume, hippocampus, insulin-like growth factor, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-220292

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 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 1,265 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. Pre-press, no. Pre-press, pp. 1-6, 2022

Authors: Babiloni, Claudio | Noce, Giuseppe | Di Bonaventura, Carlo | Lizio, Roberta | Eldellaa, Ali | Tucci, Federico | Salamone, Enrico M. | Ferri, Raffaele | Soricelli, Andrea | Nobili, Flavio | Famà, Francesco | Arnaldi, Dario | Palma, Eleonora | Cifelli, Pierangelo | Marizzoni, Moira | Stocchi, Fabrizio | Bruno, Giuseppe | Di Gennaro, Giancarlo | Frisoni, Giovanni B. | Del Percio, Claudio

Article Type: Research Article

Abstract: Background: Patients with amnesic mild cognitive impairment due to Alzheimer’s disease (ADMCI) typically show a “slowing” of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that “slowing.” Objective: Here we tested the hypothesis that the “slowing” of rsEEG rhythms is related to EEA in ADMCI patients. Methods: Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG …cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals. Results: EEA was observed in 15% (N = 8) of the ADMCI patients. The ADMCI-EEA group showed: 1) more abnormal Aβ 42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta (<4 Hz) rsEEG source activities as compared to the ADMCI-noEEA and Nold groups. Those source activities showed moderate accuracy (AUROCC = 0.70–0.75) in the discrimination between ADMCI-noEEA versus ADMCI-EEA individuals. Conclusion: It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance. Show more

Keywords: Epileptiform EEG activity, exact low-resolution brain electromagnetic source tomography, mild cognitive impairment due to Alzheimer’s disease, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-220442

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-29, 2022

Authors: Duan, Wenna | Sehrawat, Parshant | Zhou, Tony D. | Becker, James T. | Lopez, Oscar L. | Gach, H. Michael | Dai, Weiying

Article Type: Research Article

Abstract: Background: Biomarkers for Alzheimer’s disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. Objective: This study aims to quantify the forward magnetization transfer rate (k for ) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal k for in AD and AD progression. Methods: From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD …subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. Results: We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Conclusion: Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression. Show more

Keywords: Alzheimer’s disease, magnetization transfer imaging, magnetization transfer rate, mild cognitive impairment

DOI: 10.3233/JAD-220335

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-15, 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. Pre-press, no. Pre-press, pp. 1-13, 2022

Authors: García-Alberca, José María | Gris, Esther | de la Guía, Paz | Mendoza, Silvia

Article Type: Research Article

Abstract: Background: Depression is a common manifestation in Alzheimer’s disease (AD). In clinical practice, antidepressant medication is often used for depression in AD. Objective: We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting. Methods: We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received: tianeptine group (n  = 38) or other antidepressant group (n  = 88). Drug effects on depression, cognition, behavior, and …functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores. Results: Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test. Conclusion: Our results suggest that tianeptine reduces depressive symptoms and improve cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients. Show more

Keywords: Alzheimer’s disease, antidepressants, dementia, depressive symptoms, tianeptine

DOI: 10.3233/JAD-215630

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Jacob, Louis | Smith, Lee | Koyanagi, Ai | Konrad, Marcel | Haro, Josep Maria | Shin, Jae Il | Kostev, Karel

Article Type: Research Article

Abstract: Background: Little is known about the sex differences in the association between body mass index (BMI) and dementia in late life. Objective: Therefore, this retrospective cohort study aimed to analyze associations between BMI and dementia in older women and men separately in general practices in Germany. Methods: This study included patients followed in one of 832 general practices in Germany between 2006 and 2019 (index date: first visit date). Study variables included dementia (dependent variable), BMI (independent variable), age, sex, and comorbidities (control variables). Kaplan-Meier curves and adjusted Cox regression analyses were conducted to analyze associations …between BMI and the 10-year incidence of dementia in women and men, separately. Results: There were 296,767 patients included in this study (mean [standard deviation] age 70.2 [5.9 ] years; 54.3% women). The proportion of underweight, normal weight, overweight, and obesity was 0.9%, 25.5%, 41.5%, and 32.1%, respectively. The 10-year incidence of dementia significantly decreased with increasing BMI, from 11.5% in women with underweight to 9.1% in those with obesity (log-rank p  <  0.001). Respective figures in men were 12.0% and 8.2% (log-rank p  <  0.001). In women, only overweight (versus normal weight) was significantly associated with dementia (HR = 0.93, 95% CI = 0.88–0.97). In contrast, in men, the only BMI category significantly associated with the incidence of dementia was underweight (HR = 1.58, 95% CI = 1.11–2.25). Conclusion: In this study conducted in Germany, overweight was negatively associated with dementia in women, whereas there was a positive underweight-dementia relationship in men. More data are needed to confirm or refute these findings in other settings. Show more

Keywords: Body mass index, dementia, Germany, retrospective cohort study, sex differences

DOI: 10.3233/JAD-220147

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Wessels, Alette M. | Belger, Mark | Johnston, Joseph A. | Yu, Youying | Rentz, Dorene M. | Dowsett, Sherie A. | Chandler, Julie

Article Type: Research Article

Abstract: Background: The integrated Alzheimer’s Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures. Objective: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study. Methods: …Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition and/or function was the underlying explanation of any association between iADRS and health outcome change. Results: Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life. Conclusion: Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression. Show more

Keywords: Alzheimer’s disease, care burden, global burden of disease, outcome assessment (health care), outcome measures, patient relevant outcome

DOI: 10.3233/JAD-220303

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022