Journal of Alzheimer's Disease - Volume 76, issue 1

Authors: Chen, Chih-Hao | Chen, Ya-Fang | Tsai, Ping-Huan | Chiou, Jeng-Min | Lai, Liang-Chuan | Chen, Ta-Fu | Hung, Hung | Chen, Jen-Hau | Chen, Yen-Ching

Article Type: Research Article

Abstract: Background: Cerebral cortical thickness is a neuroimaging biomarker to predict cognitive decline, and kidney dysfunction (KD) is associated with cortical thinning. Objective: This study aimed to investigate the effects of KD and cortical thinning on cognitive change in a prospective cohort study. Methods: A total of 244 non-demented participants were recruited from elderly health checkup program and received cognitive exams including Montreal Cognitive Assessment (MoCA) and different cognitive domains at baseline and three biannual follow-ups afterwards. KD was defined as having either glomerular filtration rate <60 ml/min/1.73 m2 or proteinuria. Cortical thickness of global, lobar, and Alzheimer’s …disease (AD) signature area were derived from magnetic resonance imaging at baseline, and cortical thinning was defined as the lowest tertile of cortical thickness. Generalized linear mixed models were applied to evaluate the effects of KD and cortical thinning on cognitive changes. Results: KD was significantly associated with the decline in attention function (β= –0.29). Thinning of global (β= –0.06), AD signature area (β= –0.06), temporal (β= –0.06), and parietal lobes (β= –0.06) predicted poor verbal fluency over time, while temporal lobe thinning also predicted poor MoCA score (β= –0.19). KD modified the relationship between thinning of global, frontal, and limbic, and change of logical memory function (p interaction  < 0.05). When considering jointly, participants with both KD and cortical thinning had greatest decline in attention function compared with those without KD or cortical thinning (β= –0.51, p trend  = 0.008). Conclusions: KD and cortical thinning have joint effect on cognitive decline, especially the attention function. Reverse associations may exist between cortical thinning and memory function in participants with KD, though the results should be interpreted cautiously as an exploratory analysis. Show more

Keywords: Cerebral cortex, cognition, glomerular filtration rate, proteinuria

DOI: 10.3233/JAD-200053

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 225-236, 2020

Authors: Shi, Yan | Gao, Feng | Yang, Xiaoli | Liu, Dongwei | Han, Qiuxia | Liu, Zhangsuo | Zhu, Hanyu | Shen, Yong

Article Type: Research Article

Abstract: Background: It is believed that there is a certain correlation between the brain and kidneys, but it is poorly understood. Many findings suggested that there were previously unknown signaling pathways involving AβPP and BACE1 in the kidney. Objective: Exploring the changes of BACE1 activity in APP23 mouse kidneys, providing evidence for the function of AβPP and BACE1 activity in the kidney. Methods: The activity and expression of BACE1 were detected in the kidney of APP23 mice by enzymatic assay and western blotting. The protein expression levels of AβPP, claudin1, occludin, VE-cadherin, and Klotho (membrane-form klotho) were …examined by using western blotting. The renal pathological changes of APP23 mice were examined by the routine renal pathological procedures. Results: In this study, we found that the AβPP protein level was increased in kidneys of APP23 mice compared with wild-type (WT) mice. Additionally, the activity and expression of BACE1 were increased in kidneys of APP23 mice compared to that of WT. BACE1 was predominantly distributed on the lumen side of renal tubular epithelial cells. The protein levels of Klotho and VE-cadherin were decreased, occludin expression was also decreased, and claudin-1 expression was increased. Renal pathological damage which observed in kidneys of APP23 mice was more serious than that in kidneys of WT mice. Conclusion: Our findings suggest that the increase of AβPP protein levels under Thy-1 neuron promoter in the APP23 mice promoted the increase of renal BACE1 expression and enzymatic activity in the kidneys. Moreover, certain pathological damage in the kidneys of APP23 mice were observed. APP23 mice are easily affected by external risk factors compared with WT mice. Show more

Keywords: Alzheimer’s disease, APP23, BACE1, brain-renal risk factor, kidney

DOI: 10.3233/JAD-200204

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 237-248, 2020

Authors: Yang, Kun | Chen, Guanqun | Sheng, Can | Xie, Yunyan | Li, Yuxia | Hu, Xiaochen | Sun, Yu | Han, Ying

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) and brain reserve (BR) could offer protective effects on cognition in the early stage of Alzheimer’s disease (AD). However, the effects of CR or BR on cognition in individuals with subjective cognitive decline (SCD) are not clear. Objective: To explore the effects of CR and BR on cognition in subjects with SCD. Methods: We included 149 subjects from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Education was used as a proxy for CR, and head circumference was used as a proxy for BR. Multiple linear regression models were conducted to …examine the effects of CR and BR on cognitive scores. Furthermore, we assessed differences in effects between APOE ɛ 4 carriers with SCD (n  = 35) and APOE ɛ 4 non-carriers with SCD (n  = 114) and linear trends among 4 reserve levels (low BR/CR, high BR/low CR, low BR/high CR, and high BR/high CR). Results: Both CR and BR had independent positive effects on multiple cognitive measures in SCD participants, and the effects of CR were greater than those of BR. CR has positive effects on cognitive measures in both APOE ɛ 4 carriers and non-carriers with SCD. However, the positive effects of BR on cognitive measures were observed in APOE ɛ 4 non-carriers with SCD but not in APOE ɛ 4 carriers with SCD. Furthermore, there was a linear trend toward better cognitive performance on all cognitive measures in the BR+/CR+ group, followed by the BR–/CR+, BR+/CR–, and BR–/CR–groups. Conclusion: This study suggests that both CR and BR have the potential to delay or slow cognitive decline in individuals with SCD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, brain reserve, cognition, cognitive reserve, dementia, education, head circumference, reserve, subjective cognitive decline

DOI: 10.3233/JAD-200082

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 249-260, 2020

Authors: Stricker, Nikki H. | Lundt, Emily S. | Albertson, Sabrina M. | Machulda, Mary M. | Pudumjee, Shehroo B. | Kremers, Walter K. | Jack Jr., Clifford R. | Knopman, David S. | Petersen, Ronald C. | Mielke, Michelle M.

Article Type: Research Article

Abstract: Background: There are detectable cognitive differences in cognitively unimpaired (CU) individuals with preclinical Alzheimer’s disease (AD). Objective: To determine whether cross-sectional performance on the Cogstate Brief Battery (CBB) and Auditory Verbal Learning Test (AVLT) could identify 1) CU participants with preclinical AD defined by neuroimaging biomarkers of amyloid and tau, and 2) incident mild cognitive impairment (MCI)/dementia. Method: CU participants age 50+ were eligible if they had 1) amyloid (A) and tau (T) imaging within two years of their baseline CBB or 2) at least one follow-up visit. AUROC analyses assessed the ability of measures to …differentiate groups. We explored the frequency of cross-sectional subtle objective cognitive impairment (sOBJ) defined as performance ≤–1 SD on CBB Learning/Working Memory Composite (Lrn/WM) or AVLT delayed recall using age-corrected normative data. Results: A+T+ (n  = 33, mean age 79.5) and A+T– (n  = 61, mean age 77.8) participants were older than A–T– participants (n  = 146, mean age 66.3), and comparable on sex and education. Lrn/WM did not differentiate A  + T+or A+T– from A–T– participants. AVLT differentiated both A+T+ and A+T– from A–T– participants; 45% of A+T+ and 25% of A+T– participants met sOBJ criteria. The follow-up cohort included 150 CU individuals who converted to MCI/dementia and 450 age, sex, and education matched controls. Lrn/WM and AVLT differentiated between stable and converter CU participants. Conclusion: Among CU participants, AVLT helped differentiate A+T+ and A+T– from A–T– participants. The CBB did not differentiate biomarker subgroups, but showed potential for predicting incident MCI/dementia. Results inform future definitions of sOBJ. Show more

Keywords: Amyloid, Cognigram, conversion, memory, neuropsychology, one back, one card learning, sensitivity and specificity, subtle cognitive decline, tau

DOI: 10.3233/JAD-200087

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 261-274, 2020

Authors: Raji, Cyrus A. | Meysami, Somayeh | Merrill, David A. | Porter, Verna R. | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer’s disease (AD). Objective: Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD. Methods: This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen’s D effect sizes were calculated for statistically significant structures. Partial …correlations between bilingualism and brain volumes adjusted for age, gender, and TIV. Results: Bilinguals had higher brain volumes in 37 structures. Statistical significance (p  < 0.05) was observed in brainstem (t  = 2.33, p  = 0.02, Cohen’s D  = 0.71) and ventral diencephalon (t  = 3.01, p  = 0.004, Cohen’s D  = 0.91). Partial correlations showed statistical significance between bilingualism and larger volumes in brainstem (rp  = 0 .  37, p  = 0.01), thalamus (rp  = 0.31, p  = 0.04), ventral diencephalon (rp  = 0.50, p  = 0.001), and pallidum (rp  = 0.38, p  = 0.01). Bilingualism positively correlated with hippocampal volume, though not statistically significant (rp  = 0.17, p  = 0.26). No brain volumes were larger in monolinguals. Conclusion: Bilinguals demonstrated larger thalamic, ventral diencephalon, and brainstem volumes compared to matched monolinguals with AD. This may represent a neural substrate for increased cognitive reserve in bilingualism. Future studies should extrapolate this finding into cognitively normal persons at risk for AD. Show more

Keywords: Alzheimer’s disease, bilingual, brain structure, Neuroreader

DOI: 10.3233/JAD-200200

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 275-280, 2020

Authors: Cho, Soo Hyun | Choe, Yeong Sim | Kim, Young Ju | Kim, Hee Jin | Jang, Hyemin | Kim, Yeshin | Kim, Si Eun | Kim, Seung Joo | Kim, Jun Pyo | Jung, Young Hee | Kim, Byeong C. | Lockhart, Samuel N. | Farrar, Gill | Na, Duk L. | Moon, Seung Hwan | Seo, Sang Won

Article Type: Research Article

Abstract: Background: 18 F-florbetaben (FBB) and 18 F-flutemetamol (FMM) amyloid PET have been developed and approved for clinical use. It is important to understand the distinct features of these ligands to compare and correctly interpret the results of different amyloid PET studies. Objective: We performed a head-to-head comparison of FBB and FMM to compare with regard to imaging characteristics, including dynamic range of retention, and differences in quantitative measurements between the two ligands in cortical, striatal, and white matter (WM) regions. Methods: Paired FBB and FMM PET images were acquired in 107 participants. Correlations of FBB and …FMM amyloid deposition in the cortex, striatum, and WM were investigated and compared in different reference regions (cerebellar gray matter (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons). Results: The cortical SUVR (R2  = 0.97) and striatal SUVR (R2  = 0.95) demonstrated an excellent linear correlation between FBB and FMM using a WC as reference region. There was no difference in the cortical SUVR ratio between the two ligands (p  = 0.90), but the striatal SUVR ratio was higher in FMM than in FBB (p  < 0.001). Also, the effect size of differences in striatal SUVR seemed to be higher with FMM (2.61) than with FBB (2.34). These trends were similarly observed according to four different reference regions (CG, WC, WC + B, and pons). Conclusion: Our findings suggest that FMM might be better than FBB to detect amyloid burden in the striatum, although both ligands are comparable for imaging AD pathology in vivo . Show more

Keywords: Alzheimer’s disease, amyloid imaging, 18F-florbetaben, 18F-flutemetamol, head to head

DOI: 10.3233/JAD-200079

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 281-290, 2020

Authors: Chatterjee, Pratishtha | Mohammadi, Maryam | Goozee, Kathryn | Shah, Tejal M. | Sohrabi, Hamid R. | Dias, Cintia B. | Shen, Kaikai | Asih, Prita R. | Dave, Preeti | Pedrini, Steve | Ashton, Nicholas J. | Hye, Abdul | Taddei, Kevin | Lovejoy, David B. | Zetterberg, Henrik | Blennow, Kaj | Martins, Ralph N.

Article Type: Research Article

Abstract: Background/Objective: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer’s disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-β load (NAL). Methods: Serum hepcidin levels in cognitively normal participants (n  = 100) aged between 65–90 years were measured using ELISA. To evaluate NAL, all …participants underwent 18 F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)<1.35 was classified as low NAL (n  = 65) and ≥1.35 (n  = 35) was classified as high NAL. Results: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOE ɛ 4 carriage (p  < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aβ42/40 ratio (AUC = 0.829). Conclusion: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required. Show more

Keywords: Alzheimer’s disease, amyloid deposits, hepcidin, iron dyshomeostasis, positron emission tomography

DOI: 10.3233/JAD-200162

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 291-301, 2020

Authors: Lim, Wei Ling Florence | Huynh, Kevin | Chatterjee, Pratishtha | Martins, Ian | Jayawardana, Kaushala S. | Giles, Corey | Mellett, Natalie A. | Laws, Simon M. | Bush, Ashley I. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Drew, Brian G. | Masters, Colin L. | Meikle, Peter J. | Martins, Ralph N. | AIBL research group

Article Type: Research Article

Abstract: Background: Lipid metabolism is altered in Alzheimer’s disease (AD); however, the relationship between AD risk factors (age, APOE ɛ 4, and gender) and lipid metabolism is not well defined. Objective: We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals. Methods: We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and …interaction analysis were used to explore the relationship between risk factors and plasma lipid species. Results: We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOE ɛ 4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOE ɛ 4 may, in part, be mediated by changes in lipid metabolism. Conclusion: This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways. Show more

Keywords: Aging, Alzheimer’s disease, APOE ɛ4, gender, lipid species

DOI: 10.3233/JAD-191304

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 303-315, 2020

Authors: Traini, Enea | Carotenuto, Anna | Fasanaro, Angiola Maria | Amenta, Francesco

Article Type: Research Article

Abstract: Background: Cerebral atrophy is a common feature of several neurodegenerative disorders, including Alzheimer’s disease (AD). In AD, brain atrophy is associated with loss of gyri and sulci in the temporal and parietal lobes, and in parts of the frontal cortex and cingulate gyrus. Objective: The ASCOMALVA trial has assessed, in addition to neuropsychological analysis, whether the addition of the cholinergic precursor choline alphoscerate to treatment with donepezil has an effect on brain volume loss in patients affected by AD associated with cerebrovascular injury. Methods: 56 participants to the randomized, placebo-controlled, double-blind ASCOMALVA trial were assigned to …donepezil + placebo (D + P) or donepezil + choline alphoscerate (D + CA) treatments and underwent brain magnetic resonance imaging and neuropsychological tests every year for 4 years. An interim analysis of 3-year MRI data was performed by voxel morphometry techniques. Results: The D + P group (n  = 27) developed atrophy of the gray and white matter with concomitant increase in ventricular space volume. In the D + CA group (n  = 29) the gray matter atrophy was less pronounced compared to the D + P group in frontal and temporal lobes, hippocampus, and amygdala. These morphological data are consistent with the results of the neuropsychological tests. Conclusion: Our findings indicate that the addition of choline alphoscerate to standard treatment with the cholinesterase inhibitor donepezil counters to some extent the loss in volume occurring in some brain areas of AD patients. The observation of parallel less pronounced decrease in cognitive and functional tests in patients with the same treatment suggests that the morphological changes observed may have functional relevance. Show more

Keywords: Alzheimer’s disease, association, brain atrophy, cerebrovascular injury, choline alphoscerate, donepezil

DOI: 10.3233/JAD-190623

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 317-329, 2020

Authors: Nicastro, Nicolas | Malpetti, Maura | Cope, Thomas E. | Bevan-Jones, William Richard | Mak, Elijah | Passamonti, Luca | Rowe, James B. | O’Brien, John T.

Article Type: Research Article

Abstract: Background: The changes of cortical structure in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are usually described in terms of atrophy. However, neurodegenerative diseases may also affect the complexity of cortical shape, such as the fractal dimension of the brain surface. Objective: In this study, we aimed at assessing the regional patterns of cortical thickness and fractal dimension changes in a cross-sectional cohort of patients with AD and FTD. Methods: Thirty-two people with symptomatic AD-pathology (clinically probable AD, n  = 18, and amyloid-positive mild cognitive impairment, n  = 14), 24 with FTD and 28 healthy controls underwent high-resolution …3T structural brain MRI. Using surface-based morphometry, we created vertex-wise cortical thickness and fractal dimension maps for group comparisons and correlations with cognitive measures in AD and FTD. Results: In addition to the well-established pattern of cortical thinning encompassing temporoparietal regions in AD and frontotemporal areas in FTD, we observed reductions of fractal dimension encompassing cingulate areas and insula for both conditions, but specifically involving orbitofrontal cortex and paracentral gyrus for FTD (FDR p  < 0.05). Correlational analyses between fractal dimension and cognition showed that these regions were particularly vulnerable with regards to memory and language impairment, especially in FTD. Conclusion: While the present study demonstrates globally similar patterns of fractal dimension changes in AD and FTD, we observed distinct cortical complexity correlates of cognitive domains impairment. Further studies are required to assess cortical complexity measures at earlier disease stages (e.g., in prodromal/asymptomatic carriers of FTD-related gene mutations) and determine whether fractal dimension represents a sensitive imaging marker for prevention and diagnostic strategies. Show more

Keywords: Alzheimer’s disease, cortical thickness, dementia, fractal dimension, frontotemporal dementia, magnetic resonance imaging

DOI: 10.3233/JAD-200246

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 331-340, 2020