Journal of Alzheimer's Disease - Volume 90, issue 1

Authors: Sagües-Sesé, Elena | Rioja, José | Garzón-Maldonado, Francisco J. | Narváez, Manuel | García-Arnés, Juan A. | García-Casares, Natalia

Article Type: Systematic Review

Abstract: Background: Glucose metabolism and insulin signaling alterations play an important role in Alzheimer’s disease (AD) pathogenesis. Researchers have extensively attempted to characterize the exact pathophysiological mechanisms in the cerebrospinal fluid (CSF), as evidence concerning this fluid biomarkers is expected to enhance AD diagnosis’ specificity and accuracy and serve as an early disease detection tool. There is controversy about insulin levels in the CSF relationship with mild cognitive impairment (MCI) and AD. Objective: This systematic review provides an overview of the state-of-the-art knowledge about insulin-related CSF biomarkers in AD and MCI. Methods: We performed a qualitative systematic …literature review of reported data of CSF glucose, insulin, or insulin-related molecules in humans with AD or MCI, consulting the electronic databases Medline, Scopus, Web of Science, Cochrane, and BASE until May 2022. Results: We selected 19 studies, 10 of them reporting data on CSF insulin and 8 on insulin-related molecules like growth factors or their binding proteins. They predominantly found decreased levels of CSF insulin and increased levels of CSF insulin-related growth factors and their binding proteins. Conclusion: Due to the studies’ protocols and results heterogeneity, we recommend a larger database of clinical trials with similar characteristics for a better understanding of this relationship. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, glucose, insulin, insulin-growth factor, mild cognitive impairment

DOI: 10.3233/JAD-220688

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 1-13, 2022

Authors: Qiao, Yu-Shun | Tang, Xingyao | Chai, Yin-He | Gong, Hong-Jian | Xu, Hui | Patel, Ikramulhaq | Li, Li | Lu, Tong | Zhao, Wan-Ying | Li, Ze-Yu | Cardoso, Marly Augusto | Zhou, Jian-Bo

Article Type: Systematic Review

Abstract: Background: Reduction in cerebral blood flow (CBF) plays an essential role in the cognitive impairment and dementia in obesity. However, current conclusions regarding CBF changes in patients with obesity are inconsistent. Objective: A systematic review and meta-analysis was performed to evaluate the relationship between obesity and CBF alterations. Methods: We systematically screened published cross-sectional and longitudinal studies focusing on the differences in CBF between obese and normal-weight individuals. Eighteen studies including 24,866 participants, of which seven articles reported longitudinal results, were evaluated in the present study. Results: The results of the meta-analysis showed that …in cross-sectional studies, body mass index (BMI) was negatively associated with CBF (β= –0.31, 95% confidence interval [CI]: –0.44, –0.19). Moreover, this systematic review demonstrated that obese individuals showed global and regional reductions in the CBF and increased CBF in diverse functional areas of the frontal lobe, including the prefrontal cortex, left frontal superior orbital, right frontal mid-orbital cortex, and left premotor superior frontal gyrus. Conclusion: Our findings suggest that BMI, rather than waist circumference and waist-to-hip ratio, is inversely associated with CBF in cross-sectional studies. The CBF of obese individuals showed global and regional reductions, including the frontal lobe, temporal and parietal lobes, cerebellum, hippocampus, and thalamus. Show more

Keywords: Body mass index, cerebral blood flow, obesity, waist circumference, waist-to-hip ratio

DOI: 10.3233/JAD-220601

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 15-31, 2022

Authors: Trumbore, Conrad N. | Raghunandan, Aditya

Article Type: Research Article

Abstract: This paper suggests a chemical mechanism for the earliest stages of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) flow stresses provide the energy needed to induce molecular conformation changes leading to AD by initiating amyloid-β (Aβ) and tau aggregation. Shear and extensional flow stresses initiate aggregation in the laboratory and in natural biophysical processes. Energy-rich CSF flow regions are mainly found in lower brain regions. MRI studies reveal flow stress “hot spots” in basal cisterns and brain ventricles that have chaotic flow properties that can distort molecules such as Aβ and tau trapped in these regions into unusual conformations. Such fluid …disturbance is surrounded by tissue deformation. There is strong mapping overlap between the locations of these hot spots and of early-stage AD pathology. Our mechanism creates pure and mixed protein dimers, followed by tissue surface adsorption, and long-term tissue agitation ultimately inducing chemical reactions forming more stable, toxic oligomer seeds that initiate AD. It is proposed that different flow stress energies and flow types in different basal brain regions produce different neurotoxic aggregates. Proliferating artery hardening is responsible for enhanced heart systolic pulses that drive energetic CSF pulses, whose critical maximum systolic pulse energy location migrates further from the heart with increasing vascular disease. Two glymphatic systems, carotid and basilar, are suggested to contain the earliest Aβ and tau AD disease pathologies. A key to the proposed AD mechanism is a comparison of early chronic traumatic encephalopathy and AD pathologies. Experiments that test the proposed mechanism are needed. Show more

Keywords: Alzheimer disease, amyloid-β , cerebral aqueduct, chronic traumatic encephalopathy, extensional flow, locus coeruleus, protein aggregation, shear, strain, tau protein

DOI: 10.3233/JAD-220622

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 33-59, 2022

Authors: Clark, Alexandra L. | Haley, Andreana P. | Duarte, Audrey | O’Bryant, Sid

Article Type: Short Communication

Abstract: We examined ethnoracial differences in fatty acid binding protein (FABP)—a family of intracellular lipid carriers—and clarified FABP3 associations with gray and white matter. Relative to Mexican Americans (MAs), FABP3 was higher in Non-Hispanic Whites (NHWS, p  < 0.001). Regressions revealed, independent of traditional AD markers, FABP3 was associated with neurodegeneration (B = –0.08, p  = 0.003) and WMH burden (B = 0.18, p  = 0.03) in MAs, but not in NHWs (ps > 0.18). Findings suggest FABP3 is related to neural health within MAs and highlight its potential as a prognostic marker of brain health in ethnoracially diverse older adults.

Keywords: Alzheimer’s disease, FABP3, Hispanic/Latino, lipid dyshomeostasis, mild cognitive impairment

DOI: 10.3233/JAD-220524

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 61-68, 2022

Authors: Spinelli, Giuseppe | Bakardjian, Hovagim | Schwartz, Denis | Potier, Marie-Claude | Habert, Marie-Odile | Levy, Marcel | Dubois, Bruno | George, Nathalie

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) includes progressive symptoms spread along a continuum of preclinical and clinical stages. Although numerous studies uncovered the neuro-cognitive changes of AD, very little is known on the natural history of brain lesions and modifications of brain networks in elderly cognitively-healthy memory complainers at risk of AD for carrying pathophysiological biomarkers (amyloidopathy and tauopathy). Objective: We analyzed resting-state electroencephalography (EEG) of 318 cognitively-healthy subjective memory complainers from the INSIGHT-preAD cohort at the time of their first visit (M0) and two-years later (M24). Methods: Using 18 F-florbetapir PET-scanner, subjects were stratified between amyloid negative …(A–; n  = 230) and positive (A+; n  = 88) groups. Differences between A+ and A– were estimated at source-level in each band-power of the EEG spectrum. Results: At M0, we found an increase of theta power in the mid-frontal cortex in A+ compared to A–. No significant association was found between mid-frontal theta and the individuals’ cognitive performance. At M24, theta power increased in A+ relative to A– individuals in the posterior cingulate cortex and the pre-cuneus. Alpha band revealed a peculiar decremental trend in posterior brain regions in the A+ relative to the A– group only at M24. Theta power increase over the mid-frontal and mid-posterior cortices suggests an hypoactivation of the default-mode network in the A+ individuals and a non-linear longitudinal progression at M24. Conclusion: We provide the first source-level longitudinal evidence on the impact of brain amyloidosis on the EEG dynamics of a large-scale, monocentric cohort of elderly individuals at-risk for AD. Show more

Keywords: Alzheimer’s disease, amyloidosis, EEG, INSIGHT-preAD study, pre-clinical

DOI: 10.3233/JAD-220204

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 69-84, 2022

Authors: Camargo, Marina von Zuben de Arruda | Pais, Marcos Vasconcelos | Bellan, Ariella Fornachari Ribeiro | Tahira, Ana Carolina | dos Santos, Bernardo | Sant’Ana, Livea Carla Fidalgo Garcêz | Radanovic, Marcia | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Background: Eye-movement behavior has been used as a reliable tool to identify cognitive and behavioral patterns in individuals with different neuropsychiatric disorders including Alzheimer’s disease (AD). Most studies in the field have been dedicated to evaluating eye-movement behavior during cognitive tasks in different protocols using multiple parameters. Objective: We aimed to evaluate the differences of eye-movement behavior in healthy subjects, subjects with mild cognitive impairment (MCI), and those with AD in a simple color task with and without cognitive demand. Methods: 91 subjects: 18 AD, 47 MCI, and 26 healthy controls had their oculomotor parameters assessed …during baseline (no cognitive demand involved) and during a simple computational color memory task using an eye-tracker. Results: Baseline showed statistically different and heterogeneous results between normal cognition and MCI groups. Familiarization phase of the task could not discriminate between groups in any of the analyzed parameters. AD subjects made longer fixations and visits on distractors, and more frequent fixations and visits on the target areas than other groups during the response phase. Conclusion: Eye-tracking time-related parameters differentiate AD subjects from other groups under cognitive demand even in a simple color memory task. Show more

Keywords: Alzheimer’s disease, cognitive impairment, eye movement, eye-tracking, mild cognitive impairment, visual search impairment

DOI: 10.3233/JAD-220385

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 85-95, 2022

Authors: Teichmann, Birgit | Melchior, Florian | Kruse, Andreas

Article Type: Research Article

Abstract: Background: There are almost no validated tools in German that assess dementia knowledge, attitude toward dementia, and confidence in the general population. Objective: Translation and validation of the German version of the Dementia Knowledge Assessment Tool 2 (DKAT2), the Dementia Attitude Scale (DAS), and the Confidence in Dementia Scale (CODE). Methods: Instruments were translated into German and adapted for the general public. A convenience sample of 263 persons was recruited via an online platform. Validation of the tools’ psychometric properties consisted of an assessment of its reliability (internal consistency and 4-week test-retest reliability of a subgroup …with n  = 110), an analysis of its construct validity through principal component analysis and known-group analysis, convergent validity, and an item analysis for DKAT2-D. This study used the STROBE checklist for reporting. Results: Acceptable to excellent internal reliability was found for DAS-D (α= 0.90), DKAT2-D (α= 0.78), and CODE-D (α= 0.93). The principal component analysis confirmed the two-factor model for the DAS-D as well as the one-factor solution for CODE-D. The intra-class correlation coefficient between the first and the 4-week retest was good (CODE-D: 0.897; 0.849–0.929) to excellent (DKAT2-D: 0.918; 0.879–0.945 and DAS-D: 0.940; 0.910–0.960). Known-group analysis revealed that DAS-D, DKAT-D, and CODE-D could distinguish between individuals with or without experience with people with dementia and with or without participation in a dementia course. Conclusion: The German versions DAS-D, DKAT2-D, and CODE-D are reliable and valid tools to measure knowledge, attitude, and confidence in dementia in the German-speaking general population. Show more

Keywords: Attitude, dementia, knowledge, psychometrics, reliability, self-efficacy, validity

DOI: 10.3233/JAD-220678

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 97-108, 2022

Authors: Shelton, Morgan G. | Kerns, Kimberly A. | Castora, Frank J. | Coleman, Randolph A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease is a specific form of dementia characterized by the aggregation of amyloid-β plaques and tau tangles. New research has found that the formation of these aggregates occurs after dysregulation of cellular respiration and the production of radical oxygen species. Proteomic data shows that these changes are also related to unique gene expression patterns. Objective: This study is designed to incorporate both proteomic and gene expression data into a testable mathematical model for AD. Manipulation of this new model allows the identification of potential therapeutic targets for AD. Methods: We investigate the impact of …these findings on new therapeutic targets via metabolic flux analysis of sirtuin stress response pathways while also highlighting the importance of metabolic enzyme activity in maintaining proper respiratory activity. Results: Our results indicate that protective changes in SIRT1 and AMPK expression are potential avenues for therapeutics. Conclusion: Combining our mitochondrial gene expression analyses with available protein data allowed the construction of a new mathematical model for AD that provides a useful approach to test the efficacy of potential AD therapeutic targets. Show more

Keywords: AD mathematical model, Alzheimer’s disease, AMPK, gene expression changes, SIRT1

DOI: 10.3233/JAD-220163

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 109-117, 2022

Authors: Castora, Frank J. | Kerns, Kimberly A. | Pflanzer, Haley K. | Hitefield, Naomi L. | Gershon, Blake | Shugoll, Jason | Shelton, Morgan | Coleman, Randolph A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurological disease that has both a genetic and non-genetic origin. Mitochondrial dysfunction is a critical component in the pathogenesis of AD as deficits in oxidative capacity and energy production have been reported. Objective: Nuclear-encoded mitochondrial genes were studied in order to understand the effects of mitochondrial expression changes on mitochondrial function in AD brains. These expression data were to be incorporated into a testable mathematical model for AD used to further assess the genes of interest as therapeutic targets for AD. Methods: RT2 -PCR arrays were used to assess expression …of 84 genes involved in mitochondrial biogenesis in AD brains. A subset of mitochondrial genes of interest was identified after extensive Ingenuity Pathway Analysis (IPA) (Qiagen). Further filtering of this subset of genes of interest was achieved by individual qPCR analyses. Expression values from this group of genes were included in a mathematical model being developed to identify potential therapeutic targets. Results: Nine genes involved in trafficking proteins to mitochondria, morphology of mitochondria, maintenance of mitochondrial transmembrane potential, fragmentation of mitochondria and mitochondrial dysfunction, amyloidosis, and neuronal cell death were identified as significant to the changes seen. These genes include TP53, SOD2, CDKN2A, MFN2, DNM1L, OPA1, FIS1, BNIP3, and GAPDH. Conclusion: Altered mitochondrial gene expression indicates that a subset of nuclear-encoded mitochondrial genes compromise multiple aspects of mitochondrial function in AD brains. A new mathematical modeling system may provide further insights into potential therapeutic targets. Show more

Keywords: Alzheimer’s disease, apoptosis, mitochondrial biogenesis, mitochondrial fission and fusion, sirtuins

DOI: 10.3233/JAD-220161

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 119-137, 2022

Authors: Wang, Xin | Wang, Yaqin | Liu, Hui | Zhu, Xiangyu | Hao, Xiaoli | Zhu, Yuan | Xu, Bei | Zhang, Sizhe | Jia, Xiaoliang | Weng, Ling | Liao, Xinxin | Zhou, Yafang | Tang, Beisha | Zhao, Rongchang | Jiao, Bin | Shen, Lu

Article Type: Research Article

Abstract: Background: Some previous studies showed abnormal pathological and vascular changes in the retina of patients with Alzheimer’s disease (AD). However, whether retinal microvascular density is a diagnostic indicator for AD remains unclear. Objective: This study evaluated the macular vessel density (m-VD) in the superficial capillary plexus and fovea avascular zone (FAZ) area in AD, explored their correlations with clinical parameters, and finally confirmed an optimal machine learning model for AD diagnosis. Methods: 77 patients with AD and 145 healthy controls (HCs) were enrolled. The m-VD and the FAZ area were measured using optical coherence tomography angiography …(OCTA) in all participants. Additionally, AD underwent neuropsychological assessment, brain magnetic resonance imaging scan, cerebrospinal fluid (CSF) biomarker detection, and APOE ɛ4 genotyping. Finally, the performance of machine learning algorithms based on the OCTA measurements was evaluated by Python programming language. Results: The m-VD was noticeably decreased in AD compared with HCs. Moreover, m-VD in the fovea, superior inner, inferior inner, nasal inner subfields, and the whole inner ring declined significantly in mild AD, while it was more serious in moderate/severe AD. However, no significant difference in the FAZ was noted between AD and HCs. Furthermore, we found that m-VD exhibited a significant correlation with cognitive function, medial temporal atrophy and Fazekas scores, and APOE ɛ4 genotypes. No significant correlations were observed between m-VD and CSF biomarkers. Furthermore, results revealed the Adaptive boosting algorithm exhibited the best diagnostic performance for AD. Conclusion: Macular vascular density could serve as a diagnostic biomarker for AD. Show more

Keywords: Alzheimer’s disease, diagnosis, machine learning, optical coherence tomography angiography, vessel density

DOI: 10.3233/JAD-220482

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 139-149, 2022

Authors: Cejudo, Juan Carlos | Samaniego, Melissa | Almeria, Marta | Castrillo, Susana | Medina, Lidia | Gil, Domènec

Article Type: Research Article

Abstract: Background: Semantic memory (SM) constitutes a cognitive system that is seriously affected by Alzheimer’s disease (AD). There are several tests for assessing SM, but a tool is needed to assess AD in the early stages of the illness. Objective: The study aimed to create, validate, and normalize a new test to assess SM, called the Ikos test, for AD and early AD in clinical practice. Methods: 62 healthy adults as a control group (CG), 62 AD, and 60 amnestic mild cognitive impairment (aMCI) subdivided into a group that progresses to AD, and another group that does …not progress to AD were selected. The internal consistency (IC), the construct validity (CV), and reliability between raters and the test-retest were analyzed. We used the Bayesian approach to establish the accuracy of the diagnosis of the Ikos test in AD and early AD. Results: IC showed a Kuder-Richardson index of r = 0.945. The CV between the Ikos test and Pyramids and Palm Trees; Intraclass Correlation Coefficient (ICC) index was 0.897. The Kappa index was between 0.865 and 0.912, and the ICC index was 0.873 for the test-retest reliability. The Area Under the Curve was 0.981, sensitivity (SE) was 0.95, and specificity (SP) was 0.96 in AD/CG. In contrast, in the MCI-AD/CG group, SE = 0.77 and SP = 0.80. Conclusion: The Ikos test accomplishes the criteria of validity and reliability with high correlation indexes. Therefore, it can be considered a valid, reliable, and easily applicable tool for SM assessment in diagnosing AD and the early stages of clinical disease. Show more

Keywords: Early Alzheimer’s disease, neuropsychology of memory, semantic knowledge, semantic knowledge in dementia, semantic memory test

DOI: 10.3233/JAD-220516

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 151-160, 2022

Authors: Tariot, Pierre N. | Braeckman, Rene | Oh, Charles

Article Type: Research Article

Abstract: Background: Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States. Objective: To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil. Methods: Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18–55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5. …Results: All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0–168 h) were 88.7 (81.7–96.2) and 108.6 (100.5–117.4) for 10-mg/d and 86.1 (79.8–92.9) and 105.3 (97.6–113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% –125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively). Conclusion: Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type. Show more

Keywords: Alzheimer’s disease, Alzheimer type dementia, bioequivalence, donepezil, transdermal patch

DOI: 10.3233/JAD-220530

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 161-172, 2022

Authors: Zhang, Jinhuan | Hu, Shan | Liu, Yongfeng | Lyu, Hanqing | Huang, Xingxian | Li, Xinbei | Chen, Jianxiang | Hu, Qingmao | Xu, Jinping | Yu, Haibo

Article Type: Research Article

Abstract: Background: Although acupuncture is widely used to improve cognitive and memory in the amnesic mild cognitive impairment (aMCI) patients with impressive effectiveness, its neural mechanism remains largely unclear. Objective: We aimed to explore functional magnetic resonance imaging (fMRI) mechanism of acupuncture for aMCI. Methods: A randomized, controlled, single-blind research was performed. A total of 46 aMCI patients were randomly assigned into verum and sham acupuncture group, who received a total of 24 times treatments (3 times/week, 8 weeks). Clinical evaluation and fMRI scanning were performed at baseline and after treatment for all aMCI patients. The interaction …effects and inter-group effects of regional homogeneity (ReHo) were performed using mixed effect models, and the correlations between clinical improvement and neuroimaging changes before and after verum acupuncture treatment were analyzed using Pearson correlations. Results: As a result, interaction effects showed increased ReHo value in left dorsal lateral prefrontal cortex (DLPFC), increased functional connectivity between left DLPFC and left precuneus, and decreased functional connectivity between left DLPFC and left inferior temporal gyrus after verum acupuncture but inversely after sham acupuncture in the aMCI. Condition effects showed increased ReHo in right lingual gyrus, and bilateral post-central gyrus after verum and sham acupuncture in the aMCI. In addition, the changed Montreal Cognitive Assessment scores in verum acupuncture group were significantly correlated with changed ReHo values in left DLPFC. Conclusion: Together, our findings further confirmed that acupuncture could be used as a promising complementary therapy for aMCI by modulating function of left DLPFC to improve cognitive symptoms. Show more

Keywords: Acupuncture, amnesic mild cognitive impairments, dorsal lateral prefrontal cortex, regional homogeneity

DOI: 10.3233/JAD-220592

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 173-184, 2022

Authors: Peng, Yan | Zhang, Li | Zhou, Fanlin | Wang, Yangyang | Zhang, Xiong | Fan, Jianing | Li, Shijie | Li, Xiaoju | Li, Yu

Article Type: Research Article

Abstract: Background: Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer’s disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear. Objective: We aimed to explore the cause and mechanism of impaired glucose uptake in AD. Methods: N2a/WT and N2a/APP695swe cells were cultured in vitro , and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen …species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again. Results: GLUT1 expression was significantly decreased (p  = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p  > 0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p  = 0.0006, p  = 0.0008, p  = 0.0009, p  = 0.0001, p  = 0.0013), while Aβ levels were significantly decreased (p  = 0.0058, p  = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p  = 0.0008), and Aβ levels were increased (p  = 0.0009, p  = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p  = 0.0002, p  = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p  = 0.0212, p  = 0.0006). Conclusion: Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells. Show more

Keywords: Alzheimer’s disease, glucose uptake, GLUT1, PI3K/Akt, reactive oxygen species

DOI: 10.3233/JAD-220610

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 185-198, 2022

Authors: Silberstein, Richard B. | Pipingas, Andrew | Scholey, Andrew B.

Article Type: Research Article

Abstract: Background: Homocysteine, a methionine metabolite, is a recognized risk factor for accelerated age-related cognitive decline and dementia. Objective: In the light of studies indicating increases in brain activity and brain functional connectivity in the early stages of age-related cognitive decline, we undertook a study to examine the relationship between plasma homocysteine levels and brain functional connectivity in a group of late middle-aged males at risk of cognitive decline due to high body mass index and a sedentary lifestyle. Methods: Brain functional connectivity was measured using the steady state visual evoked potential event related partial coherence while …38 participants performed a memory task where each trial comprised an object recognition task followed by a location memory task. Results: We observed a significant transient peak in the correlation between plasma homocysteine levels and fronto-parietal brain functional connectivity immediately before the presentation of the memory location component of the task. Significantly, this correlation was only apparent if the participant pool included individuals with homocysteine concentrations above 11μmole/L. Conclusion: Our findings suggest that the increased brain functional connectivity observed in the earlier stages of age-related cognitive decline reflects pathognomonic changes in brain function and not compensatory changes engaged to enhance task performance. Our findings also suggest that homocysteine interferes with the inhibition of cortical networks where this inhibition is necessary for optimum task performance. Finally, we observed that the effect of homocysteine on brain functional connectivity is only apparent at concentrations above 11μmol/L. Show more

Keywords: Brain functional connectivity, cognitive decline, homocysteine, memory

DOI: 10.3233/JAD-220612

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 199-209, 2022

Authors: Du, Xianglin L. | Song, Lulu | Schulz, Paul E. | Xu, Hua | Chan, Wenyaw

Article Type: Research Article

Abstract: Background: Long term risk of Alzheimer’s disease (AD) and related dementias (ADRD) associated with vascular diseases in people with colorectal cancer is unknown. Objective: To determine the risk of ADRD in association with cardiovascular diseases (CVD), stroke, hypertension, and diabetes in a cohort of patients with colorectal cancer. Methods: This retrospective cohort study consisted of 210,809 patients diagnosed with colorectal cancer at age≥65 years in 1991–2015 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with follow-up from 1991–2016, who were free of any ADRD at the baseline (<12 months prior to or < 30 days after …the date of cancer diagnosis). Results: The crude 26-year cumulative incidence of total ADRD in men and women with colorectal cancer was higher in those with versus without CVD (31.92% versus 28.12%), with versus without stroke (39.82% versus 26.39%), with versus without hypertension (31.88% versus 24.88%), and with versus without diabetes (32.01% versus 27.66%). After adjusting for socio-demographic and tumor factors, the risk of developing ADRD was significantly higher in patients with CVD (adjusted hazard ratio: 1.17, 95% confidence intervals: 1.14–1.20), stroke (1.65, 1.62–1.68), hypertension (1.07, 1.05–1.09), and diabetes (1.26, 1.24–1.29) versus persons without. For those with 1, 2, 3 and 4 vascular diseases present versus absent, the risk of AD increased from 1.12 (1.07–1.16) to 1.31 (1.25–1.36), 1.66 (1.57–1.75), and 2.03 (1.82–2.27). Conclusion: In older patients with colorectal cancer, a significant dose-response relationship was observed between an increasing number of these vascular diseases and the risk of all types of dementia. Show more

Keywords: Alzheimer’s disease, colorectal cancer, dementias, medicare, vascular diseases

DOI: 10.3233/JAD-220548

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 211-231, 2022

Authors: Nolan, John M. | Power, Rebecca | Howard, Alan N. | Bergin, Paula | Roche, Warren | Prado-Cabrero, Alfonso | Pope, George | Cooke, John | Power, Tommy | Mulcahy, Ríona

Article Type: Research Article

Abstract: Background: Preliminary work by our center has reported behavior and functional benefits in patients with Alzheimer’s disease (AD) following targeted micronutritional supplementation. Objective: To build on the existing exploratory research and investigate the impact of these micronutrients on the natural progression of AD in a randomized controlled trial. Methods: Patients with mild-moderate AD consumed daily 1 g fish oil (of which 500 mg DHA, 150 mg EPA), 22 mg carotenoids (10 mg lutein, 10 mg meso -zeaxanthin, 2 mg zeaxanthin), and 15 mg vitamin E or placebo for 12 months in a double-blind, placebo-controlled, randomized clinical trial. Carotenoids, ω-3FAs, and vitamin E were quantified …in blood. Carotenoids were also measured in skin. AD severity was measured using the mini-mental state examination and dementia severity rating scale tools. Behavior, mood, and memory were measured using an informant-based questionnaire. Results: Following 12 months of supplementation, the active group (n  = 50) compared to the placebo group (n  = 27), demonstrated statistically significant improvements in skin carotenoid measurements, blood carotenoids, ω-3FAs, and vitamin E concentrations (p  < 0.05, for all). The active group also performed better in objective measures of AD severity (i.e., memory and mood), with a statistically significant difference reported in the clinical collateral for memory (p  < 0.001). Conclusion: Exponential increases in the prevalence of AD and its relentless progressive nature is driving the need for interventions that help to ameliorate symptoms and improve quality of life in AD patients. Given the positive outcomes demonstrated in this trial, this combined micronutrient dietary supplement should be considered in the overall management of AD. Show more

Keywords: Alzheimer’s disease, antioxidants, carotenoids, clinical collateral, disease management, disease progression, nutrition, omega-3 fatty acids, vitamin E

DOI: 10.3233/JAD-220556

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 233-249, 2022

Authors: Migliorati, Martine | Manrique, Christine | Rahrah, Melinda | Escoffier, Guy | El Ahmadi, Abdessadek | Girard, Stéphane D. | Khrestchatisky, Michel | Rivera, Santiago | Baranger, Kévin | Roman, François S.

Article Type: Research Article

Abstract: Background: The 5XFAD model of Alzheimer’s disease (AD) bearing five familial mutations of Alzheimer’s disease on human APP and PSEN1 transgenes shows deposits of amyloid-β peptide (Aβ) as early as 2 months, while deficits in long-term memory can be detected at 4 months using the highly sensitive olfactory-dependent tests that we previously reported. Objective: Given that detecting early dysfunctions in AD prior to overt pathology is of major interest in the field, we sought to detect memory deficits at earlier stages of the disease in 3-month-old male 5XFAD mice. Methods: To this end, we …used the Helico Maze, a behavioral task that was recently developed and patented. This device allows deeper analysis of learning and subcategories of hippocampal-dependent long-term memory using olfactory cues. Results: Eight male 5XFAD and 6 male wild-type (WT: C57Bl6 background) mice of 3 months of age were tested in the Helico Maze. The results demonstrated, for the first time, a starting deficit of pure reference long-term memory. Interestingly, memory impairment was clearly correlated with Aβ deposits in the hippocampus. While we also found significant differences in astrogliosis between 5XFAD and WT mice, this was not correlated with memory abilities. Conclusion: Our results underline the efficiency of this new olfactory-dependent behavioral task, which is easy to use, with a small cohort of mice. Using the Helico Maze may open new avenues to validate the efficacy of treatments that target early events related to the amyloid-dependent pathway of the disease and AD progression. Show more

Keywords: Alzheimer’s disease, astrogliosis, 5XFAD mouse, Helico Maze, hippocampal Aβ deposits, reference memory deficit

DOI: 10.3233/JAD-220281

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 251-262, 2022

Authors: Wang, Ge | Estrella, Alliyah | Hakim, Ornin | Milazzo, Paul | Patel, Sonali | Pintagro, Clara | Li, Daniel | Zhao, Rui | Vance, David E. | Li, Wei

Article Type: Research Article

Abstract: Background: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are two commonly used cognitive screening and diagnostic tools. Objective: Our goal was to assess their efficacy for monitoring cognitive changes, as well as the correlation between the two tests. Methods: At baseline, participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were divided into four groups based on their cognitive diagnoses: healthy control (HC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer’s disease (AD). MMSE or MoCA scores were compared among the four groups using an analysis of variance (ANOVA) model with …repeated measures with post-hoc Bonferroni correction. For those participants who had both MMSE and MoCA assessments done, a Pearson correlation analysis was performed between the two assessments for each visit. Results: The MMSE scores were significantly different among the four groups at baseline, which was true for each of the three annual follow-up visits. By contrast, the MoCA scores were not significantly different between HC and EMCI groups at either baseline or any of the follow-up visits. For participants with a diagnosis of LMCI, the cognitive performance deteriorated in a linear manner 12 months after the baseline, which was independent of MMSE or MoCA. At last, the MMSE scores were moderately related to MoCA scores, which got stronger along with the time of follow-up. Conclusion: MMSE and MoCA are comparable as cognitive assessment tools to monitor cognitive changes. In addition, the measurements of MMSE and MoCA are moderately correlated for the follow-up visits. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neuroimaging initiative, apolipoprotein E, early mild cognitive impairment, healthy control, late mild cognitive impairment, mild cognitive impairment, Mini-Mental State Examination, Montreal Cognitive Assessment

DOI: 10.3233/JAD-220397

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 263-270, 2022

Authors: Sukik, Layan | Liu, Jianghong | Shi, Zumin

Article Type: Research Article

Abstract: Background: Previous studies suggest a positive effect of tea intake on cognition. Additional micronutrients that may moderate this association was not previously examined. Objective: To examine the association between tea consumption and cognition and explore the interaction between tea consumption and iron intake. Methods: Data from the China Health and Nutrition Survey between 1997 and 2011 was used. 4,820 individuals (≥55 years) were included in the analyses. Measurement of cognitive function was conducted in 1997, 2000, 2004, and 2006. Tea consumption was self-reported. Food intake was assessed by 24-hour dietary recalls of three consecutive days during …home visits between 1997 and 2011. Multivariable mixed linear regression and logistic regression was used to assess the association. Results: Tea consumption was associated with reduced global cognitive function decline. In fully adjusted models, regression coefficients (95% CIs) for those who consumed 0 cups/day,<2 cups/day, 2–3.9 cups/day, and≥4 cups/day of tea were 0, –0.09 (–0.55–0.37), 0.05 (–0.34–0.45), and 0.87 (0.46–1.29), respectively. This effect was stronger in adults > 60 years. Tea consumption of≥4 cups/day was inversely associated with self-reported poor memory (OR 0.70 (95% CI 0.56–0.86)) and memory decline (OR, 0.73 (95% CI 0.62–0.87)). There was a significant interaction between tea consumption and iron intake in relation to cognition. High iron intake was inversely associated with cognition in non-consumers of tea but not in tea consumers. Conclusion: Higher tea intake is associated with reduced cognitive decline in adults and inhibits the adverse effect of high iron intake. Show more

Keywords: Adults, Chinese, cognition, iron intake, tea consumption

DOI: 10.3233/JAD-220344

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 271-282, 2022

Authors: Latgé-Tovar, Sofia | Bertrand, Elodie | Cosentino, Stephanie | Dourado, Marcia C.N. | Laks, Jerson | Landeira-Fernandez, Jesus | Morris, Robin G. | Mograbi, Daniel C.

Article Type: Research Article

Abstract: Background: Impaired awareness of ability is common in dementia and has important clinical implications. Evidence from different clinical groups has shown that awareness can vary according to whether evaluation refers to self or other performance. Objective: The present study aimed to investigate awareness for self- and other-performance in Alzheimer’s disease (AD) patients, exploring if results vary according to cognitive domain of the tasks. It was hypothesized that, particularly for memory tasks, AD patients would be inaccurate in relation to self-but not other-performance. Methods: Twenty-two mild to moderate AD patients and twenty-two healthy older adults participated. Two …tasks, with reaction time and working memory tasks, were carried out, and each had a success and a failure condition. Participants were asked to estimate their own performance, as well as the performance of another person they observed. Awareness of performance was measured comparing participant estimations of performance with actual performance. Results: For both the reaction time and working memory tasks, results indicate that participants from both groups overestimated the performance in the failure condition and underestimated the performance in the success condition. They tended to overestimate more the performance of the other person compared to themselves. Additionally, for the working memory task, AD patients tended to overestimate more performances compared to controls. Conclusion: Findings suggest that the AD and control groups present the same pattern, with attribution of better performance to another person. For the AD group, the pattern of response was different for memory tasks, which may suggest domain-specific limited awareness. Show more

Keywords: Alzheimer’s disease, awareness, dementia, metacognition, perspective-taking

DOI: 10.3233/JAD-220453

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 283-294, 2022

Authors: Ota, Miho | Sato, Noriko | Nakaya, Moto | Shigemoto, Yoko | Kimura, Yukio | Chiba, Emiko | Yokoi, Yuma | Tsukamoto, Tadashi | Matsuda, Hiroshi

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) and tau protein accumulation in the brain is thought to be one of the causes of Alzheimer’s disease (AD). Recent study found that the glymphatic system was waste drainage system in the brain and promoting the elimination of Aβ and tau protein. Objective: We evaluated the relationships between the glymphatic system activity and the Aβ and tau protein deposition. Methods: Subjects were 21 patients with AD and 36 healthy subjects who underwent diffusion tensor imaging (DTI) scan and the positron emission tomography (PET) using with the Aβ tracer: 11 C-PiB and the tau/inflammatory …tracer: 18 F-THK5351. We computed diffusion tensor image analysis along the perivascular space (DTI-ALPS) index as the proxy of glymphatic system activity, and estimated the relationships between the DTI-ALPS index and Aβ and tau protein/inflammatory deposition. Results: We found significant negative correlations between DTI-ALPS index and the standard uptake value ratio (SUVR) of 11 C-PiB in the bilateral temporal and left parietal cortices and left posterior cingulate gyrus in all subjects. Further, we detected significant negative correlations between DTI-ALPS index and the SUVR of 18 F-THK5351 in the bilateral temporal cortices and right parietal cortex in all participants, too. Conclusion: Our data suggested that DTI-ALPS index was a good biomarker for the evaluation of Aβ and tau deposition and neuroinflammation, and this marker might be effective to estimate the glymphatic system activity. Show more

Keywords: Diffusion tensor image analysis along the perivascular space (DTI-ALPS), positron emission tomography, 11C-PiB, 18F-THK5351

DOI: 10.3233/JAD-220534

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 295-303, 2022

Authors: Yeh, Wei-Chih | Hsu, Chung-Yao | Li, Kuan-Ying | Chien, Ching-Fang | Huang, Ling-Chun | Yang, Yuan-Han

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia. Aging is a risk factor for both AD and seizures. Subclinical epileptiform discharge (SED) has no evident clinical manifestation in patients with AD. Therefore, SED is liable to be overlooked in these patients since electroencephalography is not routinely performed in clinical settings. Previous studies about the association between SED and AD have yielded inconsistent results. Objective: The current study aimed to evaluate the prevalence of SED and its effect on AD severity and clinical outcomes. Methods: Patients with AD from Kaohsiung Municipal Ta-tung Hospital were …included in this study. International 10–20 system scalp electroencephalography for 13 minutes was performed to detect SED. Clinical outcomes of patients with and without SED were assessed by neuropsychological tests [Cognitive Abilities Screening Instrument (CASI), Mini-Mental State Examination (MMSE), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)]. Results: 288 patients (mean age 80.5 years, 60.4% female) were enrolled in this study. Fifty-seven (19.8%) out of 288 patients with AD had SED. The prevalence of SED increased with the severity of cognitive impairment. Compared with patients without SED, those with SED showed significantly greater decline in CASI (–9.32 versus –3.52 points, p  = 0.0001) and MMSE (–2.52 versus –1.12 points, p  = 0.0042) scores in one year. Conclusion: SED may play a significant role in AD progression and is a potential therapeutic target. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, electroencephalography, mental status and dementia tests, neuropsychological tests

DOI: 10.3233/JAD-220567

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 305-312, 2022

Authors: Loewenstein, David A. | Curiel Cid, Rosie E. | Kitaigorodsky, Marcela | Ortega, Alexandra | Hincapie, Diana | Zheng, D. Diane | Amaya, Alexandra | Gallardo, Liz | Manso, Leslie | Sosa, Jaylene | Crocco, Elizabeth A.

Article Type: Research Article

Abstract: Background: Susceptibility to proactive semantic interference (PSI) and the inability to ameliorate these difficulties with one additional learning trial have repeatedly been implicated as early features of incipient Alzheimer’s disease (AD). Unfortunately, persistent failure to recover from PSI (frPSI) after repeated learning trials, are not captured by existing memory measures, or been examined in pre-mild cognitive impairment (PreMCI). Objective: A novel Cognitive Stress Test (CST) was employed to measure the impact of PSI, initial failure to recover from PSI and persistent effects of PSI, despite multiple learning trials of the new to-be-remembered material (pfrPSI). We hypothesized that PSI …deficits on the CST would persist in both PreMCI and amnestic MCI (aMCI) groups over repeated learning trials when compared to cognitively unimpaired (CU) older adults. Methods: One hundred fifty older adults (69 CU, 31 PreMCI, and 50 aMCI) underwent a standardized clinical and neuropsychological evaluation. The CST was independent of diagnostic classification. Results: Even after adjusting for strength of initial learning, aMCI and PreMCI groups demonstrated greater persistent PSI (pfrPSI) relative to the CU group despite repeated learning trials of List B. Further, the aMCI group made a higher number of semantic intrusion errors relative to the PreMCI and CU groups on all List B Cued Recall trials. Conclusion: Persistent PSI appears to be a common feature of aMCI and PreMCI. The possible theoretical mechanisms and empirical implications of these new findings are discussed. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, persistent semantic interference, proactive semantic interference

DOI: 10.3233/JAD-220348

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 313-322, 2022

Authors: Thomas, Kelsey R. | Bangen, Katherine J. | Weigand, Alexandra J. | Ortiz, Gema | Walker, Kayla S. | Salmon, David P. | Bondi, Mark W. | Edmonds, Emily C.

Article Type: Research Article

Abstract: Background: There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer’s disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults. Objective: We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of ≤129 across subgroups. Methods: Hierarchical cluster analysis was conducted on individual baseline neuropsychological test scores from …365 CU participants in the UCSD Shiley-Marcos Alzheimer’s Disease Research Center longitudinal cohort. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score ≤129, by cluster group. Results: Cluster analysis identified 5 groups: All-Average (n  = 139), Low-Visuospatial (n  = 46), Low-Executive (n  = 51), Low-Memory/Language (n  = 83), and Low-All Domains (n  = 46). Subgroups had unique demographic and clinical characteristics. Rates of progression to MCI/dementia or to DRS ≤129 were faster for all subgroups (Low-All Domains progressed the fastest > Low Memory/Language≥Low-Visuospatial and Low-Executive) relative to the All-Average subgroup. Conclusion: Faster progression in the Low-Visuospatial, Low-Executive, and Low-Memory/Language groups compared to the All-Average group suggests that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. Use of comprehensive neuropsychological test batteries that assess several domains may be a key first step toward an individualized approach to early detection and fewer missed opportunities for early intervention. Show more

Keywords: Alzheimer’s disease, cognitive phenotypes, heterogeneity, subtle cognitive decline

DOI: 10.3233/JAD-220684

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 323-331, 2022

Authors: Sturchio, Andrea | Dwivedi, Alok K. | Malm, Tarja | Wood, Matthew J.A. | Cilia, Roberto | Sharma, Jennifer S. | Hill, Emily J. | Schneider, Lon S. | Graff-Radford, Neill R. | Mori, Hiroshi | Nübling, Georg | El Andaloussi, Samir | Svenningsson, Per | Ezzat, Kariem | Espay, Alberto J.

Article Type: Research Article

Abstract: Background: In amyloid-positive individuals at risk for Alzheimer’s disease (AD), high soluble 42-amino acid amyloid-β (Aβ42 ) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. Objective: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer’s disease (AD)-causing mutations (APP , PSEN1 , or PSEN2 ) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). Methods: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal …cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. Results: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19–0.67; p  = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68–0.96; p  = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels. Conclusion: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations. Show more

Keywords: Alzheimer’s disease, amyloid-β , atrophy, cognition, FDG-PET

DOI: 10.3233/JAD-220808

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 333-348, 2022

Authors: Wei, Shan | Dang, Liangjun | Gao, Fan | Wang, Jingyi | Wang, Jin | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Abnormal blood lipids are associated with cognitive impairment and amyloid-β (Aβ) deposition in the brain. However, the effects of statins on Alzheimer’s disease (AD) have not been determined. Objective: Considering that plasma Aβ are related to Aβ deposition in the brain, we investigated the effects of simvastatin on plasma Aβ transport. Methods: This was a randomized, double-blind, placebo-controlled trial. One hundred and twenty patients with hyperlipidemia were randomly assigned to receive 40 mg of simvastatin per day or matching placebo for 12 weeks (sixty patients per group). Plasma Aβ, sLRP1, sRAGE, and lipid levels were measured …at baseline and at the 6-week and 12-week visits. Results: The ITT database ultimately included 108 participants (placebo group: n  = 53; simvastatin group: n  = 55) and 64 (59.3%) were women, ranging in age from 45 to 75 years (mean 57.2±6.9 years). Multiple linear regression analysis showed that, after 12 weeks of follow-up, compared with the placebo group, Δ Aβ42 levels (the change of Aβ42 levels from baseline at week 12) increased more and Δ sRAGE levels decreased more in the simvastatin group (Aβ42 : β= 5.823, p  = 0.040; sRAGE: β= –72.012, p  = 0.031), and a significant negative association was found between Δ Aβ42 and Δ sRAGE levels (β= –0.115, p  = 0.045). In addition, generalized estimation equation analysis showed that triglycerides levels were negatively correlated with Aβ40 (β= –16.79, p  = 0.023), Aβ42 (β= –6.10, p  = 0.001), and sRAGE (β= –51.16, p  = 0.003). Conclusion: Daily oral simvastatin (40 mg/day) in patients with hyperlipidemia for 12 weeks can significantly increase plasma Aβ42 levels compared with placebo, which was associated with reduced triglycerides and sRAGE levels, indicating that statins may affect plasma Aβ transport. Show more

Keywords: Alzheimer’s disease, hyperlipidemia, plasma amyloid-β, simvastatin, soluble low-density lipoprotein receptor-related protein-1, soluble receptor of advanced glycation end products

DOI: 10.3233/JAD-220240

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 349-362, 2022

Authors: Bolsewig, Katharina | Hok-A-Hin, Yanaika S. | Sepe, Federica N. | Boonkamp, Lynn | Jacobs, Dirk | Bellomo, Giovanni | Paoletti, Federico Paolini | Vanmechelen, Eugeen | Teunissen, Charlotte E. | Parnetti, Lucilla | Willemse, Eline A. J.

Article Type: Research Article

Abstract: Background: The differential diagnosis of frontotemporal dementia (FTD) is still a challenging task due to its symptomatic overlap with other neurological diseases and the lack of biofluid-based biomarkers. Objective: To investigate the diagnostic potential of a combination of novel biomarkers in cerebrospinal fluid (CSF) and blood. Methods: We included 135 patients from the Center for Memory Disturbances, University of Perugia, with the diagnoses FTD (n  = 37), mild cognitive impairment due to Alzheimer’s disease (MCI-AD, n  = 47), Lewy body dementia (PDD/DLB, n  = 22), and cognitively unimpaired patients as controls (OND, n  = 29). Biomarker levels of neuronal pentraxin-2 …(NPTX2), neuronal pentraxin receptor, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were measured in CSF, as well as NfL and GFAP in serum. We assessed biomarker differences by analysis of covariance and generalized linear models (GLM). We performed receiver operating characteristics analyses and Spearman correlation to determine biomarker associations. Results: CSF NPTX2 and serum GFAP levels varied most between diagnostic groups. The combination of CSF NPTX2, serum NfL and serum GFAP differentiated FTD from the other groups with good accuracy (FTD versus MCI-AD: area under the curve (AUC) [95% CI] = 0.89 [0.81–0.96]; FTD versus PDD/DLB: AUC = 0.82 [0.71–0.93]; FTD versus OND: AUC = 0.80 [0.70–0.91]). CSF NPTX2 and serum GFAP correlated positively only in PDD/DLB (ρ = 0.56, p  < 0.05). NPTX2 and serum NfL did not correlate in any of the diagnostic groups. Serum GFAP and serum NfL correlated positively in all groups (ρ = 0.47–0.74, p  < 0.05). Conclusion: We show the combined potential of CSF NPTX2, serum NfL, and serum GFAP to differentiate FTD from other neurodegenerative disorders. Show more

Keywords: Biomarker, differential diagnosis, frontotemporal dementia, glial fibrillary acidic protein, neurofilament light, NPTX2, NPTXR

DOI: 10.3233/JAD-220318

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 363-380, 2022

Authors: van Harten, Thijs W. | Heijmans, Anne | van Rooden, Sanneke | Wermer, Marieke J.H. | van Osch, Matthias J.P. | Kuijf, Hugo J. | van Veluw, Susanne J. | Greenberg, Steven M. | van Buchem, Mark A. | van der Grond, Jeroen | van Walderveen, Marianne A.A.

Article Type: Research Article

Abstract: Background: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer’s disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer’s disease. So far, DMVs have not been evaluated in CAA. Objective: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. Methods: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n  = 8), symptomatic D-CAA mutation carriers (n  = 8), and controls …(n  = 25). Hemorrhagic MRI markers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. Results: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA. Conclusion: This study indicates that vascular amyloid-β deposition does not affect DMV parameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA. Show more

Keywords: Cerebral small vessel disease, cerebral veins, hereditary cerebral amyloid angiopathy, magnetic resonance imaging

DOI: 10.3233/JAD-220354

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 381-388, 2022

Authors: Fu, Jingzhu | Zhu, Yun | Sun, Yue | Liu, Qian | Duan, Huilian | Huang, Ling | Zhou, Dezheng | Wang, Zehao | Zhao, Jing | Li, Zhenshu | Du, Yue | Liu, Huan | Ma, Fei | Chen, Yongjie | Sun, Changqing | Wang, Guangshun | Li, Wen | Huang, Guowei

Article Type: Research Article

Abstract: Background: The high cost, limited availability, and perceived invasiveness of amyloid PET and cerebrospinal fluid biomarkers limit their use for the diagnosis of Alzheimer’s disease. Objective: The present study aimed to assess the associations of mild cognitive impairment (MCI) with circulating amyloid-β (Aβ), methionine circulating metabolites (MCMs), and their downstream products, and to develop a nomogram based on these easily accessible blood indexes for the individualized prediction of MCI risk in older adults. Methods: In this nested case-control study, we recruited 74 MCI patients and, for each, 3 matched controls (n  = 222) within the context of …the Tianjin Elderly Nutrition and Cognition (TENC) cohort, a population-based prospective study in China. Concentrations of Aβ, MCMs, and their circulating downstream factors (i.e., leukocyte telomere length and inflammatory cytokines) were evaluated in fasting blood sample using standard procedures. We constructed a nomogram for MCI harnessed multivariable logistic models incorporating variables selected in the Lasso regression. Results: Among the many biomarkers examined, the final prediction nomogram retained only 3 factors: Aβ42 /Aβ40 ratio, Hcy, and SAM/SAH ratio. The model achieved favorable discrimination, with a C-statistic of 0.75 (95% confidence interval 0.69–0.81) in internal validation after adjustment of optimism. The calibration accuracy was satisfactory; the Brier score of the model was 0.161 in internal validation after adjustment of optimism. Conclusion: his study presents an individualized prediction nomogram incorporating only three blood biomarkers (i.e., Aβ42 /Aβ40 ratio, Hcy, and SAM/SAH ratio), which can be conveniently utilized to facilitate early identification and the development of high-risk prevention strategies for MCI in older adults. Show more

Keywords: Inflammatory factor, leukocyte telomere length, methionine circulating metabolites, mild cognitive impairment, nested case-control study, older adult, plasma amyloid-β, predictive model

DOI: 10.3233/JAD-220373

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 389-404, 2022

Authors: Lachner, Christian | Day, Gregory S. | Camsari, Gamze Balci | Kouri, Naomi | Ertekin-Taner, Nilüfer | Boeve, Bradley F. | Labuzan, Sydney A. | Lucas, John A. | Thompson, E. Aubrey | Siddiqui, Habeeba | Crook, Julia E. | Cabrera-Rodriguez, Janisse N. | Josephs, Keith A. | Petersen, Ronald C. | Dickson, Dennis W. | Reichard, R. Ross | Mielke, Michelle M. | Knopman, David S. | Graff-Radford, Neill R. | Murray, Melissa E.

Article Type: Research Article

Abstract: Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n  = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based …on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p  = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p  = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p  = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p  = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p  = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p  < 0.01) and lower Braak stage (p  = 0.01). Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old. Show more

Keywords: Aging, Alzheimer’s disease, cancer, dementia, neuropathology, vascular disease

DOI: 10.3233/JAD-220440

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 405-417, 2022

Authors: Baldeiras, Inês | Silva-Spínola, Anuschka | Lima, Marisa | Leitão, Maria João | Durães, João | Vieira, Daniela | Tábuas-Pereira, Miguel | Cruz, Vitor Tedim | Rocha, Raquel | Alves, Luisa | Machado, Álvaro | Milheiro, Miguel | Santiago, Beatriz | Santana, Isabel

Article Type: Research Article

Abstract: Background: The ATN scheme was proposed as an unbiased biological characterization of the Alzheimer’s disease (AD) spectrum, grouping biomarkers into three categories: brain Amyloidosis-A, Tauopathy-T, Neurodegeneration-N. Although this scheme was mainly recommended for research, it is relevant for diagnosis. Objective: To evaluate the ATN scheme performance in real-life cohorts reflecting the inflow of patients with cognitive complaints and different underlying disorders in general neurological centers. Methods: We included patients (n  = 1,128) from six centers with their core cerebrospinal fluid-AD biomarkers analyzed centrally. A was assessed through Aβ42 /Aβ40 , T through pTau-181, and N through tTau. …Association between demographic features, clinical diagnosis at baseline/follow-up and ATN profiles was assessed. Results: The prevalence of ATN categories was: A-T-N-: 28.3%; AD continuum (A  + T-/+N-/+): 47.8%; non-AD (A- plus T or/and N +): 23.9%. ATN profiles prevalence was strongly influenced by age, showing differences according to gender, APOE genotype, and cognitive status. At baseline, 74.6% of patients classified as AD fell in the AD continuum, decreasing to 47.4% in mild cognitive impairment and 42.3% in other neurodegenerative conditions. At follow-up, 41% of patients changed diagnosis, and 92% of patients that changed to AD were classified within the AD continuum. A  + was the best individual marker for predicting a final AD diagnosis, and the combinations A  + T+ (irrespective of N) and A  + T+N+ had the highest overall accuracy (83%). Conclusion: The ATN scheme is useful to guide AD diagnosis in real-life neurological centers settings. However, it shows a lack of accuracy for patients with other types of dementia. In such cases, the inclusion of other markers specific for non-AD proteinopathies could be an important aid to the differential diagnosis. Show more

Keywords: Alzheimer’s disease, ATN scheme, cerebrospinal fluid biomarkers, cognitive complaints

DOI: 10.3233/JAD-220587

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 419-432, 2022

Authors: Mattioli, Pietro | Pardini, Matteo | Girtler, Nicola | Brugnolo, Andrea | Orso, Beatrice | Donniaquio, Andrea | Calizzano, Francesco | Mancini, Raffaele | Massa, Federico | Terzaghi, Michele | Bauckneht, Matteo | Morbelli, Silvia | Sambuceti, Gianmario | Nobili, Flavio | Arnaldi, Dario

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a heterogeneous condition. Idiopathic REM sleep behavior disorder (iRBD) can be associated with MCI (MCI-RBD). Objective: To investigate neuropsychological and brain metabolism features of patients with MCI-RBD by comparison with matched MCI-AD patients. To explore their predictive value toward conversion to a full-blown neurodegenerative disease. Methods: Seventeen MCI-RBD patients (73.6±6.5 years) were enrolled. Thirty-four patients with MCI-AD were matched for age (74.8±4.4 years), Mini-Mental State Exam score and education with a case-control criterion. All patients underwent a neuropsychological assessment and brain 18 F-FDG-PET. Images were compared between groups to identify …hypometabolic volumes of interest (MCI-RBD-VOI and MCI-AD-VOI). The dependency of whole-brain scaled metabolism levels in MCI-RBD-VOI and MCI-AD-VOI on neuropsychological test scores was explored with linear regression analyses in both groups, adjusting for age and education. Survival analysis was performed to investigate VOIs phenoconversion prediction power. Results: MCI-RBD group scored lower in executive functions and higher in verbal memory compared to MCI-AD group. Also, compared with MCI-AD, MCI-RBD group showed relative hypometabolism in a posterior brain area including cuneus, precuneus, and occipital regions while the inverse comparison revealed relative hypometabolism in the hippocampus/parahippocampal areas in MCI-AD group. MCI-RBD-VOI metabolism directly correlated with executive functions in MCI-RBD (p  = 0.04). MCI-AD-VOI metabolism directly correlated with verbal memory in MCI-AD (p  = 0.001). MCI-RBD-VOI metabolism predicted (p  = 0.03) phenoconversion to an alpha-synucleinopathy. MCI-AD-VOI metabolism showed a trend (p  = 0.07) in predicting phenoconversion to dementia. Conclusion: MCI-RBD and MCI-AD showed distinct neuropsychological and brain metabolism profiles, that may be helpful for both diagnosis and prognosis purposes. Show more

Keywords: Alpha-synucleinopathies, Alzheimer’s disease, brain metabolism, mild cognitive impairment, REM sleep behavior disorder

DOI: 10.3233/JAD-220653

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 433-444, 2022

Authors: Sun, Lin | Li, Wei | Yue, Ling | Xiao, Shifu

Article Type: Correction

DOI: 10.3233/JAD-229011

Citation: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 445-445, 2022