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