Journal of Alzheimer's Disease - Volume 85, issue 1

Authors: Qiao, Yanan | Sun, Yu | Guo, Jing | Chen, Yaojing | Hou, Wenjie | Zhang, Junying | Peng, Dantao

Article Type: Research Article

Abstract: Background: Lobar cerebral microbleeds (CMBs), which can impair white matter (WM), are often concomitant with definite Alzheimer’s disease (AD). Objective: To explore the features of cognitive impairments and WM disruptions due to lobar CMBs in patients with AD. Methods: There were 310 participants who underwent Florbetapir F18 (AV45) amyloid PET and susceptibility-weighted imaging. Participants with cognitive impairment and amyloid-β positive (ADCI) were included into three groups: ADCI without CMBs, with strictly lobar CMBs (SL-CMBs), and with mixed CMBs (M-CMBs). Tract-based spatial statistics were performed to detect the group differences in WM integrity. Results: There …were 82 patients and 29 healthy controls finally included. A decreasing tendency in memory and executive performance can be found among HCs > no CMBs (n  = 16) >SL-CMBs (n  = 41) >M-CMBs (n  = 25) group. Compared to no CMBs, M-CMBs group had significantly decreased fractional anisotropy in left anterior thalamic radiation (ATR), forceps major, forceps minor and inferior longitudinal fasciculus, bilateral inferior fronto-occipital fasciculus (IFOF), and superior longitudinal fasciculus. M-CMBs group also had lower fractional anisotropy in left ATR, IFOF, uncinate fasciculus, and forceps minor compared with SL-CMBs. Furthermore, analysis of Pearson correlation indicated damages in discrepant WMs were positively associated with impairment of memory, executive function, and attention. Conclusion: This study showed lobar CMBs had intensively aggravated cognitive impairments associated with extensive WM damages in definite AD. These findings highlight that lobar CMBs play an important role in AD progression and need to be taken into consideration for the early detection of AD. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, cognitive impairment, diffusion tensor imaging, Florbetapir F18 amyloid PET

DOI: 10.3233/JAD-215251

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 369-380, 2022

Authors: Wilkins, Heather M. | Troutwine, Benjamin R. | Menta, Blaise W. | Manley, Sharon J. | Strope, Taylor A. | Lysaker, Colton R. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists. Objective: We considered how mitochondrial biology may impact AβPP and Aβ biology. Methods: SH-SY5Y cells were transfected with AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP was …also measured. All parameters listed were measured in ρ 0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results. Results: We showed that mitochondrial depolarization routes AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed. Conclusion: Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promotes Aβ secretion while depressed mitochondrial activity minimizes Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function. Show more

Keywords: Amyloid, amyloid-beta protein precursor, membrane potential, mitochondria

DOI: 10.3233/JAD-215280

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 381-394, 2022

Authors: Bergamino, Maurizio | Keeling, Elizabeth G. | Baxter, Leslie C. | Sisco, Nicholas J. | Walsh, Ryan R. | Stokes, Ashley M.

Article Type: Research Article

Abstract: Background: Imaging biomarkers are increasingly used in Alzheimer’s disease (AD), and the identification of sex differences using neuroimaging may provide insight into disease heterogeneity, progression, and therapeutic targets. Objective: The purpose of this study was to investigate differences in grey matter (GM) volume and white matter (WM) microstructural disorganization between males and females with AD using voxel-based morphometry (VBM) and free-water-corrected diffusion tensor imaging (FW-DTI). Methods: Data were downloaded from the OASIS-3 database, including 158 healthy control (HC; 86 females) and 46 mild AD subjects (24 females). VBM and FW-DTI metrics (fractional anisotropy (FA), axial and …radial diffusivities (AxD and RD, respectively), and FW index) were compared using effect size for the main effects of group, sex, and their interaction. Results: Significant group and sex differences were observed, with no significant interaction. Post-hoc comparisons showed that AD is associated with reduced GM volume, reduced FW-FA, and higher FW-RD/FW-index, consistent with neurodegeneration. Females in both groups exhibited higher GM volume than males, while FW-DTI metrics showed sex differences only in the AD group. Lower FW, lower FW-FA and higher FW-RD were observed in females relative to males in the AD group. Conclusion: The combination of VBM and DTI may reveal complementary sex-specific changes in GM and WM associated with AD and aging. Sex differences in GM volume were observed for both groups, while FW-DTI metrics only showed significant sex differences in the AD group, suggesting that WM tract disorganization may play a differential role in AD pathophysiology between females and males. Show more

Keywords: Alzheimer’s disease, diffusion tensor MRI, free-water DTI, sexual dimorphism, voxel-based morphometry

DOI: 10.3233/JAD-210406

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 395-414, 2022

Authors: Barthélemy, Nicolas R. | Toth, Balazs | Manser, Paul T. | Sanabria-Bohórquez, Sandra | Teng, Edmond | Keeley, Michael | Bateman, Randall J. | Weimer, Robby M. | Wildsmith, Kristin R.

Article Type: Research Article

Abstract: Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18 F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18 F]GTP1) and amyloid PET ([18 F]florbetapir or [18 F]florbetaben). Cohort A included cognitively normal amyloid …negative (n  = 6) and positive (n  = 5) individuals, and amyloid positive prodromal (n  = 13), mild (n  = 12), and moderate AD patients (n  = 10); and Cohort B included amyloid positive prodromal (n  = 24) and mild (n  = 40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with SUVR measures from [18 F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18 F]GTP1 and amyloid PET. Conclusion: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, [18F]GTP1, PET, tau, NCT02640092, NCT03289143

DOI: 10.3233/JAD-210677

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 415-429, 2022

Authors: Contarino, Valeria Elisa | Siggillino, Silvia | Arighi, Andrea | Scola, Elisa | Fumagalli, Giorgio Giulio | Conte, Giorgio | Rotondo, Emanuela | Galimberti, Daniela | Pietroboni, Anna Margherita | Carandini, Tiziana | Leemans, Alexander | Bianchi, Anna Maria | Triulzi, Fabio Maria

Article Type: Research Article

Abstract: Background: Superficial white matter (SWM) alterations correlated with cognitive decline have been described in Alzheimer’s disease (AD). Objective: The study aims to extend the investigation of the SWM alterations to AD and non-AD neurodegenerative dementia (ND) and explore the relationship with cerebrospinal fluid (CSF) biomarkers and clinical data. Methods: From a database of 323 suspected dementia cases, we retrospectively recruited 55 ND with abnormal amyloid-β42 (AD) and 38 ND with normal amyloid-β42 (non-AD) and collected clinical data, CSF biomarkers, and magnetic resonance images. Ten healthy controls (HC) were recruited for imaging and Mini-Mental State …Examination (MMSE). Diffusion tensor imaging (DTI) measurements were performed in the lobar SWM regions and Kruskal Wallis tests were used for among-group comparison. Spearman’s correlation tests were performed between DTI measures, CSF biomarkers, and clinical data. Results: AD and non-AD showed significant differences in the DTI measures across the SWM compared to HC. Significant differences between AD and non-AD were detected in the left parietal lobe. DTI measures correlated with amyloid-β42 and MMSE diffusely in the SWM, less extensively with total-tau and phosphorylated tau, and with disease duration in the parietal lobe bilaterally. Conclusion: Widespread SWM alterations occur in both AD and non-AD ND and AD shows appreciably more severe alterations in the parietal SWM. Notably, the alterations in the SWM are strongly linked not only to the cognitive decline but also to the diagnostic CSF biomarkers. Further studies are encouraged to evaluate the DTI measures in the SWM as in vivo non-invasive biomarkers in the preclinical phase. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid proteins, dementia, diffusion tensor imaging, mental status and dementia tests, neurodegenerative diseases, white matter

DOI: 10.3233/JAD-215003

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 431-442, 2022

Authors: Sun, Xiaodi | Suo, Xinjun | Xia, Xianyou | Yu, Chunshui | Dou, Yan

Article Type: Research Article

Abstract: Background: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer’s disease (AD), DMF is a potential therapeutic option for AD. Objective: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. Methods: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic …resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. Results: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition. Conclusion: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway. Show more

Keywords: Alzheimer’s disease, dimethyl fumarate, hippocampal atrophy, Nrf2 pathway, oxidative stress

DOI: 10.3233/JAD-215074

Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 443-456, 2022