Journal of Alzheimer's Disease - Volume 88, issue 1

Authors: Leng, Fangda | Zhan, Zhenying | Sun, Yunchuang | Liu, Fang | Edison, Paul | Sun, Yongan | Wang, Zhaoxia | on behalf of Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Recently it has been proposed that microglial response has a stage-dependent effect on the progression of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) sTREM2 has emerged as a promising microglial activation marker. Objective: To test the stage-dependent role of microglia by studying the association between baseline sTREM2 and dynamic brain structural changes in AD and mild cognitive impairment (MCI) patients. Methods: 22 amyloid-β-positive (A+) and tau-positive (T+) AD and 24 A+T+MCI patients were identified from the Alzheimer’s Disease Neuroimaging Initiative. The patients had baseline CSF amyloid-β, phosphorylated-tau, and sTREM2, and were followed up for at least …one year by T1-weighted and diffusion tensor imaging scans. Gray matter volumes and white matter microstructural integrity were evaluated. Linear mixed models were applied to analyze how baseline sTREM2 may influence the rate of brain structural changes while adjusting for the effects of age, APOE4 status, and the CSF core markers. Results: In A+T+AD patients, baseline CSF sTREM2 was associated with faster mean diffusivity increase in the bilateral posterior corona radiata and right superior longitudinal fasciculus. In A+T+MCI patients, baseline CSF sTREM2 was associated slower gray matter volumetric loss in parahippocampal gyrus, left fusiform cortex, left middle temporal gyrus, and left lateral occipital cortex. Baseline CSF sTREM2 also had a protective effect against mean diffusivity increase in right inferior fronto-occipital fasciculus, left superior longitudinal fasciculus, left forceps minor, and left uncinate fasciculus. Conclusion: Microglial activation at early stage might have a protective effect against neurodegeneration, while at late stage it might facilitate AD. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, disease progression, microglial activation, sTREM2, voxel-based morphometry

DOI: 10.3233/JAD-220102

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 117-126, 2022

Authors: Fernandes, Mariana | Chiaravalloti, Agostino | Manfredi, Natalia | Placidi, Fabio | Nuccetelli, Marzia | Izzi, Francesca | Camedda, Riccardo | Bernardini, Sergio | Schillaci, Orazio | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Research Article

Abstract: Background: Sleep disorders may cause dysregulation in cerebral glucose metabolism and synaptic functions, as well as alterations in cerebrospinal fluid (CSF) biomarker levels. Objective: This study aimed at measuring sleep, CSF Alzheimer’s disease (AD) biomarkers, and cerebral glucose consumption in patients with obstructive sleep apnea syndrome (OSAS) and patients with periodic limb movement disorder (PLMD), compared to controls. Methods: OSAS and PLMD patients underwent 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET), polysomnographic monitoring, and lumbar puncture to quantify CSF levels of amyloid-β42 (Aβ42 ), total tau, and phosphorylated tau. All patients were compared to …controls, who were not affected by sleep or neurodegenerative disorders. Results: Twenty OSAS patients, 12 PLMD patients, and 15 controls were included. Sleep quality and sleep structure were altered in both OSAS and PLMD patients when compared to controls. OSAS and PLMD patients showed lower CSF Aβ42 levels than controls. OSAS patients showed a significant increase in glucose uptake in a wide cluster of temporal-frontal areas and cerebellum, as well as a reduced glucose consumption in temporal-parietal regions compared to controls. PLMD patients showed increased brain glucose consumption in the left parahippocampal gyrus and left caudate than controls. Conclusion: Sleep dysregulation and nocturnal hypoxia present in OSAS patients, more than sleep fragmentation in PLMD patients, were associated with the alteration in CSF and 18 F-FDG PET AD biomarkers, namely reduction of CSF Aβ42 levels and cerebral glucose metabolism dysregulation mainly in temporal areas, thus highlighting the possible role of sleep disorders in driving neurodegenerative processes typical of AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β , brain glucose consumption, cerebrospinal fluid, positron emission tomography, sleep

DOI: 10.3233/JAD-215734

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 127-139, 2022

Authors: Zhang, Yinghan | Hu, Yazhuo | Han, Zhitao | Geng, Yan | Xia, Zheng | Zhou, Yongsheng | Wang, Zhenfu | Wang, Yuanyuan | Kong, Eryan | Wang, Xiaoning | Jia, Jianjun | Zhang, Honghong

Article Type: Research Article

Abstract: Background: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer’s disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-β (Aβ) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aβ deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. Objective: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 …(PSD-95) palmitoylation, Aβ pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. Methods: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. Results: CEGI treatment in APP/PS1 mice significantly reduced Aβ deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aβ expression and PSD-95 palmitoylation in APP/PS1 mice. Conclusion: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment. Show more

Keywords: Alzheimer’s disease, APP/PS1 transgenic mice, palmitoylation, postsynaptic density protein 95

DOI: 10.3233/JAD-220009

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 141-154, 2022

Authors: Tancheva, Lyubka | Lazarova, Maria | Velkova, Lyudmila | Dolashki, Alexander | Uzunova, Diamara | Minchev, Borislav | Petkova-Kirova, Polina | Hassanova, Yozljam | Gavrilova, Petja | Tasheva, Krasimira | Taseva, Teodora | Hodzhev, Yordan | Atanasov, Atanas G. | Stefanova, Miroslava | Alexandrova, Albena | Tzvetanova, Elina | Atanasov, Ventseslav | Kalfin, Reni | Dolashka, Pavlina

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disease with multifactorial etiology, unsatisfactory treatment, and a necessity for broad-spectrum active substances for cure. The mucus from Helix aspersa snail is a mixture of bioactive molecules with antimicrobial, anti-inflammatory, antioxidant, and anti-apoptotic effects. So far there are no data concerning the capacity of snail extract (SE) to affect neurodegenerative disorders. Objective: The effects of SE from Helix aspersa on learning and memory deficits in Alzheimer’s type dementia (ATD) induced by scopolamine (Sco) in male Wistar rats were examined and some mechanisms of action underlying these effects were …evaluated. Methods: SE (0.5 mL/100 g) was applied orally through a food tube for 16 consecutive days: 5 days before and 11 days simultaneously with Sco (2 mg/kg, intraperitoneally). At the end of Sco treatment, using behavioral methods, we evaluated memory performance. Additionally, in cortex and hippocampus the acetylcholinesterase (AChE) activity, acetylcholine and monoamines (dopamine, noradrenaline, and serotonin) content, levels of main oxidative stress markers, and expression of brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) were determined. Results: We demonstrated that, according to all behavioral tests used, SE significantly improved the cognitive deficits induced by Sco. Furthermore, SE possessed AChE inhibitory activity, moderate antioxidant properties and the ability to modulate monoamines content in two brain structures. Moreover, multiple SE applications not only restored the depressed by Sco expression of CREB and BDNF, but significantly upregulated it. Conclusion: Summarizing results, we conclude that complex mechanisms underlie the beneficial effects of SE on impaired memory in Alzheimer’s type dementia. Show more

Keywords: Antioxidant system, BDNF, cholinergic function, CREB, scopolamine, snail Helix aspersa

DOI: 10.3233/JAD-215693

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 155-175, 2022

Authors: Welty, Starr | Thathiah, Amantha | Levine, Arthur Samuel

Article Type: Research Article

Abstract: Background: Recent studies suggest a strong association between neuronal DNA damage, elevated levels of amyloid-β (Aβ), and regions of the brain that degenerate in Alzheimer’s disease (AD). Objective: To investigate the nature of this association, we tested the hypothesis that extensive DNA damage leads to an increase in Aβ40 and Aβ42 generation. Methods: We utilized an immortalized human neuronal progenitor cell line (NPCs), ReN VM GA2. NPCs or 20 day differentiated neurons were treated with hydrogen peroxide or etoposide and allowed to recover for designated times. Sandwich ELISA was used to assess secreted Aβ40 …and Aβ42 . Western blotting, immunostaining, and neutral comet assay were used to evaluate the DNA damage response and processes indicative of AD pathology. Results: We determined that global hydrogen peroxide damage results in increased cellular Aβ40 and Aβ42 secretion 24 h after treatment in ReN GA2 NPCs. Similarly, DNA double strand break (DSB)-specific etoposide damage leads to increased Aβ40 and Aβ42 secretion 2 h and 4 h after treatment in ReN GA2 NPCs. In contrast, etoposide damage does not increase Aβ40 and Aβ42 secretion in post-mitotic ReN GA2 neurons. Conclusion: These findings provide evidence that in our model, DNA damage is associated with an increase in Aβ secretion in neuronal progenitors, which may contribute to the early stages of neuronal pathology in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , DNA repair, double strand breaks, etoposide, neurodegenerative disease, oxidative damage

DOI: 10.3233/JAD-220030

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 177-190, 2022

Authors: Das, Tushar K. | Blasco-Conesa, Maria P. | Korf, Janelle | Honarpisheh, Pedram | Chapman, Matthew R. | Ganesh, Bhanu P.

Article Type: Research Article

Abstract: Background: Substantial evidence from recent research suggests an influential and underappreciated force in Alzheimer’s disease (AD) pathogenesis: the pathological signals originate from outside the brain. Pathogenic bacteria produce amyloid-like proteins “curli” that form biofilms and show functional similarities to human amyloid-β (Aβ). These proteins may contribute to neurological disease progression via signaling cascade from the gut to the brain. Objective: We propose that curli causes neuroendocrine activation from the gut to brain that promotes central Aβ pathology. Methods: PGP9.5 and TLR2 levels in response to curli in the lumen of Tg2576 AD mice were analyzed by …immunohistochemical and qRT-PCR analysis. Western blot and human 3D in vitro enteroids culture systems were also used. 16S rRNA gene sequencing was used to investigate bacterial dysbiosis. Results: We found significant increase in bacterial-amyloid curli with elevated TLR2 at the mRNA level in the pre- and symptomatic Tg-AD gut compared to littermate WT controls. This data associates with increased gram-positive bacterial colonization in the ileum of the symptomatic AD mice. We found fundamental evidence for vagus nerve activation in response to bacterial curli. Neuroendocrine marker PGP9.5 was significantly elevated in the gut epithelium of symptomatic AD mice, and this was colocalized with increased TLR2 expression. Enteroids, 3D-human ileal mini-gut monolayer in vitro model system also revealed increase levels of TLR2 upon stimulation with purified bacterial curli fibrils. Conclusion: These findings reveal the importance of pathological changes within the gut-vagus-brain signaling in response to luminal bacterial amyloid that might play a vital role in central Aβ pathogenesis seen in the AD brain. Show more

Keywords: Alzheimer’s disease, amyloid-β, bacterial amyloid, curli, dysbiosis, enteroendocrine cell, gut barrier, gut-brain axis, neuroendocrine, PGP9.5, TLR2, vagus nerve

DOI: 10.3233/JAD-220106

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 191-205, 2022

Authors: Helboe, Lone | Rosenqvist, Nina | Volbracht, Christiane | Pedersen, Lars Ø. | Pedersen, Jan T. | Christensen, Søren | Egebjerg, Jan | Christoffersen, Claus T. | Bang-Andersen, Benny | Beach, Thomas G. | Serrano, Geidy E. | Falsig, Jeppe

Article Type: Research Article

Abstract: Background: Deposits of hyperphosphorylated tau fibrils are hallmarks of a broad spectrum of tauopathies, including Alzheimer’s disease (AD). Objective: To investigate heterogeneity of tau pathology across brain extracts from a broad selection of different tauopathies and examine the binding properties of the humanized pS396-tau antibody hC10.2 and six other anti-tau antibodies. Methods: 76 individual tauopathy tissue samples were analyzed in a battery of assays: immunohistochemistry, ELISA, tau aggregation assay, western blot, [3 H]PI-2620 and [3 H]MK-6240 tau tracer binding, and aggregated seeding activity in RD_P301S HEK293T Biosensor cells. The efficiency of seven anti-tau antibodies to engage …with pathological tau species was directly compared. Results: Our data indicate that a strong correlation existed between the tau tracer binding, amount of tau aggregates, pS396-tau phosphorylation, and seeding activity. The hC10.2 antibody, which has entered clinical development, effectively engaged with its epitope across all individual cases of mid-stage and late AD, and primary tauopathies. hC10.2 was superior compared to other phospho- and total tau antibodies to prevent seeded tau aggregation in the biosensor cells. hC10.2 effectively depleted hyperphosphorylated and aggregated tau species across all tauopathy samples proportionally to the amount of tau aggregates. In AD samples, hC10.2 bound to ghost tangles which represent extracellular pathological tau species. Conclusion: S396 hyperphosphorylation is a feature of the formation of seeding-competent tau across different tauopathies and it is present both in intra- and extracellular pathological tau. hC10.2 represents an excellent candidate for a hyperphosphorylation-selective therapeutic tau antibody for the treatment of AD and primary tauopathies. Show more

Keywords: Alzheimer’s disease, human brain tissue, humanized antibody, PET tracer, seeding and spreading, tau aggregate, tauopathy, therapeutic monoclonal antibody

DOI: 10.3233/JAD-220125

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 207-228, 2022

Authors: Hendriks, Stevie | Peetoom, Kirsten | Tange, Huibert | van Bokhoven, Marloes A. | van der Flier, Wiesje M. | Bakker, Christian | Papma, Janne M. | Koopmans, Raymond | Verhey, Frans | Köhler, Sebastian | de Vugt, Marjolein

Article Type: Research Article

Abstract: Background: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD. Objective: Identify early symptoms that are more common in the pre-diagnostic phase of YOD. Methods: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted …from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom’s time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported. Results: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77%), for the highest percentage of correctly diagnosed persons. Conclusion: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD. Show more

Keywords: Case-control study, dementia, general practice, middle aged

DOI: 10.3233/JAD-220215

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 229-239, 2022

Authors: Ang, Su Fen | Low, Serena | Ng, Tze Pin | Tan, Clara S.H. | Ang, Keven | Lim, Ziliang | Tang, Wern Ee | Subramaniam, Tavintharan | Sum, Chee Fang | Lim, Su Chi

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer’s disease and T2DM. Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients. Methods: 590 Chinese patients aged 45–86 from the SMART2D study were genotyped for PAX4 R192H variation using …Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains. Results: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (β= –8.46, 95% CI [–13.71, –3.21], p  = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOE ɛ 4 allele. Conclusion: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care. Show more

Keywords: Cognitive impairment, ethnic-specific, PAX4, type 2 diabetes

DOI: 10.3233/JAD-220036

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 241-249, 2022

Authors: Wu, Fen | Davey, Samuel | Clendenen, Tess V. | Koenig, Karen L. | Afanasyeva, Yelena | Zhou, Boyan | Bedi, Sukhleen | Li, Huilin | Zeleniuch-Jacquotte, Anne | Chen, Yu

Article Type: Research Article

Abstract: Background: Epidemiological studies that investigate alterations in gut microbial composition associated with cognitive dysfunction are limited. Objective: To examine the association between the gut microbiota and subjective memory complaints (SMCs), a self-reported, validated indicator of cognitive dysfunction. Methods: In this cross-sectional study of 95 older women selected from the New York University Women’s Health Study (NYUWHS), we characterized the gut microbial composition using 16S rRNA gene sequencing. We estimated odds ratio (OR) from beta regression which approximates the ratio of mean relative abundances of individual bacterial taxon from phylum to genus levels by binary (2+ versus …< 2) and continuous SMCs. Results: Women reporting 2 or more SMCs had higher relative abundances of genus Holdemania and family Desulfovibrionaceae compared with those reporting one or no complaint. Compared with women with < 2 SMCs, the relative abundances of Holdemania and family Desulfovibrionaceae were 2.09 times (OR: 2.09, 95% confidence interval [CI]: 1.38–3.17) and 2.10 times (OR: 2.10, 95% CI: 1.43–3.09) higher in women with 2+ SMCs, respectively (false discovery rate (FDR)-adjusted p = 0.038 and 0.010, respectively). A dose-response association was observed for genus Sutterella and family Desulfovibrionaceae . Every one-unit increase in SMCs was associated with 25% and 27% higher relative abundances of Sutterella (OR: 1.25; 95% CI: 1.11–1.40) and Desulfovibrionaceae (OR: 1.27; 95% CI: 1.13–1.42), respectively (FDR-adjusted p  = 0.018 and 0.006, respectively). Conclusion: Our findings support an association between alterations in the gut bacterial composition and cognitive dysfunction. Show more

Keywords: 16S RNA gene sequencing, cross-sectional, gut microbiota, NYUWHS, subjective memory complaints

DOI: 10.3233/JAD-220011

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 251-262, 2022