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

Authors: Liang, Yajun | Gao, Ya | Wang, Rui | Grande, Giulia | Monastero, Roberto | Dong, Yanhong | Jiang, Xin | Lv, Peiyuan | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: The potential impact of migraine on cognitive aging among older adults remains controversial. Objective: To examine the relationship of migraine and subtypes with cognitive decline and dementia in an older Swedish population. Methods: This population-based study included 3,069 participants (age ≥ 60 years) from the Swedish National study on Aging and Care in Kungsholmen, Stockholm. Baseline examination was conducted in 2001–2004, and participants were followed every 3 or 6 years until 2013–2016. Data were collected through face-to-face interviews, clinical examinations, laboratory tests, and linkage with registers. Global cognitive function was measured with the Mini-Mental State …Examination (MMSE). Dementia was diagnosed according to the DSM-IV criteria. Migraine and subtypes were defined following the international classification system. Data were analyzed using logistic regression, Cox regression, and linear mixed-effects models. Results: At baseline, 305 participants were defined with non-migraine headache and 352 with migraine. The cross-sectional analysis showed that the multivariable-adjusted odds ratio (95% confidence interval) of prevalent dementia was 0.49 (0.20–1.21) for migraine and 0.66 (0.26–1.66) for migraine without aura. The longitudinal analysis showed that the multivariable-adjusted hazard ratios of incident dementia associated with migraine and subtypes ranged 0.68–0.89 (p  > 0.05). Furthermore, migraine and subtypes were not significantly associated with either baseline MMSE score or MMSE changes during follow-ups (p  > 0.05). The nonsignificant associations did not vary substantially by age, APOE ɛ 4 allele, cerebrovascular disease, and antimigraine treatment (p for interactions > 0.05). Conclusion: This study shows no evidence supporting the associations of migraine and its subtypes with cognitive decline and dementia among older adults. Show more

Keywords: Cognitive aging, dementia, headache, migraine, population-based study

DOI: 10.3233/JAD-220013

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 263-271, 2022

Authors: Zhang, Xingxing | Guan, Qing | Li, Yingjia | Zhang, Jianfeng | Zhu, Wanlin | Luo, Yuejia | Zhang, Haobo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: BOLD signals in the gray matter (GM) and white matter (WM) are tightly coupled. However, our understanding of the cross-tissue functional network in Alzheimer’s disease (AD) is limited. Objective: We investigated the changes of cross-tissue functional connectivity (FC) metrics for the GM regions susceptible to AD damage. Methods: For each GM region in the default mode (DMN) and limbic networks, we obtained its low-order static FC with any WM region, and the high-order static FC between any two WM regions based on their FC pattern similarity with multiple GM regions. The dynamic and directional properties …of cross-tissue FC were then acquired, specifically for the regional pairs whose low- or high-order static FCs showed significant differences between AD and normal control (NC). Moreover, these cross-tissue FC metrics were correlated with voxel-based GM volumes and MMSE in all participants. Results: Compared to NC, AD patients showed decreased low-order static FCs between the intra-hemispheric GM-WM pairs (right ITG-right fornix ; left MoFG-left posterior corona radiata ), and increased low-order static, dynamic, and directional FCs between the inter-hemispheric GM-WM pairs (right MTG-left superior/posterior corona radiata ). The high-order static and directional FCs between the left cingulate bundle -left tapetum were increased in AD, based on their FCs with the GMs of DMN. Those decreased and increased cross-tissue FC metrics in AD had opposite correlations with memory-related GM volumes and MMSE (positive for the decreased and negative for the increased). Conclusion: Cross-tissue FC metrics showed opposite changes in AD, possibly as useful neuroimaging biomarkers to reflect neurodegenerative and compensatory mechanisms. Show more

Keywords: Alzheimer’s disease, directional, dynamic, functional connectivity, gray matter, high-order, static, white matter

DOI: 10.3233/JAD-215649

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 273-290, 2022

Authors: Contador, Israel | Alzola, Patricia | Bermejo-Pareja, Félix | del Ser, Teodoro | Llamas-Velasco, Sara | Fernández-Calvo, Bernardino | Benito-León, Julián

Article Type: Research Article

Abstract: Background: A protective effect of education on cognitive decline after stroke has been claimed, but evidence from prospective population-based cohorts is very limited. The differential role of literacy and education on dementia after stroke remains unexplored. Objective: This research addresses the role of education and literacy in dementia incidence after stroke and transient ischemic attack (TIA). Methods: 131 participants with stroke or TIA were identified within the population-based NEDICES study (N  = 5,278 persons). Participants were fully assessed at baseline (1994–1995) and incident dementia diagnosis was made by expert neurologists (DSM-IV criteria) after a mean follow-up of …3.4 years. Adjusted Cox regression analyses were applied to test the association between education, literacy, and dementia risk. Results: Within the 131 subjects with stroke or TIA, 19 (14%) developed dementia at follow-up. The Cox’s regression model (age and sex adjusted) showed that low education (HR = 3.48, 95% CI = 1.28, 9.42, p  = 0.014) and literacy (HR = 3.16, 95% CI = 1.08, 9.22, p  = 0.035) were significantly associated with a higher dementia risk. Low education was also associated with dementia when main confounders (i.e., cognitive/functional performance) were considered in the Cox’s model. However, after including stroke recurrence, only low/null literacy (versus education) remained as significant predictor of dementia. Finally, low/null literacy showed an effect over-and-above education on dementia risk when both factors were introduced in the adjusted Cox’s regression. Conclusion: These findings underline the importance of literacy to estimate cognitive decline after stroke in low-educated populations. Show more

Keywords: Cognitive reserve, illiteracy, low education, stroke, transient ischemic attack

DOI: 10.3233/JAD-220109

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 291-299, 2022

Authors: Yeung, Michael K. | Lee, Tsz-lok | Chan, Agnes S.

Article Type: Research Article

Abstract: Background: Identifying individuals at increased risks for developing Alzheimer’s disease (AD) is crucial for early intervention. Memory complaints are associated with brain abnormalities characteristic of AD in cognitively normal older people. However, the utility of memory complaints for predicting mild cognitive impairment (MCI) or AD onset remains controversial, likely due to the heterogeneous nature of this construct. Objective: We investigated whether prefrontal oxygenation changes measured by functional near-infrared spectroscopy (fNIRS) during an arduous cognitive task, previously shown to be associated with the AD syndrome, could differentiate memory abilities among individuals with memory complaints. Episodic memory performance was adopted …as a proxy for MCI/AD risks since it has been shown to predict AD progression across stages. Methods: Thirty-six adults self-reporting memory complaints in the absence of memory impairment completed a verbal list learning test and underwent a digit n -back paradigm with an easy (0-back) and a difficult (2-back) condition. K-means clustering was applied to empirically derive memory complaint subgroups based on fNIRS-based prefrontal oxygenation changes during the effortful 2-back task. Results: Cluster analysis revealed two subgroups characterized by high (n  = 12) and low (n  = 24) bilateral prefrontal activation during the 2-back but not a 0-back task. The low activation group was significantly less accurate across the n -back task and recalled significantly fewer words on the verbal memory test compared to the high activation group. Conclusion: fNIRS may have the potential to differentiate verbal memory abilities in individuals with self-reported memory complaints. Show more

Keywords: Episodic memory, fNIRS, k-means, memory complaints, n-back, prefrontal cortex

DOI: 10.3233/JAD-220130

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 301-310, 2022

Authors: Wittfeld, Katharina | Raman, Mekala R. | Conner, Sarah C. | Aslam, Asra | Teumer, Alexander | Nauck, Matthias | Hosten, Norbert | Habes, Mohamad | DeCarli, Charles | Vasan, Ramachandran S. | Beiser, Alexa S. | Himali, Jayandra J. | Seshadri, Sudha | Grabe, Hans J. | Satizabal, Claudia L.

Article Type: Research Article

Abstract: Background: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer’s disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. Objective: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer’s disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. Methods: We included participants from the Framingham Heart Study (n  = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n  = 674, mean age …50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. Results: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], –0.05 [–0.09, –0.02], p  = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p  = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. Conclusion: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife. Show more

Keywords: Alzheimer’s disease endophenotype, C-reactive protein, cohort study, epidemiology, hippocampus, insulin-like growth factor, neuroimaging, white matter hyperintensity

DOI: 10.3233/JAD-220356

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 311-322, 2022

Authors: Blujus, Jenna Katherine | Korthauer, Laura Elizabeth | Awe, Elizabeth | Frahmand, Marijam | Driscoll, Ira

Article Type: Research Article

Abstract: Background: Disease-modifying treatments for Alzheimer’s disease (AD) may be more successful if interventions occur early, prior to significant neurodegeneration and subsequent to the onset of clinical symptoms, potentially during middle age. Polymorphisms within BDNF , COMT , and KIBRA have been implicated in AD and relate to episodic memory and executive functioning, two domains that decline early in AD. Objective: The purpose of the current study was to use an endophenotype approach to examine in healthy, non-demented middle-aged adults the association between polymorphisms in BDNF , COMT , and KIBRA and functional connectivity within networks related …to episodic memory and executive function (i.e., default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN)). Methods: Resting state networks were identified using independent component analysis and spatial maps with associated time courses were extracted using a dual regression approach. Results: Functional connectivity within the DMN was associated with polymorphisms in BDNF (rs11030096, rs1491850) and KIBRA (rs1030182, rs6555791, rs6555802) (p s < 0.05), ECN connectivity was associated with polymorphisms in KIBRA (rs10475878, rs6555791) (p s < 0.05), and FPN connectivity was associated with KIBRA rs6555791 (p  < 0.05). There were no COMT -related differences in functional connectivity of any of the three networks investigated (p s > 0.05). Conclusion: Our study demonstrates that in middle age, polymorphisms in BDNF and KIBRA are associated with altered functional connectivity in networks that are affected early in AD. Future preclinical work should consider these polymorphisms to further elucidate their role in pathological aging and to aid in the identification of biomarkers. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, endophenotypes, functional neuroimaging, genetic polymorphism, middle aged

DOI: 10.3233/JAD-215477

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 323-334, 2022

Authors: Agger, Mikkel Pejstrup | Carstensen, Marcus Schultz | Henney, Mark Alexander | Hansen, Luna Skytte | Baandrup, Anders Ohlhues | Nguyen, Mai | Petersen, Paul Michael | Madsen, Kristoffer Hougaard | Kjær, Troels Wesenberg

Article Type: Research Article

Abstract: Background: Exposure to 40 Hz stroboscopic light, for one hour a day, has previously been published as a potential treatment option for Alzheimer’s disease in animal models. However, exposure for an hour a day to 40 Hz stroboscopic light can be strenuous and examining other types of 40 Hz inducing stimuli is paramount if chronic treatment is wanted. Objective: A core assumption behind ensuring a therapeutic outcome is that the visual stimuli can induce 40 Hz gamma entrainment. Here, we examine whether a specific visual stimulus, 40 Hz invisible spectral flicker (ISF), can induce gamma entrainment and how it differs from both continuous …light (CON) and 40 Hz stroboscopic light (STROBE). Methods: The study included non-simultaneous EEG-fMRI neuroimaging of 13 young healthy volunteers during light exposure. Each light condition (i.e., CON, ISF, or STROBE) was active for 30 seconds followed immediately by the next. Results: Entrainment of 40 Hz neural activity were significantly higher signal-to-noise ratio during exposure to ISF (mean: 3.03, 95% CI 2.07 to 3.99) and STROBE (mean: 12.04, 95% CI 10.18 to 13.87) compared to CON. Additionally STROBE had a higher entrainment than ISF (mean: 9.01, 95% CI 7.16 to 12.14). Conclusion: This study presents a novel method of 40 Hz entrainment using ISF. This enables the possibility of future randomized placebo-controlled clinical trials with acceptable double blinding due to the essentially imperceivable flicker, which is expected to substantially reduce discomfort compared to interventions with stroboscopic flicker. Show more

Keywords: 40 Hz, Alzheimer’s disease, electroencephalograph, functional MRI, gamma entrainment, GENUS, invisible spectral flicker, light-based neurostimulation, steady state visually evoked potentials

DOI: 10.3233/JAD-220081

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 335-344, 2022

Authors: Wolfova, Katrin | Creese, Byron | Aarsland, Dag | Ismail, Zahinoor | Corbett, Anne | Ballard, Clive | Hampshire, Adam | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied. Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort. Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, …spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models. Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p  = 0.001) and social inappropriateness (12% versus 15%; p  < 0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36%; p  < 0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females. Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier. Show more

Keywords: Behavioral symptoms, cognition, dementia, gender differences, sex differences

DOI: 10.3233/JAD-220040

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 345-355, 2022

Authors: Zhang, Kaixia | Ma, Xiaoying | Zhang, Rui | Liu, Zanchao | Jiang, Lei | Qin, Yushi | Zhang, Di | Tian, Pei | Gao, ZhaoYu | Zhang, Nan | Shi, Zhongli | Xu, Shunjiang

Article Type: Research Article

Abstract: Background: The interactions between environmental factors and genetic variants have been implicated in the pathogenesis of Alzheimer’s disease (AD). The altered gut microbiota (GM) and vitamin D deficiency are closely associated with the higher risk of AD. Objective: This study was performed to evaluate whether the crosstalk between GM and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) or vitamin D binding protein (VDBP) have a link with the risk of amnestic mild cognitive impairment (aMCI) in the Chinese elderly population. Methods: A total of 171 aMCI patients and 261 cognitive normal controls (NC) were …enrolled in this study. Six tag SNPs of VDR and VDBP were genotyped by PCR-RFLP. The serum levels of vitamin D, Aβ1-42 , and p-tau (181P) were determined by using of ELISA kits. The alterations in the GM were analyzed by full-length 16S ribosomal RNA (rRNA) gene sequencing. Results: The frequencies of AG genotype and A allele of VDR rs1544410 in aMCI group were significantly higher than that in NC group (genotype: p  = 0.002, allele: p  = 0.003). Patients with aMCI showed an abnormal GM composition compared with NC group. Interestingly, significant differences in GM composition were found between aMCI and NC group among individuals with AG genotype, as well as between individuals with AG and GG genotype of VDR rs1544410 among patients with aMCI. Conclusion: These results implicated that the crosstalk between gut microflora and vitamin D receptor variants are associated with the risk of aMCI in Chinese elderly population. Show more

Keywords: Amnestic mild cognitive impairment, full-length 16S rRNA sequencing, gut microbiota, single nucleotide polymorphisms, vitamin D receptor

DOI: 10.3233/JAD-220101

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 357-373, 2022

Authors: Cheng, Yuan | Jian, Jie-Ming | He, Chen-Yang | Ren, Jun-Rong | Xu, Man-Yu | Jin, Wang-Sheng | Tan, Cheng-Rong | Zeng, Gui-Hua | Shen, Ying-Ying | Chen, Dong-Wan | Li, Hui-Yun | Yi, Xu | Zhang, Yuan | Zeng, Fan | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. Objective: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-β (Aβ) and tau in the plasma and cerebrospinal fluid (CSF). Methods: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The …levels of FABP1 in plasma, and Aβ and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aβ levels. Results: The level of plasma FABP1 was significantly elevated in the AD group (p  = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aβ42 (AUC = 0.6794, p  = 0.0071) and FABP1/t-tau (AUC = 0.7168, p  = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aβ42 , Aβ40 , and t-tau, both FABP1/Aβ42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ42 had the highest diagnostic value (AUC = 0.8075, p  < 0.0001). Conclusion: These findings indicate that FABP1 may play a role in AD pathogenesis and be worthy of further investigation in the future. Show more

Keywords: Alzheimer’s disease, amyloid-β, liver-type fatty acid-binding protein, tau

DOI: 10.3233/JAD-220126

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 375-383, 2022

Authors: Dennison, Jessica L. | Volmar, Claude-Henry | Modarresi, Farzaneh | Ke, Danbing | Wang, James | Gravel, Emilie | Hammond-Vignini, Sabrina | Li, Zuomei | Timmons, James A. | Lohse, Ines | Hayward, Marshall A. | Brothers, Shaun P. | Wahlestedt, Claes

Article Type: Correction

DOI: 10.3233/JAD-229006

Citation: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 385-385, 2022