Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Turró-Garriga, Oriol | Viñas-Díez, Vanesa | Conde-Sala, Josep Lluís | Calvó-Perxas, Laia | Cullell-Juncà, Marta | Mas-Vall-Llosera, Glòria | Flaqué, Margarida | Turon-Estrada, Antoni | Juvinyà-Canal, Dolors | Mioshi, Eneida | Garre-Olmo, Josep

Article Type: Research Article

Abstract: Background: Dementia care is associated with physical, emotional, and monetary impact on the informal carers providing unpaid care. Differences in the personal characteristics of caregivers may help explain the variations in the costs of dementia care. Objective: The aim of this study was to analyze the effect of caregivers’ sense of coherence (SOC) on direct and indirect costs in dementia care. Methods: A cross-sectional study was conducted in community dwelling caregivers of patients with Alzheimer’s disease. Data of healthcare services were obtained from clinical registries, and information was collected from caregivers regarding their use of social …care resources and time spent caregiving. The transformation of all costs into Euros was made assigning a fixed cost of 10.29 € /h and 16.24 € /h for assisting in instrumental and basic activities of daily living, respectively. Caregivers’ SOC was assessed using the Orientation to Life Questionnaire (OLQ-13). Adjusted regression models were developed, with different types of costs as dependent variables. Results: A sample of 147 caregivers was recruited. The mean OLQ-13 score was 73.3 points (SD = 11.6). The regression models showed a small association between caregivers’ SOC and direct costs, mainly linked to the use of social care resources (r2  = 0.429; β = –15.6 € /month), and a greater association between SOC and indirect costs (r2  = 0.562; β = –222.3 € /month). Conclusion: Increasing caregivers’ SOC could reduce dementia care costs by decreasing the use of social care resources and caregiving time. Show more

Keywords: Alzheimer’s disease, caregiver, cost of illness, dementia, direct service cost, healthcare cost, sense of coherence

DOI: 10.3233/JAD-200350

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Mold, Matthew John | O’Farrell, Adam | Morris, Benjamin | Exley, Christopher

Article Type: Research Article

Abstract: Background: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer’s disease (fAD) is an early-onset and aggressive form of Alzheimer’s disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson’s disease, dementia onset is known to follow neurofibrillary tangle deposition. Objective: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high …level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson’s disease, and epilepsy donors. Methods: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue. Results: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell. Conclusion: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson’s disease. Show more

Keywords: α-synuclein, aluminum in human brain tissue, amyloid-β , epilepsy, familial Alzheimer’s disease, Parkinson’s disease, tau

DOI: 10.3233/JAD-200838

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: de Oliveira, Jade | Engel, Daiane F. | de Paula, Gabriela C. | dos Santos, Danúbia B. | Lopes, Jadna B. | Farina, Marcelo | Moreira, Eduardo L.G. | de Bem, Andreza F.

Article Type: Research Article

Abstract: Background: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr–/–), a mouse model of familial hypercholesterolemia. Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/–mice. Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/–mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi. …Results: A tenfold elevation in plasma cholesterol levels of LDLr–/–mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr–/–mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/–mice treated with a hypercholesterolemic diet. The LDLr–/–mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr–/–mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. Conclusion: Therefore, LDLr–/–mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations. Show more

Keywords: Blood-brain barrier, familial hypercholesterolemia, LDLr–/– mice, memory impairment, mild cognitive impairment, neuroinflammation

DOI: 10.3233/JAD-200541

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Stephen, Ruth | Solomon, Alina | Ngandu, Tiia | Levälahti, Esko | Rinne, Juha O. | Kemppainen, Nina | Parkkola, Riitta | Antikainen, Riitta | Strandberg, Timo | Kivipelto, Miia | Soininen, Hilkka | Liu, Yawu | for the FINGER study group

Article Type: Research Article

Abstract: Background: Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain and how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia. Objectives: To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60–77 years) from the general population. …Methods: This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n  = 34) or control group (general health advice, n  = 26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed. Results: FA decreased, and cognition improved more in the intervention group compared to the control group (p  <  0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group. Conclusion: The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations. Show more

Keywords: Alzheimer’s disease, dementia, diffusion tensor imaging, randomized controlled trial

DOI: 10.3233/JAD-200423

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Pietroboni, Anna M. | Colombi, Annalisa | Carandini, Tiziana | Scarpini, Elio | Galimberti, Daniela | Bozzali, Marco

Article Type: Review Article

Abstract: Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer’s disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at …the earliest disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology. Show more

Keywords: Amyloid-β , inflammation, neurodegeneration, white matter damage

DOI: 10.3233/JAD-200868

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Bergeron, David | Beauregard, Jean-Mathieu | Jean-Guimond, | Soucy, Jean-Paul | Verret, Louis | Poulin, Stéphane | Matias-Guiu, Jordi A. | Cabrera-Martín, María Nieves | Bouchard, Rémi W. | Laforce Jr , Robert

Article Type: Research Article

Abstract: Background: Hypometabolism of the posterior cingulate cortex (PCC) is an important diagnostic feature of late-onset, amnestic Alzheimer’s disease (AD) measured with 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, it is unclear whether PCC hypometabolism has diagnostic value in young-onset, non-amnestic variants of AD, which exhibit less pathology in the hippocampus and default mode network. Objective: Evaluate the prevalence and diagnostic value of PCC hypometabolism in non-amnestic variants of AD. Methods: We retrospectively identified 60 patients with young-onset, atypical dementia who have undergone a detailed clinical evaluation, FDG-PET, and an amyloid biomarker (amyloid-PET or cerebrospinal fluid analysis). …We quantitatively analyzed regional hypometabolism in 70 regions of interest (ROI) using the MIMneuro® software. Results: Based on a cut-off of z-score < –1.5 for significant PCC hypometabolism, the prevalence of PCC hypometabolism in non-amnestic variants of AD was 65% compared to 28% in clinical variants of frontotemporal dementia (FTD). The ROI with the maximal hypometabolism was the dominant middle temporal gyrus in the language variant of AD (mean z score –2.28), middle occipital gyrus in PCA (–3.24), middle temporal gyrus in frontal AD (–2.70), and angular gyrus in corticobasal syndrome due to AD (–2.31). The PCC was not among the 10 most discriminant regions between non-amnestic variants of AD versus clinical variants of FTD. Conclusion: We conclude that PCC hypometabolism is not a discriminant feature to distinguish non-amnestic variants of AD from clinical variants of FTD—and should be interpreted with caution in patients with young-onset, non-amnestic dementia. Show more

Keywords: Alzheimer’s disease, FDG-PET, non-amnestic variants of AD, primary progressive aphasia, posterior cingulate cortex

DOI: 10.3233/JAD-200567

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: He, Fan | Tang, James J. | Zhang, Tao | Lin, Junfen | Li, Fudong | Gu, Xue | Chen, Ruoling

Article Type: Research Article

Abstract: Background: The impact of air pollution on cognitive impairment in older people has not been fully understood. It is unclear which air pollutants are the culprit. Objective: We assessed the associations of six air pollutants and air quality index (AQI) with cognitive impairment. Methods: We examined 7,311 participants aged ≥60 years from the ZJMPHS cohort in China. They were interviewed for baseline socio-demographic and disease risk factors in 2014, and re-interviewed in 2015 and 2016, respectively. The presence of cognitive impairment was determined by the Chinese version of the Mini-Mental State Examination. Daily area-level data monitored …for air pollution during 2013-2015 was then examined for associations with cognitive impairment in logistic regression models. Results: Over the two years follow-up, 1,652 participants developed cognitive impairment, of which 917 were severe cases. Continuous air pollution data showed the risk of cognitive impairment increased with exposure to PM2.5 (fully adjusted odds ratio [aOR] 1.04, 95% CI 1.01–1.08), PM10 (1.03, 1.001–1.06), and SO2 (1.04, 1.01–1.08), but not with NO2 , CO, O3 , and AQI. Categorized data analysis for low, middle, and high level exposure demonstrated that the aOR increased with PM2.5 and AQI, somehow with PM10 and CO, but not significantly with SO2 and NO2 , and decreased with O3 . The patterns for these associations with severe cognitive impairment were stronger. Conclusion: Lowering PM2.5 , PM10 , SO2 , and CO level could reduce the risk of cognitive impairment in older Chinese. Strategies to target most important air pollutants should be an integral component of cognitive interventions. Show more

Keywords: Air pollution, air quality index, China, cognitive impairment, cohort study

DOI: 10.3233/JAD-200587

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Blazel, Madeleine M. | Lazar, Karen K. | Van Hulle, Carol A. | Ma, Yue | Cole, Aleshia | Spalitta, Alice | Davenport-Sis, Nancy | Bendlin, Barbara B. | Wahoske, Michelle | Illingworth, Chuck | Gleason, Carey E. | Edwards, Dorothy F. | Blazel, Hanna | Asthana, Sanjay | Johnson, Sterling C. | Carlsson, Cynthia M.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) provides insight into the spectrum of Alzheimer’s disease (AD) pathology. While lumbar punctures (LPs) for CSF collection are generally considered safe procedures, many participants remain hesitant to participate in research involving LPs. Objective: To explore factors associated with participant willingness to undergo a research LP at baseline and follow-up research study visit. Methods: We analyzed data from 700 participants with varying cognition (unimpaired, mild cognitive impairment, and dementia) in the Wisconsin Alzheimer’s Disease Research Center. We evaluated the relationship of demographic variables (age, sex, race, ethnicity, and years of education) and clinical …variables (waist-to-hip ratio, body mass index, AD parental history, cognitive diagnosis) on decision to undergo baseline LP1. We evaluated the relationship of prior LP1 experience (procedure success and adverse events) with the decision to undergo follow-up LP2. The strongest predictors were incorporated into regression models. Results: Over half of eligible participants opted into both baseline and follow-up LP. Participants who underwent LP1 had higher mean education than those who declined (p  = 0.020). White participants were more likely to choose to undergo LP1 (p  <  0.001); 33% of African American participants opted in compared to 65% of white participants. Controlling for age, education, and AD parental history, race was the only significant predictor for LP1 participation. Controlling for LP1 mild adverse events, successful LP1 predicted LP2 participation. Conclusion: Race was the most important predictor of baseline LP participation, and successful prior LP was the most important predictor of follow-up LP participation. Show more

Keywords: Biomarkers, community participation, lumbar puncture, research subject recruitment

DOI: 10.3233/JAD-200394

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Xu, Hui | Jia, Jianping

Article Type: Research Article

Abstract: Background: The pathogenesis of Alzheimer’s disease (AD) involves various immune-related phenomena; however, the mechanisms underlying these immune phenomena and the potential hub genes involved therein are unclear. An understanding of AD-related immune hub genes and regulatory mechanisms would help develop new immunotherapeutic targets. Objective: The aim of this study was to explore the hub genes and the mechanisms underlying the regulation of competitive endogenous RNA (ceRNA) in immune-related phenomena in AD pathogenesis. Methods: We used the GSE48350 data set from the Gene Expression Omnibus database and identified AD immune-related differentially expressed RNAs (DERNAs). We constructed protein–protein …interaction (PPI) networks for differentially expressed mRNAs and determined the degree for screening hub genes. By determining Pearson’s correlation coefficient and using StarBase, DIANA-LncBase, and Human MicroRNA Disease Database (HMDD), the AD immune-related ceRNA network was generated. Furthermore, we assessed the upregulated and downregulated ceRNA subnetworks to identify key lncRNAs. Results: In total, 552 AD immune-related DERNAs were obtained. Twenty hub genes, including PIK3R1 , B2M , HLA-DPB1 , HLA-DQB1 , PIK3CA , APP , CDC42 , PPBP , C3AR1 , HRAS , PTAFR , RAB37 , FYN , PSMD1 , ACTR10 , HLA-E , ARRB2 , GGH , ALDOA , and VAMP2 were identified on PPI network analysis. Furthermore, upon microRNAs (miRNAs) inhibition, we identified LINC00836 and DCTN1-AS1 as key lncRNAs regulating the aforementioned hub genes. Conclusion: AD-related immune hub genes include B2M , FYN , PIK3R1 , and PIK3CA , and lncRNAs LINC00836 and DCTN1-AS1 potentially contribute to AD immune-related phenomena by regulating AD-related hub genes. Show more

Keywords: Alzheimer’s disease, competitive endogenous RNA, hub genes, immune system

DOI: 10.3233/JAD-200081

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Hulme, Bethany | Didikoglu, Altug | Bradburn, Steven | Robinson, Andrew | Canal, Maria | Payton, Antony | Pendleton, Neil | Murgatroyd, Chris

Article Type: Research Article

Abstract: Background: An early symptom of Alzheimer’s disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles. Objective: To investigate if BMAL1 , a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology. Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1 , determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score, and Thal phase, longitudinal changes in …cognition, sleep measurements, and cross-section measures of depressive symptoms (BDI score). Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92) = 2.47, p  = 0.015) and CERAD (t(94) = 2.04, p  = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed, and memory tests, but methylation at CpG1 (r  = 0.20, p  = 0.05) and CpG4 (r  = 0.20, p  = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r  = 0.20 p  = 0.05) and vocabulary (r  = 0.22 p  = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep, and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI = 0.00/0.06, p  = 0.03) and CpG5 (B = 0.04, 95% CI = 0.01,0.07, p  = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = –0.27, 95% CI=0.49/–0.05, p  = 0.02). Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle. Show more

Keywords: Alzheimer’s disease, BMAL1, circadian cycle, cognition, depressive symptoms, sleep quality

DOI: 10.3233/JAD-200634

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020