Journal of Alzheimer's Disease - Volume 79, issue 2

Authors: Fanet, Hortense | Tournissac, Marine | Leclerc, Manon | Caron, Vicky | Tremblay, Cyntia | Vancassel, Sylvie | Calon, Frédéric

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized. Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in the triple-transgenic mouse model of AD (3xTg-AD), a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment. …Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat – CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days. Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies. Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic deficits accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders. Show more

Keywords: 3xTg-AD mice, Alzheimer’s disease, high-fat diet, tetrahydrobiopterin (BH4)

DOI: 10.3233/JAD-200637

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 709-727, 2021

Authors: Minta, Karolina | Brinkmalm, Gunnar | Portelius, Erik | Johansson, Per | Svensson, Johan | Kettunen, Petronella | Wallin, Anders | Zetterberg, Henrik | Blennow, Kaj | Andreasson, Ulf

Article Type: Research Article

Abstract: Background: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). Objective: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer’s disease (AD) and vascular dementia (VaD) compared with controls. Methods: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, …and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. Results: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p ≤0.05) and as compared with the control group (AUC = 0.79.0.87, p  ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p  ≤ 0.05) and to controls (AUC = 0.80.0.82, p  ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p  > 0.05). No peptides differed between AD and controls. Conclusion: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD. Show more

Keywords: Alzheimer’s disease, brevican, cerebrospinal fluid, extracellular matrix, neurocan, vascular dementia

DOI: 10.3233/JAD-201039

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 729-741, 2021

Authors: McGrattan, Andrea M. | Zhu, Yueping | Richardson, Connor D. | Mohan, Devi | Soh, Yee Chang | Sajjad, Ayesha | van Aller, Carla | Chen, Shulin | Paddick, Stella-Maria | Prina, Matthew | Siervo, Mario | Robinson, Louise A. | Stephan, Blossom C.M.

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a cognitive state associated with increased risk of dementia. Little research on MCI exists from low-and middle-income countries (LMICs), despite high prevalence of dementia in these settings. Objective: This systematic review aimed to review epidemiological reports to determine the prevalence of MCI and its associated risk factors in LMICs. Methods: Medline, Embase, and PsycINFO were searched from inception until November 2019. Eligible articles reported on MCI in population or community-based studies from LMICs and were included as long as MCI was clearly defined. Results: 5,568 articles were screened, …and 78 retained. In total, n  = 23 different LMICs were represented; mostly from China (n  = 55 studies). Few studies were from countries defined as lower-middle income (n  = 14), low income (n  = 4), or from population representative samples (n  = 4). There was large heterogeneity in how MCI was diagnosed; with Petersen criteria the most commonly applied (n  = 26). Prevalence of amnesic MCI (aMCI) (Petersen criteria) ranged from 0.6%to 22.3%. Similar variability existed across studies using the International Working Group Criteria for aMCI (range 4.5%to 18.3%) and all-MCI (range 6.1%to 30.4%). Risk of MCI was associated with demographic (e.g., age), health (e.g., cardio-metabolic disease), and lifestyle (e.g., social isolation, smoking, diet and physical activity) factors. Conclusion: Outside of China, few MCI studies have been conducted in LMIC settings. There is an urgent need for population representative epidemiological studies to determine MCI prevalence in LMICs. MCI diagnostic methodology also needs to be standardized. This will allow for cross-study comparison and future resource planning. Show more

Keywords: Epidemiology, low-and middle-income country,, mild cognitive impairment, prevalence, risk factors, systematic review

DOI: 10.3233/JAD-201043

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 743-762, 2021

Authors: Basta, Maria | Zaganas, Ioannis | Simos, Panagiotis | Koutentaki, Eirini | Dimovasili, Christina | Mathioudakis, Lambros | Bourbouli, Mara | Panagiotakis, Symeon | Kapetanaki, Stefania | Vgontzas, Alexandros

Article Type: Research Article

Abstract: Background: Apolipoprotein E gene (APOE ) ɛ4 allele increases the risk for Alzheimer’s disease (AD). Furthermore, among patients with cognitive impairment, longer sleep duration is associated with worse cognitive performance. To date, literature examining the associations between APOE ɛ4 allele and objective sleep duration is limited. Objective: Our aim was to assess the association between APOE ɛ4 and objective sleep duration, among patients with mild cognitive impairment (MCI) and AD. A sub-sample of 89 patients with AD (n  = 49) and MCI (n  = 40) were recruited from a large, population-based cohort of 3,140 elders (>60 years) residing …on Crete, Greece. Methods: All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24 h actigraphy and APOE ɛ4 allele genotyping. Comparisons of sleep duration variables between APOE ɛ4 allele carriers and non-carriers were assessed using ANCOVA, controlling for confounders. Results: The sample included 18 APOE ɛ4 carriers and 71 non-carriers, aged 78.6±6.6 and 78.2±6.5 years, respectively. Comparisons between the APOE ɛ4 carriers and non-carriers revealed no significant differences in terms of demographic and clinical variables. In terms of objective sleep duration across the two groups, APOE ɛ4 carriers compared to non-carriers had significantly longer nighttime Total Sleep Time (nTST) (7.7±1.4 versus 7.2±1.3  h, respectively, p  = 0.011), as well as 24 h TST (8.5±1.6 versus 7.8±1.5  h, respectively, p  = 0.012). Conclusion: Among patients with MCI and AD, APOE ɛ4 carriers have longer objective nighttime and 24 h sleep duration compared to non-carriers. These findings further support that objective long sleep duration is a genetically-driven pre-clinical marker associated with worse prognosis in elderly with cognitive impairment. Show more

Keywords: Actigraphy, Alzheimer’s disease, cognitive disorders, genetic risk factors, mild cognitive impairment, sleep

DOI: 10.3233/JAD-200958

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 763-771, 2021

Authors: Hirt, Julian | Ballhausen, Nicola | Hering, Alexandra | Kliegel, Matthias | Beer, Thomas | Meyer, Gabriele

Article Type: Research Article

Abstract: Background: Using non-pharmacological interventions is a current approach in dementia care to manage responsive behaviors, to maintain functional capacity, and to reduce emotional stress. Novel technologies such as social robot interventions might be useful to engage people with dementia in activities and interactions as well as to improve their cognitive, emotional, and physical status. Objective: Assessing the effects and the quality of reporting of social robot interventions for people with dementia. Methods: In our systematic review, we included quasi-experimental and experimental studies published in English, French, or German, irrespective of publication year. Searching CINAHL, Cochrane …Library, MEDLINE, PsycINFO, and Web of Science Core Collection was supplemented by citation tracking and free web searching. To assess the methodological quality of included studies, we used tools provided by the Joanna Briggs Institute. To assess the reporting of the interventions, we applied CReDECI 2 and TIDieR. Results: We identified sixteen studies published between 2012 and 2018, including two to 415 participants with mostly non-defined type of dementia. Eight studies had an experimental design. The predominant robot types were pet robots (i.e., PARO). Most studies addressed behavioral, emotion-related, and functional outcomes with beneficial, non-beneficial, and mixed results. Predominantly, cognitive outcomes were not improved. Overall, studies were of moderate methodological quality. Conclusion: Heterogeneous populations, intervention characteristics, and measured outcomes make it difficult to generalize the results with regard to clinical practice. The impact of social robot interventions on behavioral, emotion-related, and functional outcomes should therefore be assessed considering the severity of dementia and intervention characteristics. Show more

Keywords: Dementia, robotics, systematic review, technology

DOI: 10.3233/JAD-200347

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 773-792, 2021

Authors: Wu, Wenzhe | Lee, Inhan | Spratt, Heidi | Fang, Xiang | Bao, Xiaoyong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia caused by irreversible neurodegeneration, with the onset mechanisms elusive. tRNA-derived RNA fragments (tRFs), a recently discovered family of small non-coding RNAs (sncRNAs), have been found to associate with many human diseases, including infectious, metabolic, and neurological diseases. However, whether tRFs play a role in human AD development is not known. Objective: This study aimed to explore whether tRFs are involved in human AD. Methods: Thirty-four postmortem human hippocampus samples were used. The expression of Drosha, Dicer, and angiogenin (ANG), three ribonucleases responsible for the biogenesis …of sncRNAs, was determined by qRT-PCR and western blot. The tRFs in the hippocampus was detected by qRT-PCR or northern blot. We also used qRT-PCR to quantify NOP2/Sun RNA methyltransferase 2 (NSun2) and polyadenylation factor I subunit 1 (CLP1), two tRNA modification enzymes. Results: tRFs derived from a subset of tRNAs are significantly altered in the hippocampus of AD patients. The expression change of some tRFs showed age- and disease stage-dependent. ANG is significantly enhanced in AD, suggesting its role in inducing tRFs in AD. The expression of NSun2 in AD patients younger than 65 was significantly decreased. According to a previous report supporting NSun2-mediated tRNA methylation modification making tRNA less susceptible to ANG-mediated cleavage, our results suggested that the decrease in NSun2 may make tRNAs less methylated and subsequently enhanced tRF production from ANG-mediated tRNA cleavage. Conclusion: Our studies demonstrated for the first time the involvement of tRFs in human AD. Show more

Keywords: Alzheimer’s disease, biomarkers, neuropathology, small non-coding RNAs, tRNA-derived RNA fragments

DOI: 10.3233/JAD-200917

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 793-806, 2021

Authors: Yuan, Jing | Maserejian, Nancy | Liu, Yulin | Devine, Sherral | Gillis, Cai | Massaro, Joseph | Au, Rhoda

Article Type: Research Article

Abstract: Background: Studies providing Alzheimer’s disease (AD) prevalence data have largely neglected to characterize the proportion of AD that is mild, moderate, or severe. Estimates of the severity distribution along the AD continuum, including the mild cognitive impairment (MCI) stage, are important to plan research and allocate future resources, particularly resources targeted at particular stages of disease. Objective: To characterize the distribution of severity of AD dementia and MCI among prevalent cases in the population-based Framingham Heart Study. Methods: Participants (aged 50–94) with prevalent MCI or AD dementia clinical syndrome were cross-sectionally selected from three time-windows of …the population-based Framingham Heart Study in 2004-2005 (n  = 381), 2006-2007 (n  = 422), and 2008-2009 (n  = 389). Summary estimates of the severity distribution were achieved by pooling results across time-windows. Diagnosis and severity were assessed by consensus dementia review. MCI-progressive was determined if the participant had documented progression to AD dementia clinical syndrome using longitudinal data. Results: Among AD dementia participants, the pooled percentages were 50.4%for mild, 30.3%for moderate, and 19.3%for severe. Among all MCI and AD participants, the pooled percentages were 29.5%, 19.6%, 25.7%, and 45.2%for MCI-not-progressive, MCI-progressive, mild AD dementia, and the combined group of MCI-progressive and mild AD dementia, respectively. Distributions by age and sex were presented. Conclusion: The finding that half of the people living with AD have mild disease underscores the need for research and interventions to slow decline or prevent progression of this burdensome disease. Show more

Keywords: Alzheimer’s disease, dementia, epidemiological study, epidemiology, Framingham Heart Study, mild cognitive impairment, prevalence

DOI: 10.3233/JAD-200786

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 807-817, 2021

Authors: Bao, Yi-Wen | Chau, Anson C.M. | Chiu, Patrick Ka-Chun | Shea, Yat Fung | Kwan, Joseph S.K. | Chan, Felix Hon Wai | Mak, Henry Ka-Fung

Article Type: Research Article

Abstract: Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18 F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18 F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18 F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included …13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18 F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18 F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, early-onset Alzheimer’s disease, 18F-Flutemetamol, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-200890

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 819-832, 2021

Authors: Wang, Yang-Yang | Yan, Qian | Huang, Zhen-Ting | Zou, Qian | Li, Jing | Yuan, Ming-Hao | Wu, Liang-Qi | Cai, Zhi-You

Article Type: Research Article

Abstract: Background: Berberine (BBR) plays a neuroprotective role in the pathogenesis of Alzheimer’s disease (AD), inhibiting amyloid-β (Aβ) production and promoting Aβ clearance. Advanced glycation end products (AGEs) promote Aβ aggregation and tau hyperphosphorylation. The activation of mTOR signaling occurring at the early stage of AD has a prominent impact on the Aβ production. This work focused on whether BBR regulates the production and clearance of ribosylation-induced Aβ pathology via inhibiting mTOR signaling. Objective: To explore whether BBR ameliorates ribosylation-induced Aβ pathology in APP/PS1 mice. Methods: Western blot and immunofluorescence staining were used to detect the related …proteins of the mammalian target of Rapamycin (mTOR) signaling pathway and autophagy, as well as the related kinases of Aβ generation and clearance. Tissue sections and Immunofluorescence staining were used to observe Aβ42 in APP/PS1 mice hippocampal. Morris water maze test was used to measure the spatial learning and memory of APP/PS1 mice. Results: BBR improves spatial learning and memory of APP/PS1 mice. BBR limits the activation of mTOR/p70S6K signaling pathway and enhances autophagy process. BBR reduces the activity of BACE1 and γ-secretase induced by D-ribose, and enhances Aβ-degrading enzymes and Neprilysin, and inhibits the expression of Aβ in APP/PS1 mice. Conclusion: BBR ameliorates ribosylation-induced Aβ pathology via inhibiting mTOR/p70S6K signaling and improves spatial learning and memory of the APP/PS1 mice. Show more

Keywords: AGEs, Alzheimer’s disease, amyloid-β, autophagy, berberine, mTOR

DOI: 10.3233/JAD-200995

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 833-844, 2021

Authors: Balea-Fernandez, Francisco Javier | Martinez-Vega, Beatriz | Ortega, Samuel | Fabelo, Himar | Leon, Raquel | Callico, Gustavo M. | Bibao-Sieyro, Cristina

Article Type: Research Article

Abstract: Background: Sociodemographic data indicate the progressive increase in life expectancy and the prevalence of Alzheimer’s disease (AD). AD is raised as one of the greatest public health problems. Its etiology is twofold: on the one hand, non-modifiable factors and on the other, modifiable. Objective: This study aims to develop a processing framework based on machine learning (ML) and optimization algorithms to study sociodemographic, clinical, and analytical variables, selecting the best combination among them for an accurate discrimination between controls and subjects with major neurocognitive disorder (MNCD). Methods: This research is based on an observational-analytical design. Two …research groups were established: MNCD group (n  = 46) and control group (n  = 38). ML and optimization algorithms were employed to automatically diagnose MNCD. Results: Twelve out of 37 variables were identified in the validation set as the most relevant for MNCD diagnosis. Sensitivity of 100%and specificity of 71%were achieved using a Random Forest classifier. Conclusion: ML is a potential tool for automatic prediction of MNCD which can be applied to relatively small preclinical and clinical data sets. These results can be interpreted to support the influence of the environment on the development of AD. Show more

Keywords: Alzheimer’s disease, machine learning, neurocognitive disorders, risk factors

DOI: 10.3233/JAD-200955

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 845-861, 2021