Journal of Alzheimer's Disease - Volume 81, issue 4

Authors: De la Fuente, Mónica

Article Type: Review Article

Abstract: Trillions of commensal microbes live in our body, the majority in the gut. This gut microbiota is in constant interaction with the homeostatic systems, the nervous, immune and endocrine systems, being fundamental for their appropriate development and function as well as for the neuroimmunoendocrine communication. The health state of an individual is understood in the frame of this communication, in which the microbiota-gut-brain axis is a relevant example. This bidirectional axis is constituted in early age and is affected by many environmental and lifestyle factors such as diet and stress, among others, being involved in the adequate maintenance of homeostasis …and consequently in the health of each subject and in his/her rate of aging. For this, an alteration of gut microbiota, as occurs in a dysbiosis, and the associated gut barrier deterioration and the inflammatory state, affecting the function of immune, endocrine and nervous systems, in gut and in all the locations, is in the base of a great number of pathologies as those that involve alterations in the brain functions. There is an age-related deterioration of microbiota and the homeostatic systems due to oxi-inflamm-aging, and thus the risk of aging associated pathologies such as the neurodegenerative illness. Currently, this microbiota-gut-brain axis has been considered to have a relevant role in the pathogenesis of Alzheimer’s disease and represents an important target in the prevention and slowdown of the development of this pathology. In this context, the use of probiotics seems to be a promising help. Show more

Keywords: Aging, Alzheimer’s disease, endocrine system, immune system, microbiota, microbiota-gut-brain axis, nervous system, neuroimmunoendocrine communication

DOI: 10.3233/JAD-201587

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1345-1360, 2021

Authors: Somaa, Fahad

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is considered as the most common cause of dementia in elderly population. While the exact mechanism of AD has not been discovered, hyperbolic oxygen therapy (HBOT) has been proven to be effective in the treatment of this degenerative disease. The objectives of this article are to review the literature available on molecular and physiological mechanisms underlying HBOT and its efficacy in treating AD and to review the effectiveness of HBOT as an alternate treatment intervention in both human and animal models. 391 full text articles were included in the review after literature search between 1980–2021 from two …online data base (ScienceDirect and PubMed). The following key words were used: ‘hyperbaric oxygen therapy’ and ‘Alzheimer disease.’ Based on the outcomes of clinical and experimental studies, this review advocates the use of HBOT for the treatment of AD. This review explores future directions and recommends further research into a treatment protocol that will maintain long-term cognitive health of AD patients. Show more

Keywords: Alzheimer’s disease, dementia, hyperbaric oxygen therapy, hypoxia, neurodegenerative disorders, reactive oxygen stress

DOI: 10.3233/JAD-210157

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1361-1367, 2021

Authors: Simonsen, Anja Hviid | Musaeus, Christian Sandøe | Christensen, Gitte Lund | Hasselbalch, Steen Gregers | Waldemar, Gunhild

Article Type: Short Communication

Abstract: Amyloid-β 1–42 (Aβ1–42 ) measured in the cerebrospinal fluid (CSF) can be used as a diagnostic biomarker for Alzheimer’s disease (AD) but an upward drift when using the INNOTEST ELISA has been suggested. We investigated the upwards drift of Aβ1–42 levels over a period of twelve years in a consecutive memory clinic cohort. We found a significant increase in Aβ1–42 from 2008 to 2019 independent of changes in tau. New methods for the quantification of CSF Aβ1–42 levels are being implemented but awareness of this upwards drift is crucial during the diagnostic work-up and when selecting historical …samples for research. Show more

Keywords: Alzheimer’s disease, amyloid-β 42, biomarker, cerebrospinal fluid

DOI: 10.3233/JAD-201506

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1369-1373, 2021

Authors: El Haj, Mohamad | Moustafa, Ahmed A. | Gallouj, Karim

Article Type: Short Communication

Abstract: We assessed depression in 72 patients with Alzheimer’s disease (AD) who live in retirement homes during the COVID-19-related lockdown. We invited caregivers of 72 patients with AD who live in retirement homes to rate depression in the patients both before and during the lockdown. Analysis demonstrated increased depression in the patients during the lockdown. We attribute this increased depression to the restrictive measures on activities, visits, and physical contact between patients with AD and family members during the lockdown.

Keywords: Alzheimer’s disease, COVID-19, depression, lockdown, social isolation

DOI: 10.3233/JAD-210190

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1375-1379, 2021

Authors: Jeong, Wonjeong | Joo, Jae Hong | Kim, Hyunkyu | Kim, Yun Kyung | Park, Eun-Cheol | Jang, Sung-In

Article Type: Research Article

Abstract: Background: Hypnotics, including benzodiazepines, are extensively and inappropriately prescribed for older people to treat anxiety and sleep disorders, despite the adverse health outcomes associated with their use. Objective: This study aimed to examine the association of the use of long- and short-acting hypnotics with the risk of Alzheimer’s disease. Methods: Data from 234,634 participants, derived from the Korean National Health Insurance Service National Sample Cohort from 2002 to 2013, were examined. Individuals over the age of 50 years were included in the study. The dependent variable was the risk of Alzheimer’s disease. Hypnotics were categorized by …the period of the prescription of benzodiazepines, i.e., either till the participants were diagnosed with Alzheimer’s disease or the end of the study period (December 31, 2013). Cox regression model was built to analyze the association between variables. Results: Individuals who used long-acting hypnotics were found to have a higher risk of Alzheimer’s disease than non-users. Moreover, among individuals with sleep disorders, those who used hypnotics had a higher risk of Alzheimer’s disease than those who did not. Conclusion: This study identified an association between the use of hypnotics and the risk of Alzheimer’s disease among South Korean middle-aged and older people. Show more

Keywords: Alzheimer’s disease, benzodiazepines, dementia, hypnotics

DOI: 10.3233/JAD-201319

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1381-1389, 2021

Authors: Huang, Li | Yin, Xuan | Li, Wei | Cao, Yan | Chen, Yueqi | Lao, Lixing | Zhang, Zhangjin | Mi, Yiqun | Xu, Shifen

Article Type: Research Article

Abstract: Background: Acupuncture has been used for treating vascular cognitive impairment, but evidence for its effectiveness remains limited. Objective: This single-center, patient-accessor blinded, randomized controlled trial was designed to assess whether acupuncture could improve the cognitive function of patients with vascular cognitive impairment with no dementia (VCIND). Methods: 120 VCIND patients were randomly assigned to the electro-acupuncture (EA) or sham acupuncture (SA) group at a 1 : 1 ratio, with treatment conducted thrice weekly for 8 weeks. The primary outcome was the changes of cognitive function measured by the Montreal Cognitive Assessment (MoCA) from baseline to week 8. The …secondary outcomes included the scores of the Mini-Mental State Examination (MMSE), the Modified Barthel Index (MBI) and the Self-rating Depression Scale (SDS). Follow-up assessments were performed with MoCA and MMSE at week 16 and 32. Linear mixed-effects models were used for analysis and all statistical tests were two-sided. Results: The results showed that patients in the EA group had a significantly greater improvement in MoCA score (23.85±4.18) than those in the SA group (21.48±4.44) at week 8 (95% CI = 0.80, 3.92, p  = 0.04), as well as higher MoCA scores over time (p  < 0.001 for interaction). Patients who received EA showed a greater increase in MMSE scores (26.41±3.47) than those who received SA (24.40±3.85) along 8 weeks (95% CI = 0.69, 3.34, p  = 0.004). However, results diminished over time. No serious adverse events occurred during the trial. Conclusion: EA is a safe and effective technique to improve cognition over the short term of 8 weeks in VCIND patients. Show more

Keywords: Acupuncture, montreal cognitive assessment, randomized controlled trial, vascular cognitive impairment with no dementia

DOI: 10.3233/JAD-201353

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1391-1401, 2021

Authors: Wang, Xin | Liu, Qian | Li, Xiao-Guang | Zhou, Qiu-Zhi | Wu, Dong-Qin | Li, Shi-Hong | Liu, Yan-Chao | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Background: Recent studies show that an increased T217-phosphorylation of tau in plasma could diagnose AD at an early stage with high accuracy and high specificity, while the potential toxic role of tau T217-phosphorylation is not known. Objective: To study the potential toxic role of tau T217-phosphorylation. Methods: We performed stereotactic brain injection, behavioral testing, immunohistochemistry and immunofluorescence, western blotting, Golgi staining, in vitro recombinant tau polymerization, and other measurements. Results: We first constructed tau T217-wild-type (T217), T217-phospho-mimic (T217E), and T217-non-phospho-mimic (T217A) plasmids or their virus vectors on the basis of wild-type tau. We …found that expressing tau-T217E induced a significantly increased tau phosphorylation at multiple AD-associated sites with inhibited proteolysis and increased cleavage/fibrillization of tau, while expressing tau-T217A abolished the above changes of tau both in vitro and in vivo . By mutating T217E on tau-P301L, a dominant mutation identified in patients with frontotemporal dementia, we did not observe significant exacerbation of tau-P301L phosphorylation and cognitive impairment although the increased tau cleavage and propagation were shown. Conclusion: T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments, while overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation. Show more

Keywords: Alzheimer’s disease, cognition, propagation, tau, T217-phosphorylation

DOI: 10.3233/JAD-210297

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1403-1418, 2021

Authors: Borelli, Wyllians Vendramini | Leal-Conceição, Eduardo | Andrade, Michele Alberton | Esper, Nathalia Bianchini | Feltes, Paula Kopschina | Soder, Ricardo Bernardi | Matushita, Cristina Sebastião | Hartmann, Louise Mross | Radaelli, Graciane | Schilling, Lucas Porcello | Moriguchi-Jeckel, Cristina | Marques da Silva, Ana Maria | Portuguez, Mirna Wetters | Franco, Alexandre Rosa | da Costa, Jaderson Costa

Article Type: Research Article

Abstract: Background: Individuals at 80 years of age or above with exceptional memory are considered SuperAgers (SA), an operationalized definition of successful cognitive aging. SA showed increased thickness and altered functional connectivity in the anterior cingulate cortex as a neurobiological signature. However, their metabolic alterations are yet to be uncovered. Objective: Herein, a metabolic (FDG-PET), amyloid (PIB-PET), and functional (fMRI) analysis of SA were conducted. Methods: Ten SA, ten age-matched older adults (C80), and ten cognitively normal middle-aged (C50) adults underwent cognitive testing and multimodal neuroimaging examinations. Anterior and posterior regions of the cingulate cortex and hippocampal …areas were primarily examined, then subregions of anterior cingulate were segregated. Results: The SA group showed increased metabolic activity in the left and right subgenual anterior cingulate cortex (sACC, p  < 0.005 corrected, bilateral) and bilateral hippocampi (right: p  < 0.0005 and left: p  < 0.005, both corrected) as compared to that in the C80 group. Amyloid deposition was above threshold in 30% of SA and C80 (p  > 0.05). The SA group also presented decreased connectivity between right sACC and posterior cingulate (p  < 0.005, corrected) as compared to that of the C80 group. Conclusion: These results support the key role of sACC and hippocampus in SA, even in the presence of amyloid deposition. It also suggests that sACC may be used as a potential biomarker in older adults for exceptional memory ability. Further longitudinal studies measuring metabolic biomarkers may help elucidate the interaction between these areas in the cognitive aging process. Show more

Keywords: Amyloid deposit, FDG, functional fMRI, high-performing older adults, successful cognitive aging

DOI: 10.3233/JAD-210063

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1419-1428, 2021

Authors: Vorobyov, Vasily | Deev, Alexander | Sengpiel, Frank | Nebogatikov, Vladimir | Ustyugov, Aleksey A.

Article Type: Research Article

Abstract: Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in Δ FUS(1–359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt …were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. Conclusion: We suggest that revealed EEG modifications in Δ FUS(1–359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations. Show more

Keywords: ALS progression, dopamine, EEG, frequency spectrum, primary motor cortex, putamen

DOI: 10.3233/JAD-201472

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1429-1443, 2021

Authors: Serpente, Maria | Fenoglio, Chiara | Arighi, Andrea | Fumagalli, Giorgio G. | Arcaro, Marina | Sorrentino, Federica | Visconte, Caterina | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: Background: C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with > 30 repeats are often considered pathogenic, but the repeat length threshold is still undefined. It is also unclear if C9orf72 intermediate alleles (9–30 repeats) have clinically significant effects. Objectives: We correlated the presence of C9orf72 intermediate alleles with clinical diagnoses in a perspective cohort referred to a secondary memory clinic. Methods: All samples were genotyped with AmplideXPCR/CE C9ORF72 Kit (Asuragen, Inc), an …optimized C9orf72 PCR amplification reagent. Results: We showed that in patients with Alzheimer’s disease (AD) the frequency of the intermediate repeat alleles was significantly increased versus controls (34/54, 63%AD versus 16/39, 41%CTRLs, * p  = 0.01, OR 2.91 CI 95%1.230–6.077), whereas no significant differences (p  > 0.05) were observed when comparing all other dementias with non-demented individuals. Conclusion: Our findings suggest that C9orf72 intermediate repeat units may represent a genetic risk factor, contributing to the occurrence of AD. Nevertheless, further longitudinal studies, including larger cohort of subjects with intermediate alleles with long-term follow-up, would be needed to confirm these results. Show more

Keywords: Alzheimer’s disease, C9orf72, intermediate repeats, risk factor, two-mode multiplexed PCR chemistry

DOI: 10.3233/JAD-210249

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1445-1451, 2021