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

Authors: Sun, Zhiqing | Sun, Lei | Tu, Lixiang

Article Type: Research Article

Abstract: Background: Oxidative stress has been implicated in Alzheimer’s disease (AD) as a common pathway underlying neuronal damage causing huge impacts on cognitive functions in the AD process. Objective: Reduction and remodeling of γ -aminobutyric acid (GABA) signaling in AD may promote neuronal survival by regulating PI3K/Akt axis. Moreover, its activation exerts beneficial effects on AD by alleviating the neuronal oxidative stress injury. Considering these facts, we hypothesized the GABAB receptor as a novel therapeutic target for AD. Methods: To evaluate this hypothesis, a rat AD model was established by intraperitoneal injection of the GABAB …receptor agonist (baclofen), PI3K/Akt signaling pathway agonist (740 Y-P), and antagonist (LY294002), respectively. The effects of GABAB activation on spatial memory and learning ability in the AD rats were measured by Morris water maze. Whereas the effects of GABAB and PI3K/Akt signaling pathway on apoptosis and oxidative stress injury were determined in vivo and in vitro using primary neuronal cultures. Results: We found that GABAB receptor activation restored spatial memory and learning ability of AD rats and suppressed the neuronal apoptosis and hippocampal atrophy by activating the PI3K/Akt signaling pathway. Additionally, GABAB receptor activation reduced the oxidative stress injury by lowering the MDA levels and increased the SOD, GSH-Px, and CAT levels via activation of the PI3K/Akt signaling pathway. Conclusion: Taken together, our results suggest that GABAB receptor activation repressed the oxidative stress injury implicated in neurons in AD rats via PI3K/Akt signaling pathway activation which may suggest a potential new therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, GABAB receptor, oxidative stress injury, PI3K/Akt signaling pathway

DOI: 10.3233/JAD-191032

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Schaefer, Sydney Y. | Hooyman, Andrew | Duff, Kevin

Article Type: Short Communication

Abstract: Affordable, noninvasive methods of predicting functional decline are needed for individuals at risk for Alzheimer’s disease. This study tested whether a timed upper-extremity motor task predicted functional decline over one year in 79 adults diagnosed with amnestic mild cognitive impairment. Participants completed subjective and objective measures of daily functioning at baseline and one year later. Motor task performance and delayed memory were also evaluated at baseline. Motor task performance was a significant predictor of one-year follow-up daily functioning, improving model fits by 18– 35%. Thus, motor behavior has potential to be an affordable enrichment strategy that is sensitive to functional …decline. Show more

Keywords: Activities of daily living, functional decline, mild cognitive impairment, motor behavior

DOI: 10.3233/JAD-200518

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Singh, Pradeep K. | Chen, Zu-Lin | Strickland, Sidney | Norris, Erin H.

Article Type: Short Communication

Abstract: An activated plasma contact system is an abnormality observed in many Alzheimer’s disease (AD) patients. Since mild cognitive impairment (MCI) patients often develop AD, we analyzed the status of contact system activation in MCI patients. We found that kallikrein activity, high molecular weight kininogen cleavage, and bradykinin levels— measures of contact system activation— were significantly elevated in MCI patient plasma compared to plasma from age- and education-matched healthy individuals. Changes were more pronounced in MCI patients with impaired short-term recall memory, indicating the possible role of the contact system in early cognitive changes.

Keywords: Alzheimer’s disease, bradykinin, contact activation, high molecular weight kininogen, memory impairment, mild cognitive impairment, plasma kallikrein

DOI: 10.3233/JAD-200343

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Tousi, Babak

Article Type: Article Commentary

Abstract: Patients with dementia are particularly vulnerable during the COVID-19 pandemic. The initial response to COVID-19 promoted behavioral changes in both society and healthcare, while a long-term solution is sought by prioritizing societal values. In addition, there has been disruption to clinical care and clinical research. This pandemic might have significantly changed the care for our patients with dementia toward increased acceptance of telemedicine by the patients and providers, and its utilization in both clinical care and research.

Keywords: Access, Alzheimer’s disease, caregivers, clinical trial, coronavirus, COVID-19, dementia, health care, pandemic, telehealth, telemedicine

DOI: 10.3233/JAD-200461

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Capozzo, Rosa | Zoccolella, Stefano | Frisullo, Maria Elisa | Barone, Roberta | Dell’Abate, Maria Teresa | Barulli, Maria Rosaria | Musio, Marco | Accogli, Miriam | Logroscino, Giancarlo

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage. Objective: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic. Methods: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)–FTD were used by the neurologist with …patients and/or caregivers. Index symptoms of COVID-19 infection were searched. Results: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p  = 0.01) and language functions (p  = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab. Conclusion: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency. Show more

Keywords: COVID-19, frontotemporal lobar dementia, multidisciplinary care, pandemic, quality life, telemedicine

DOI: 10.3233/JAD-200589

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

Authors: Calfio, Camila | Gonzalez, Andrea | Singh, Sandeep Kumar | Rojo, Leonel E. | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer’s disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics’ pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants …that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, β-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence. Show more

Keywords: Alzheimer’s disease, anti-tau molecules, disease prevention and treatment, mechanisms, multitarget approaches, nutraceutical compounds

DOI: 10.3233/JAD-200443

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

Authors: Mei, Xinchun | Zheng, Hai-Lin | Li, Cheng | Ma, Xin | Zheng, Hui | Marcantonio, Edward | Xie, Zhongcong | Shen, Yuan

Article Type: Research Article

Abstract: Background: Postoperative delirium is associated with adverse postoperative outcomes. However, whether intravenous and inhalation anesthetics are associated with different risks of postoperative delirium remains unknown. Objective: We set up to determine the incidence and duration of postoperative delirium in older patients who had surgery under the intravenous anesthetic propofol or the inhalational anesthetic sevoflurane. Methods: Participants were patients who had total hip/knee replacements and were randomized to propofol (N = 106) or sevoflurane (N = 103) anesthesia group. The Confusion Assessment Method was employed by investigators who were blinded to the anesthesia regimen to assess the incidence and duration (days …of postoperative delirium per person) of postoperative delirium on postoperative days 1, 2, and 3. Results: A total of 209 participants (71.2±6.7 years old, 29.2% male) were included in the final data analysis. The incidence of postoperative delirium was 33.0% with propofol anesthesia and 23.3% with sevoflurane anesthesia (p  = 0.119, Chi-square test ), and we estimated that we would need 316 participants in each arm to detect a potential statistically significant difference. Days of postoperative delirium per person were higher in the propofol (0.5±0.8) anesthesia group compared to the sevoflurane anesthesia group (0.3±0.5, p  = 0.049, Student ’s t-test ). Conclusion: This pilot study established a system to compare effects of different anesthetics and generated a hypothesis that propofol trended to have a higher incidence and had longer duration of postoperative delirium than sevoflurane. Additional studies with a larger sample size are needed to test this hypothesis. Show more

Keywords: Anesthesia, delirium, postoperative, propofol, sevoflurane

DOI: 10.3233/JAD-200322

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

Authors: Schwab, Simon | Afyouni, Soroosh | Chen, Yan | Han, Zaizhu | Guo, Qihao | Dierks, Thomas | Wahlund, Lars-Olof | Grieder, Matthias

Article Type: Research Article

Abstract: Background: Semantic memory impairments in semantic dementia are attributed to atrophy and functional disruption of the anterior temporal lobes. In contrast, the posterior medial temporal neurodegeneration found in Alzheimer’s disease is associated with episodic memory disturbance. The two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. Objective: To unravel mutual and divergent functional alterations in Alzheimer’s disease and semantic dementia, we assessed functional connectivity between temporal lobe regions in Alzheimer’s disease (n  = 16), semantic dementia (n  = 23), and healthy controls (n  = 17). Methods: In an exploratory study, we used a …functional parcellation of the temporal cortex to extract time series from 66 regions for correlation analysis. Results: Apart from differing connections between Alzheimer’s disease and semantic dementia that yielded reduced functional connectivity, we identified a common pathway between the right anterior temporal lobe and the right orbitofrontal cortex in both dementia subtypes. This disconnectivity might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in a holistic context of disease-specific semantic impairments and functional connectivity changes. Conclusion: Despite a major limitation owed to unbalanced databases between study groups, this study provides a preliminary picture of the brain’s functional disconnectivity in Alzheimer’s disease and semantic dementia. Future studies are needed to replicate findings of a common pathway with consistent diagnostic criteria and neuropsychological evaluation, balanced designs, and matched data MRI acquisition procedures. Show more

Keywords: Alzheimer’s disease, functional connectivity, semantic dementia, temporal lobe

DOI: 10.3233/JAD-191113

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Falcon, Carles | Grau-Rivera, Oriol | Suárez-Calvet, Marc | Bosch, Beatriz | Sánchez-Valle, Raquel | Arenaza-Urquijo, Eider M. | González-de-Echavarri, José María | Gispert, Juan Domingo | Rami, Lorena | Molinuevo, José Luis

Article Type: Research Article

Abstract: Background: There is increasing evidence that AD progression differs by sex. Objective: The aim of this work was to determine sex differences in the association of baseline levels of cerebrospinal fluid (CSF) biomarkers (Aβ42 , p-tau, YKL-40, sTREM2) with longitudinal brain changes in cognitively unimpaired (CU) older adults. Methods: This pilot study included 36 CU subjects (age 66.5±5.5, 12 male) scanned twice, two years apart. Using a voxel-wise analysis, we determined the sex differences in the association maps between CSF biomarkers and atrophy rates. Results: We did not find differences related to Aβ42 . …We found a greater impact of the rest of CSF biomarkers in areas of the Papez circuit in women versus men. Men showed greater involvement in lateral parietal and paracentral areas. Discussion: Results suggest an early differential progression of brain atrophy between sexes. Further research will elucidate whether the mechanisms responsible for sex-specific atrophy patterns are biological and/or environmental. Show more

Keywords: Cerebrospinal fluid biomarkers, cognitively unimpaired older adults, longitudinal VBM, sex differences, sTREM2, YKL-40

DOI: 10.3233/JAD-200293

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

Authors: Xiao, Jinzhong | Katsumata, Noriko | Bernier, Francois | Ohno, Kazuya | Yamauchi, Yuki | Odamaki, Toshitaka | Yoshikawa, Kenji | Ito, Kumie | Kaneko, Toshiyuki

Article Type: Research Article

Abstract: Background: Probiotics use has been associated with modulation of inflammation and considered as a possible intervention for CNS diseases such as mild cognitive impairment (MCI) and dementia. Objective: We aimed to test the effect of the probiotic strain, Bifidobacterium breve A1 (MCC1274), to restore cognition in a physically healthy, suspected MCI population. Methods: In this randomized, double-blind, placebo-controlled trial, 80 healthy older adults suffering from MCI were divided into two even groups to receive once daily either probiotic (B. breve A1, 2×1010 CFU) or placebo for 16 weeks using a computer-generated algorithm. Cognitive …functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Japanese version of the MCI Screen (JMCIS) tests before and after the study as primary and secondary endpoints, respectively. Results: 79 participants completed the study, and no adverse events were observed. RBANS total score was significantly improved in probiotic group compared with placebo (mean between-group difference 11.3 [95% CI 6.7 to 15.8]; p  < 0.0001) after 16 weeks of consumption, in particular with significant improvement in domain scores of immediate memory, visuospatial/constructional, and delayed memory (p  < 0.0001), in both intention-to-treat (ITT) analysis and per-protocol (PP) analysis. JMCIS score was also improved versus placebo in ITT analysis (p  = 0.052) and PP analysis (p  = 0.036). Conclusion: Study results indicate B. breve A1 is a safe and effective approach for improving memory functions of suspected MCI subjects. Show more

Keywords: Bifidobacterium, clinical trial, dementia, memory, mild cognitive impairment, probiotics

DOI: 10.3233/JAD-200488

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