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

Authors: Nicoli, Charles D. | Howard, Virginia J. | Judd, Suzanne E. | Struck, Joachim | Manly, Jennifer J. | Cushman, Mary

Article Type: Research Article

Abstract: Background: The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment. Objective: To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI). Methods: We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and 490 …controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing. Results: Pro-NT/NMN was higher in Blacks and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08–4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations. Conclusion: In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system. Show more

Keywords: Biomarkers, case-control studies, cognition disorders, cognitive dysfunction, neuropeptides, neurotensin, prospective studies

DOI: 10.3233/JAD-200456

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

Authors: Waragai, Masaaki | Ho, Gilbert | Takamatsu, Yoshiki | Wada, Ryoko | Sugama, Shuei | Takenouchi, Takato | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Article Commentary

Abstract: Despite the apparent neurotoxicity of amyloid-β (Aβ), recent clinical trials of Aβ immunotherapy have not shown any clinical benefit in Alzheimer’s disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD. Accordingly, preventing the adiponectin paradox by suppressing adiponectin signaling might prove therapeutic in AD.

Keywords: Aβ immunotherapy, adiponectin, adiponectin paradox, Alzheimer’s disease, amyloid-β, amyloidogenic evolvability, antagonistic pleiotropy

DOI: 10.3233/JAD-200416

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

Authors: Pekkala, Timo | Hall, Anette | Mangialasche, Francesca | Kemppainen, Nina | Mecocci, Patrizia | Ngandu, Tiia | Rinne, Juha O. | Soininen, Hilkka | Tuomilehto, Jaakko | Kivipelto, Miia | Solomon, Alina

Article Type: Short Communication

Abstract: We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE ɛ 4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.

Keywords: Amyloid-β, apolipoprotein E, plasminogen activator, positron emission tomography, type 2 diabetes

DOI: 10.3233/JAD-200145

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

Authors: Assogna, Martina | Casula, Elias Paolo | Borghi, Ilaria | Bonnì, Sonia | Samà, Domenico | Motta, Caterina | Di Lorenzo, Francesco | D’Acunto, Alessia | Porrazzini, Francesco | Minei, Marilena | Caltagirone, Carlo | Martorana, Alessandro | Koch, Giacomo

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD. Objective: Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients. Methods: Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mg×2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental …State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity. Results: Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range. Conclusion: PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission. Show more

Keywords: Brain inflammation, behavioral symptoms, EEG, executive functions, frontotemporal dementia, GABA activity, transcranial magnetic stimulation

DOI: 10.3233/JAD-200426

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

Authors: Hayashi, Kentaro | Gonzales, Tina K. | Kapoor, Amita | Ziegler, Toni E. | Meethal, Sivan Vadakkadath | Atwood, Craig S.

Article Type: Research Article

Abstract: Background: While sex hormones are essential for normal cognitive health, those individuals with greater endocrine dyscrasia around menopause and with andropause are more likely to develop cognitive loss and Alzheimer’s disease (AD). Objective: To assess whether circulating sex hormones may provide an etiologically significant, surrogate biomarker, for cognitive decline. Methods: Plasma (n  = 152) and serum (n  = 107) samples from age- and gender-matched AD and control subjects from the Wisconsin Alzheimer’s Disease Research Center (ADRC) were analyzed for11 steroids and follicle-stimulating hormone. Logistic regression (LR), correlation analyses, and recursive partitioning (RP) were used to examine the interactions …of hormones and hormone ratios and their association with AD. Models generated were then tested on an additional 43 ADRC samples. Results: The wide variation and substantial overlap in the concentrations of all circulating sex steroids across control and AD groups precluded their use for predicting AD. Classification tree analyses (RP) revealed interactions among single hormones and hormone ratios that associated with AD status, the most predictive including only the hormone ratios identified by LR. The strongest associations were observed between cortisol, cortisone, and androstenedione with AD, with contributions from progesterone and 17β-estradiol. Utilizing this model, we correctly predicted 81% of AD test cases and 64% of control test cases. Conclusion: We have developed a diagnostic model for AD, the Wisconsin Hormone Algorithm Test for Cognition (WHAT-Cog), that utilizes classification tree analyses of hormone ratios. Further refinement of this technology could provide a quick and cheap diagnostic method for screening those with AD. Show more

Keywords: Alzheimer’s disease, blood, classification tree, diagnostic, follicle-stimulating hormone, hormone ratio, model, prediction, recursive partitioning, steroids

DOI: 10.3233/JAD-200418

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Kaur, Harpreet | Golovko, Svetlana | Golovko, Mikhail Y. | Singh, Surjeet | Darland, Diane C. | Combs, Colin K.

Article Type: Research Article

Abstract: Background: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior. Objective: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer’s disease (AD). Methods: C57BL/6 wild-type (WT) mice were compared to AppNL -G -F mice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aβ, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry …was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS. Results: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL -G -F mice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL -G -F mice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL -G -F mice. No significant differences were observed between vehicle and VSL#3 fed AppNL -G -F hippocampal immunore activities of Aβ, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL -G -F mice. Conclusion: These data demonstrate intestinal dysbiosis in the AppNL -G -F mouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL -G -F mice correlating with increased expression of the neuronal activity marker, c-Fos. Show more

Keywords: Alzheimer’s disease, butyrate, gliosis, microbiota, plaques, probiotics, short chain fatty acids

DOI: 10.3233/JAD-200436

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2020

Authors: Li, Tengfei | Martin, Elodie | Abada, Yah-se | Boucher, Céline | Cès, Aurélia | Youssef, Ihsen | Fenaux, Grégory | Forand, Yona | Legrand, Annaelle | Nachiket, Nadkarni | Dhenain, Marc | Hermine, Olivier | Dubreuil, Patrice | Delarasse, Cécile | Delatour, Benoît

Article Type: Research Article

Abstract: Background: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer’s disease. Objective: We aimed to shed light on the mode of action of masitinib in Alzheimer’s disease. Methods/Results: We demonstrated here that chronic oral treatment of APPPS1dE9 transgenic mice modeling Alzheimer’s disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPPS1dE9 mice similarly rescued synaptic …impairments. Conclusion: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition. Show more

Keywords: Alzheimer’s disease, cognition, drug evaluation, masitinib, mast cells, preclinical, synapses

DOI: 10.3233/JAD-200466

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

Authors: Shi, Yun | Zhang, Lei | Gao, Xue | Zhang, Jing | Ben Abou, Matan | Liang, Ge | Meng, Qingcheng | Hepner, Adrian | Eckenhoff, Maryellen F. | Wei, Huafeng

Article Type: Research Article

Abstract: Background/Objective: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer’s disease (AD) mice. Methods: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid …immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. Results: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. Conclusions: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dantrolene, intranasal administration

DOI: 10.3233/JAD-200227

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

Authors: Kim, Dong Yeol | Choi, Sung Hyun | Lee, Jee Sun | Kim, Hyoung Jun | Kim, Ha Na | Lee, Ji Eun | Shin, Jin Young | Lee, Phil Hyu

Article Type: Research Article

Abstract: Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of the central nervous system and are currently being tested in clinical trials for neurological disorders. However, no studies have examined the various roles of embryonic stem cell derived (ES)-MSCs in eliciting therapeutic effects for Alzheimer’s disease (AD). In the present study, we investigated the neuroprotective effect of ES-MSCs in cellular and animal models of AD, as well as the safety of the intra-arterial administration of ES-MSCs in an AD animal model. ES-MSCs displayed higher cell viability than that of bone marrow (BM)-MSCs in amyloid-β (Aβ )-induced cellular …models. Moreover, the efficacy of autophagy induction in ES-MSCs was comparable to that of BM-MSCs; however, intracellular Aβ levels were more significantly reduced in ES-MSCs than in BM-MSCs. In a rat model of AD, ES-MSCs significantly inhibited Aβ -induced cell death in the hippocampus and promoted autophagolysosomal clearance of Aβ , which was concomitantly followed by decreased levels of Aβ in the hippocampus. Furthermore, ES-MSC treatment in Aβ -treated rats featured a higher memory performance than that of rats injected solely with Aβ . Finally, intra-arterial administration of an appropriate cell density of ES-MSCs was safe and free from in situ occlusion or cerebral ischemia. These data support the therapeutic potential of ES-MSCs and clinical applications of the intra-arterial route of ES-MSC administration in AD. Show more

Keywords: Alzheimer’s disease, autophagy, intra-arterial injection, mesenchymal stem cell, protection

DOI: 10.3233/JAD-200026

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Naude, James P. | Gill, Sascha | Hu, Sophie | McGirr, Alexander | Forkert, Nils D. | Monchi, Oury | Stys, Peter K. | Smith, Eric E. | Ismail, Zahinoor | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Assessing neuropsychiatric symptoms (NPS) in older adults is important for determining dementia risk. Mild behavioral impairment (MBI) is an at-risk state for cognitive decline and dementia, characterized by emergent NPS in later life. MBI has significantly higher dementia incidence than late life psychiatric conditions. However, its utility as a proxy for neurodegeneration has not been demonstrated. Plasma neurofilament light (NfL) is a validated biomarker of axonal damage, and has been shown to associate with hallmarks of neurodegeneration. Objective: The purpose of this investigation was to identify associations between NfL rate of change and the presence of MBI …symptomatology. Methods: We evaluated the association of MBI with changes in NfL in a cohort (n  = 584; MBI + n = 190, MBI– n  = 394) of non-demented participants from the Alzheimer’s Disease Neuroimaging Initiative. MBI was determined by transforming neuropsychiatric questionnaire items using a published algorithm. Change in NfL was calculated over 2 years. Results: Time*MBI status was the only significant interaction to predict change in NfL concentrations (F (1,574) = 4.59, p  = 0.032), even after controlling for age, mild cognitive impairment, and demographics. Analyses reclassifying 64 participants with new onset MBI over 2 years similarly demonstrated greater increases in NfL (F (1,574) = 5.82, p  = 0.016). Conclusion: These findings suggest MBI is a clinical proxy of early phase neurodegeneration with putative utility in identifying those at dementia risk. MBI can be used as a case ascertainment approach to capture those at high risk for cognitive decline and dementia, and is an important construct for clinicians dealing with cognitive and neuropsychiatric symptomatology in older adults. Show more

Keywords: Alzheimer’s disease, mild behavioral impairment, mild cognitive impairment, neurodegeneration, neurofilament light, neuropsychiatric symptoms

DOI: 10.3233/JAD-200011

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

Authors: Muurling, Marijn | Rhodius-Meester, Hanneke F.M. | Pärkkä, Juha | van Gils, Mark | Frederiksen, Kristian S. | Bruun, Marie | Hasselbalch, Steen G. | Soininen, Hilkka | Herukka, Sanna-Kaisa | Hallikainen, Merja | Teunissen, Charlotte E. | Visser, Pieter Jelle | Scheltens, Philip | van der Flier, Wiesje M. | Mattila, Jussi | Lötjönen, Jyrki | de Boer, Casper

Article Type: Research Article

Abstract: Background: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer’s disease pathology. Objective: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer’s disease, and 3) predict cognitive decline. Methods: Gait was measured using tri-axial accelerometers attached …to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. Results: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p  < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE. Conclusion: These findings suggest that gait—particularly measures related to pace and rhythm—are altered in dementia and have a direct link with measures of neurodegeneration. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, gait analysis, tau proteins

DOI: 10.3233/JAD-200225

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

Authors: Liang, Yingxia | Raven, Frank | Ward, Joseph F. | Zhen, Sherri | Zhang, Siyi | Sun, Haoqi | Miller, Sean J. | Choi, Se Hoon | Tanzi, Rudolph E. | Zhang, Can

Article Type: Research Article

Abstract: Background: The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Objective: Here, we aimed to investigate astrocyte-related pathological changes of Aβ …and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. Methods/Results: Weutilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Conclusion: Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD. Show more

Keywords: Alzheimer’s disease, amyloid pathology, amyloid-β , amyloid-β protein precursor, amyloidogenesis, astrocyte, autonomous

DOI: 10.3233/JAD-200128

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

Authors: Wan, Xinkun | Ma, Bin | Wang, Xiaoxuan | Guo, Chenjia | Sun, Jing | Cui, Jing | Li, Liang

Article Type: Research Article

Abstract: Background: Glutathione (GSH) is an important endogenous antioxidant protecting cells from oxidative injury. Cysteine (Cys), the substrate limiting the production of GSH, is mainly generated from the trans-sulfuration pathway. S-adenosylmethionine (SAM) is a critical molecule produced in the methionine cycle and can be utilized by the trans-sulfuration pathway. Reductions in GSH and SAM as well as dysfunction in the trans-sulfuration pathway have been documented in the brains of Alzheimer’s disease (AD) patients. Our previous in vivo study revealed that SAM administration attenuated oxidative stress induced by amyloid-β (Aβ ) through the enhancement of GSH. Objective: To …investigate the effect of Aβ -induced oxidative stress on the trans-sulfuration pathway in astrocytes and neurons, respectively, and the protective effect of SAM on neurons. Methods: APP/PS1 transgenic mice and the primary cultured astrocytes, neurons, and HT22 cells were used in the current study. Results: SAM could rescue the low trans-sulfuration pathway activity induced by Aβ only in astrocytes, accompanying with increasing levels of Cys and GSH. The decrease of cellular viability of neurons caused by Aβ was greatly reversed when co-cultured with astrocytes with SAM intervention. Meanwhile, SAM improved cognitive performance in APP/PS1 mice. Conclusion: In terms of astrocyte protection from oxidative stress, SAM might be a potent antioxidant in the therapy of AD patients. Show more

Keywords: Amyloid-β , astrocytes, glutathione, S-adenosylmethionine, trans-sulfuration pathway

DOI: 10.3233/JAD-200103

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

Authors: Duan, Wenna | Sehrawat, Parshant | Balachandrasekaran, Arvind | Bhumkar, Ashish B. | Boraste, Paresh B. | Becker, James T. | Kuller, Lewis H. | Lopez, Oscar L. | Gach, H. Michael | Dai, Weiying

Article Type: Research Article

Abstract: Background: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer’s disease (AD). Objective: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort. Methods: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study cognition study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction …of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors. Results: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate & precuneus region (p  < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p  < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBFin the bilateral posterior and middle cingulate & parietal (p  < 0.001), bilateral superior medial frontal (p  < 0.001), bilateral temporoparietal (p  < 0.02), and right hippocampus (p  = 0.02) regions. Conclusion: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as staging biomarker of cognitive status. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, cerebral blood flow, cognition

DOI: 10.3233/JAD-200034

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Fuentes, Manuel | Klostermann, Arne | Kleineidam, Luca | Bauer, Chris | Schuchhardt, Johannes | Maier, Wolfgang | Jessen, Frank | Frölich, Lutz | Wiltfang, Jens | Kornhuber, Johannes | Klöppel, Stefan | Schieting, Vera | Teipel, Stefan J. | Wagner, Michael | Peters, Oliver

Article Type: Research Article

Abstract: Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer’s disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer’s dementia (AD; MMSE = 23.9±2.88) were followed at 12 and 24 months. Lead-lag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 …neuropsychological subtest scores from the CERAD + test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (Δ MMSE 5.8±8.64; Δ CDR-SOB 4.32±4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures. Show more

Keywords: Alzheimer’s disease, bayer activities of daily living scale, cognitive changes, disease progression, functional changes, lead and lag analysis

DOI: 10.3233/JAD-200230

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

Authors: Solis, Jr. , Ernesto | Hascup, Kevin N. | Hascup, Erin R.

Article Type: Review Article

Abstract: While prevailing evidence supports that the amyloid cascade hypothesis is a key component of Alzheimer’s disease (AD) pathology, many recent studies indicate that the vascular system is also a major contributor to disease progression. Vascular dysfunction and reduced cerebral blood flow (CBF) occur prior to the accumulation and aggregation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Although research has predominantly focused on the cellular processes involved with Aβ-mediated neurodegeneration, effects of Aβ on CBF and neurovascular coupling are becoming more evident. This review will describe AD vascular disturbances as they relate to Aβ, including chronic cerebral hypoperfusion, hypertension, altered …neurovascular coupling, and deterioration of the blood-brain barrier. In addition, we will describe recent findings about the relationship between these vascular defects and Aβ accumulation with emphasis on in vivo studies utilizing rodent AD models. Show more

Keywords: Amyloid-β peptide, amyloid cascade hypothesis, blood-brain barrier, cerebral amyloid angiopathy, chronic cerebral hypoperfusion, functional hyperemia, in vivo mouse model, in vivo rat model, neurovascular coupling, vascular hypothesis

DOI: 10.3233/JAD-200473

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2020

Authors: Maccioni, Ricardo B. | Navarrete, Leonardo P. | González, Andrea | González-Canacer, Alejandra | Guzmán-Martínez, Leonardo | Cortés, Nicole

Article Type: Review Article

Abstract: Several hypotheses have been postulated to explain how Alzheimer’s disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid-β peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmuno modulation theory, based on …the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer’s disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multi targeting compounds appear to provide a new pathway for Alzheimer’s disease treatment. Show more

Keywords: Alzheimer’s disease, astrocytes, mediators, microglial cells, neuroinflammation, proinflammatory tau pathology

DOI: 10.3233/JAD-191014

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

Authors: Angehrn, Zuzanna | Sostar, Jelena | Nordon, Clementine | Turner, Andrew | Gove, Dianne | Karcher, Helene | Keenan, Alexander | Mittelstadt, Brent | de Reydet-de Vulpillieres, Frederic

Article Type: Research Article

Abstract: Background: The therapeutic paradigm in Alzheimer’s disease (AD) is shifting from symptoms management toward prevention goals. Secondary prevention requires the identification of individuals without clinical symptoms, yet “at-risk” of developing AD dementia in the future, and thus, the use of predictive modeling. Objective: The objective of this study was to review the ethical concerns and social implications generated by this new approach. Methods: We conducted a systematic literature review in Medline, Embase, PsycInfo, and Scopus, and complemented it with a gray literature search between March and July 2018. Then we analyzed data qualitatively using a thematic …analysis technique. Results: We identified thirty-one ethical issues and social concerns corresponding to eight ethical principles: (i) respect for autonomy, (ii) beneficence, (iii) non-maleficence, (iv) equality, justice, and diversity, (v) identity and stigma, (vi) privacy, (vii) accountability, transparency, and professionalism, and (viii) uncertainty avoidance. Much of the literature sees the discovery of disease-modifying treatment as a necessary and sufficient condition to justify AD risk assessment, overlooking future challenges in providing equitable access to it, establishing long-term treatment outcomes and social consequences of this approach, e.g., medicalization. The ethical/social issues associated specifically with predictive models, such as the adequate predictive power and reliability, infrastructural requirements, data privacy, potential for personalized medicine in AD, and limiting access to future AD treatment based on risk stratification, were covered scarcely. Conclusion: The ethical discussion needs to advance to reflect recent scientific developments and guide clinical practice now and in the future, so that necessary safeguards are implemented for large-scale AD secondary prevention. Show more

Keywords: Biomedical ethics, dementia, early diagnosis, early intervention, prodromal symptoms, qualitative research, secondary prevention

DOI: 10.3233/JAD-191159

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Habiba, Umma | Merlin, Sam | Lim, Jeremiah K.H. | Wong, Vickie H.Y. | Nguyen, Christine T.O. | Morley, John W. | Bui, Bang V. | Tayebi, Mourad

Article Type: Research Article

Abstract: Background: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer’s disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. Objective: This study’s aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in …the retina of a rodent model of AD. Methods: Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies. Results: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. Conclusion: Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye. Show more

Keywords: Anti-oligomer antibody, Alzheimer’s disease, amyloid-β oligomers, retina, retinal immunodetection, 5×FAD mice

DOI: 10.3233/JAD-191346

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

Authors: Wing, Jeffrey J. | Levine, Deborah A. | Ramamurthy, Arun | Reider, Carson

Article Type: Research Article

Abstract: Background: Areas within the Appalachian region may have a greater burden of under diagnosed Alzheimer’s disease and related disorders (ADRD). Objective: To estimate the prevalence of ADRD in the Appalachian counties of Ohio, and to determine if differences exist by geographic location (Appalachian/non-Appalachian and rural/urban) and across time among Medicare beneficiaries. Methods: Centers for Medicare and Medicaid Services Public Use Files from 2007–2017 were used to estimate county-level ADRD prevalence among all fee-for-service beneficiaries in Ohio. Negative binomial regression was used to estimate prevalence overall, by Appalachian Regional Commission’s Appalachian/non-Appalachian designation, and by rural/urban (Rural-Urban Continuum …Codes) classification. Models were repeated, adjusting for county-level demographics and comorbidities. Results: The prevalence of ADRD varied by both Appalachian residence and rural status (p  = 0.008). Before adjustment by county-level demographics and comorbidities, the prevalence of ADRD in urban Appalachian counties was 1–3% lower than in urban non-Appalachian counties, while rural Appalachian counties had 2–3% higher prevalence compared to rural non-Appalachian counties. After adjustment, the differences between prevalence ratios were accentuated; the prevalence ratio was consistently higher for rural Appalachian counties, yet varied across the study period for urban counties (1.03 in 2007 to 0.97 in 2017). Conclusion: The results suggest a disparate burden of ADRD in Ohio with higher prevalence in rural Appalachian counties. This potential difference by Appalachian region is important to consider for availability of services and subsequent delivery of care. In order to better understand the disparity, further epidemiologic studies are necessary to better estimate the burden of ADRD. Show more

Keywords: Alzheimer’s disease, Appalachian region, epidemiology, health disparities, medicare

DOI: 10.3233/JAD-200491

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Resende, Rosa | Ferreira-Marques, Marisa | Moreira, Patrícia | Coimbra, Judite R.M. | Baptista, Salete J. | Isidoro, Ciro | Salvador, Jorge A.R. | Dinis, Teresa C.P. | Pereira, Cláudia F. | Santos, Armanda E.

Article Type: Research Article

Abstract: Background: A disease-modifying therapy for Alzheimer’s disease (AD) is still an unmet clinical need. The formation of amyloid-β (Aβ) requires the initial cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (beta-site AβPP cleaving enzyme 1), which is a prime therapeutic target for AD. Objective: We aimed to design and develop a selective BACE1 inhibitor suitable to AD treatment. Methods: The new BACE1 inhibitors consist on a chimeric peptide including a sequence related to the human Swedish mutant form of AβPP (AβPPswe) conjugated with the TAT carrier that facilitates cell membrane permeation and the crossing of …the blood-brain barrier. Additionally to the chimeric peptide in the L -form, we developed a D -retro in verso chimeric peptide. The latter strategy, never used with BACE1 inhibitors, is considered to favor a significantly higher half-life and lower immunogenicity. Results: We found that both chimeric peptides inhibit recombinant BACE1 activity and decrease Aβ40/42 production in Neuro-2a (N2A) cells expressing AβPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aβ40/42 levels, as well as brain soluble AβPPβ production. Also, a reduction of insoluble Aβ was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AβPPβ cleavage relatively to the proteolysis of other BACE1 substrates such as close homologue of L1 (CHL1) and seizure-related gene 6 (SEZ6). Conclusions: Overall these new BACE1 chimeric peptideshold promising potential as a selective disease-modifying therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, BACE1 inhibitor, chimeric peptide, CHL1, SEZ6

DOI: 10.3233/JAD-200381

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2020

Authors: Chatzistavraki, Maria | Papazafiri, Panagiota | Efthimiopoulos, Spiros

Article Type: Research Article

Abstract: Background: Coordinated calcium influx upon neuronal depolarization activates pathways that phosphorylate CaMKII, ERKs, and the transcription factor CREB and, therefore, expression of pro-survival and neuroprotective genes. Recent evidence indicates that amyloid-β protein precursor (AβPP) is trafficked to synapses and promotes their formation. At the synapse, AβPP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function. Objective: Herein, we examined the role of AβPP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and AβPP– /– C57bl/6 mice. Methods: Depolarization of acute cerebral slices from wild-type C57bl/6 and AβPP– /– …C57bl/6 mice was used to induce synaptic signaling. Protein levels were examined by western blot and calcium dynamics were assessed using primary neuronal cultures. Results: In the absence of AβPP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-type Voltage Gated Calcium Channels (N- and P/Q-VGCCs) by ω -conotoxin GVIA and ω -conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of AβPP did not result in a statistically significant decrease of pCREB, which is a known substrate of pERKs. Finally, using calcium imaging, we found that down regulation of AβPP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response. Conclusion: AβPP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, AβPP, calcium, neuronal signaling, synapse

DOI: 10.3233/JAD-200290

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Griswold, Anthony J. | Sivasankaran, Sathesh K. | Van Booven, Derek | Gardner, Olivia K. | Rajabli, Farid | Whitehead, Patrice L. | Hamilton-Nelson, Kara L. | Adams, Larry D. | Scott, Aja M. | Hofmann, Natalia K. | Vance, Jeffery M. | Cuccaro, Michael L. | Bush, William S. | Martin, Eden R. | Byrd, Goldie S. | Haines, Jonathan L. | Pericak-Vance, Margaret A. | Beecham, Gary W.

Article Type: Research Article

Abstract: Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer’s disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional changes occurring in brain and help to identify mechanisms underlying neurodegenerative processes. Objective: We aimed to identify transcriptional differences between AD cases and controls in a cohort of diverse ancestry. Methods: We analyzed the protein coding transcriptome using RNA sequencing from peripheral blood collected from 234 African American (AA) (115 AD, 119 controls) …and 240 non-Hispanic Whites (NHW) (121 AD, 119 controls). To identify case-control differentially expressed genes and pathways, we performed stratified, joint, and interaction analyses using linear regression models within and across ancestral groups followed by pathway and gene set enrichment analyses. Results: Overall, we identified 418 (291 upregulated, 127 downregulated) and 488 genes (352 upregulated, 136 downregulated) differentially expressed in the AA and NHW datasets, respectively, with only 16 genes commonly differentially expressed in both ancestral groups. Joint analyses provided greater power to detect case-control differences and identified 1,102 differentially expressed genes between cases and controls (812 upregulated, 290 downregulated). Interaction analysis identified only 27 genes with different effects in AA compared to NHW. Pathway and gene-set enrichment analyses revealed differences in immune response-related pathways that were enriched across the analyses despite different underlying gene sets. Conclusion: These results support the hypothesis of converging underlying pathophysiological processes in AD across ancestral groups. Show more

Keywords: Gene expression profiling, population characteristics, RNA, transcriptome

DOI: 10.3233/JAD-190855

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

Authors: Vergouw, Leonie J. M. | Geut, Hanneke | Breedveld, Guido | Kuipers, Demy J. S. | Quadri, Marialuisa | Netherlands Brain Bank | Rozemuller, Annemieke J. M. | van Swieten, John C. | de Jong, Frank Jan | van de Berg, Wilma D. J. | Bonifati, Vincenzo

Article Type: Research Article

Abstract: Background: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10 ) have recently been implicated in the etiology of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. Methods: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. Results: Rare, possibly pathogenic heterozygous LRP10 variants were present in …three patients: p.Gly453Serin a patient with mixed Alzheimer’s disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. Conclusion: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum. Show more

Keywords: Genetic predisposition to disease, genotype, LRP10, neuropathology, phenotype

DOI: 10.3233/JAD-200318

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

Authors: Sy, Marie Charmaine C. | Espiritu, Adrian I. | Sy, Matthew Samuel C. | Jamora, Roland Dominic G. | Anlacan, Veeda Michelle M.

Article Type: Research Article

Abstract: Background: Scientific output in Southeast Asia (SEA) on the topic of dementia is postulated to be low in quality and quantity. It is also speculated that certain socioeconomic variables and measures of disease burden for dementia may play a significant role in driving the research output of a particular country. Objective: This study aimed to determine the research impact of published journal articles on dementia in SEA and its association with country-level socioeconomic factors and measures of disease burden for dementia. Methods: A systematic search was conducted using electronic healthcare databases. We included articles published on …dementia until August 2019 with at least 1 author affiliated with any SEA institution. We obtained bibliometric indices, relevant socioeconomic factors, and measures of disease burden for dementia from published sources. Results: One thousand six articles fulfilled the inclusion criteria. The majority of publications were related to Alzheimer’s disease (n  = 775, 77.0%). Singapore contributed the highest number of publications (n  = 457, 45.4%). Gross domestic product (GDP) per capita, % GDP for research and development, and total neurologists significantly correlated with several bibliometric indices. On the other hand, the measures of disease burden for dementia in SEA countries were not significantly associated with research productivity. Conclusion: Research productivity in SEA on dementia has substantially increased in recent years. Augmenting GDP per capita and expanding the apportionment of resources to research and development (R&D) may have a significant role in the advancement of dementia research in SEA. Show more

Keywords: Bibliometric analysis, burden of disease, dementia, scientometrics, socioeconomic factors, Southeast Asia

DOI: 10.3233/JAD-200355

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

Authors: Sancesario, Giulia Maria | Di Lazzaro, Giulia | Alwardat, Mohammad | Biticchi, Benedetta | Basile, Valerio | Salimei, Chiara | Colona, Vito Luigi | Sinibaldi Salimei, Paola | Bernardini, Sergio | Mercuri, Nicola Biagio | Pisani, Antonio | Schirinzi, Tommaso

Article Type: Research Article

Abstract: Background: Synaptopathy is critical in pathophysiology of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-β42 (Aβ42 ) are considered markers of synaptic dysfunction in neurodegenerative diseases. Objective: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aβ42 /NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. Methods: Levels of NG, Aβ42 , amyloid-β40 , total and phosphorylated tau, and Aβ42 /NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was …determined. Results: NG and Aβ42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aβ42 /NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. Conclusions: The novel Aβ42 /NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD. Show more

Keywords: Cerebrospinal fluid biomarkers, cognitive, neurogranin, Parkinson’s disease

DOI: 10.3233/JAD-200344

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Sakai, Toshihiro | Rakugi, Hiromi | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Very few studies have investigated the impact of cognitive frailty in clinical settings, especially in memory clinic populations. Objective: To examine the impact of cognitive frailty on activities of daily living (ADL), cognitive function, and conversion to dementia among memory clinic patients with mild cognitive impairment (MCI). Methods: The subjects of this retrospective study were 248 MCI patients (mean age, 76.3±5.4 years; females, 60.9%). All subjects completed a comprehensive geriatric assessment at baseline and at least one assessment during 3-year follow-up. Frailty was defined by generating a frailty index (FI), and MCI patients with frailty …(FI≥0.25) were considered to represent cognitive frailty. As primary outcomes, the Barthel Index, Mini-Mental State Examination, and incident dementia were evaluated during follow-up. At baseline, patients were assessed for apolipoprotein E (APOE ) phenotype. A linear mixed model, as well as a Cox proportional hazards regression model with adjustment for confounding variables, was performed. Results: Of these patients, 75 (30.2%) were classified as cognitive frail. APOE ɛ 4 carriers accounted for 26.7% of those with cognitive frailty and 44.5% of those without (p  = 0.008). Cognitive frail patients showed a faster ADL decline (estimate, –1.04; standard error, 0.38; p  = 0.007) than patients without cognitive frailty. Cognitive frailty was not associated with cognitive decline and incident dementia. Conclusion: Our findings demonstrated cognitive frailty increases the risk of dependence but not cognitive outcomes. Cognitive frailty may have heterogeneous conditions, including APOE ɛ 4-related pathologies, which may affect the cognitive trajectories of patients with MCI. Show more

Keywords: Cognitive frailty, disability, frailty, memory clinic, mild cognitive impairment, older persons

DOI: 10.3233/JAD-191135

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

Authors: Narukawa, Masataka | Takahashi, Suzuka | Saito, Takashi | Saido, Takaomi C. | Misaka, Takumi

Article Type: Research Article

Abstract: Background: Some studies have reported a decline in taste sensitivities in patients with Alzheimer’s disease. However, the detail remains unknown. Objective: We investigated the effect of cognitive impairment on taste sensitivity using an App knock-in mouse model of Alzheimer’s disease. Methods: Behavioral assays, a brief access test, and a 48 h two-bottle preference test, to assess taste sensitivities were started from 12 months of age in mice that were confirmed to have impaired cognition. Results: In the assays, there was no significant difference in taste sensitivities between wild type and App knock-in mice. …Additionally, no apparent difference was observed in the expression of taste markers in their taste bud cells. Conclusion: We concluded that cognitive impairment might not greatly affect taste sensitivity. Show more

Keywords: Aging, App knock-in mice, donepezil, taste sensitivity

DOI: 10.3233/JAD-200284

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Thordardottir, Steinunn | Almkvist, Ove | Johansson, Charlotte | Zetterberg, Henrik | Blennow, Kaj | Graff, Caroline

Article Type: Research Article

Abstract: Background: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) which reflect different underlying disease mechanisms. Objective: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. Methods: YKL-40 and neurogranin, as well as Aβ 42 , total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe …(p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. Results: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. Conclusion: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, chitinases, genetics, mutation, neurogranin

DOI: 10.3233/JAD-191261

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Hu, Yueming | Meuret, Cristiana | Go, Scholastica | Yassine, Hussein N. | Nedelkov, Dobrin

Article Type: Research Article

Abstract: Background: The mechanisms of how APOE ɛ 4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated. Objective: To determine the impact of APOE genotype on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma via a newly developed mass spectrometric immunoassay (MSIA) assay. Methods: Total glycosylation and isoform-specific glycosylation were analyzed in plasma and CSF from a group of non-demented older individuals (n  = 22), consisting of homozygous ɛ 3 and ɛ 4 …or heterozygous ɛ 3/ɛ 4, ɛ 2/ɛ 3, or ɛ 2/ɛ 4 carriers. The glycan structures were further confirmed after treatment with sialidase. Results: In heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O -linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In plasma and CSF, a trend of decreasing glycosylation was observed from apoE2>apoE3>apoE4. The difference in the percentage of secondary glycosylation in CSF was significantly greater in apoE4compared to the other isoforms. Conclusion: The new MSIA apoE as say robustly distinguishes among apoE isoforms and glycoformsin plasma and CSF. ApoE4 is the predominant isoform and least glycosylated in CSF. Assessing apoE isoform-specific glycosylation by MSIA may help clarifybrain apoE metabolism and AD risk. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, glycan, isoform, mass spectrometry

DOI: 10.3233/JAD-200203

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

Authors: Thomas, Jason A. | Burkhardt, Hannah A. | Chaudhry, Safina | Ngo, Anthony D. | Sharma, Saransh | Zhang, Larry | Au, Rhoda | Hosseini Ghomi, Reza

Article Type: Research Article

Abstract: Background: There is a need for fast, accessible, low-cost, and accurate diagnostic methods for early detection of cognitive decline. Dementia diagnoses are usually made years after symptom onset, missing a window of opportunity for early intervention. Objective: To evaluate the use of recorded voice features as proxies for cognitive function by using neuropsychological test measures and existing dementia diagnoses. Methods: This study analyzed 170 audio recordings, transcripts, and paired neuropsychological test results from 135 participants selected from the Framingham Heart Study (FHS), which includes 97 recordings of cognitively normal participants and 73 recordings of cognitively impaired …participants. Acoustic and linguistic features of the voice samples were correlated with cognitive performance measures to verify their association. Results: Language and voice features, when combined with demographic variables, performed with an AUC of 0.942 (95% CI 0.929–0.983) in predicting cognitive status. Features with good predictive power included the acoustic features mean spectral slope in the 500–1500 Hz band, variation in the F2 bandwidth, and variation in the Mel-Frequency Cepstral Coefficient (MFCC) 1;the demographic features employment, education, and age; and the text features of number of words, number of compound words, number of unique nouns, and number of proper names. Conclusion: Several linguistic and acoustic biomarkers show correlations and predictive power with regard to neuropsychological testing results and cognitive impairment diagnoses, including dementia. This initial study paves the way for a follow-up comprehensive study incorporating the entire FHS cohort. Show more

Keywords: Alzheimer’s disease, artificial intelligence, biomarkers, cognitive dysfunction, data collection, dementia, early diagnosis, language, neuropsychological tests, voice

DOI: 10.3233/JAD-190783

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Luukkainen, Laura | Huttula, Samuli | Väyrynen, Henri | Helisalmi, Seppo | Kytövuori, Laura | Haapasalo, Annakaisa | Hiltunen, Mikko | Remes, Anne M. | Krüger, Johanna

Article Type: Research Article

Abstract: Background: Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson’s disease (PD) overlap in clinical characteristics, neuropathology, and genetics. Objective: The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. Methods: Rare non-synonymous variants (MAF < 0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1 , ATP13A2, UCHL1, HTRA2, GBA , and SNCAIP) and low-frequency (MAF < 0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) <65 …years) dementia patients presenting with atypical features (e.g., myocloniaor spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n  = 279, mean AAO 57, range 36–65) patients. Results: No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). Discussion: Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD. Show more

Keywords: Alzheimer’s disease, dementia, dementia with Lewy bodies, frontotemporal dementia, frontotemporal lobar degeneration, gene, mutation, neurodegenerative disease, Parkinson’s disease, single nucleotide polymorphism

DOI: 10.3233/JAD-200069

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

Authors: Guthrie, Heather | Honig, Lawrence S. | Lin, Helen | Sink, Kaycee M. | Blondeau, Kathleen | Quartino, Angelica | Dolton, Michael | Carrasco-Triguero, Montserrat | Lian, Qinshu | Bittner, Tobias | Clayton, David | Smith, Jillian | Ostrowitzki, Susanne

Article Type: Research Article

Abstract: Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods: In this multicenter, double-blind study, participants (aged 50–90 years) with mild-to-moderate Alzheimer’s disease (AD) and amyloid-positive PET scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n  = 21), 60 mg/kg (Cohort 2, n  = 21), or 120 mg/kg (Cohort 3, n  = 19) or corresponding placebo (n  = 14) intravenously q4wfor 13 weeks. Seventy-one participants were subsequently …enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose proportional and maintained for each dose level. Conclusion: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials. Show more

Keywords: Alzheimer’s disease, amyloid positron emission tomography, amyloid-β peptide, crenezumab, humanized monoclonal antibody, infusion site adverse event, magnetic resonance imaging, safety

DOI: 10.3233/JAD-200134

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Robillard, Julie M. | Kabacińska, Katarzyna

Article Type: Review Article

Abstract: Socially assistive robots have the potential to improve aged care by providing assistance through social interaction. While some evidence suggests a positive impact of social robots on measures of well-being, the adoption of robotic technology remains slow. One approach to improve technology adoption is involving all stakeholders in the process of technology development using co-creation methods. To capture relevant stake holders’ priorities and perceptions on the ethics of robotic companions, we conducted an interactive co-creation workshop at the 2019 Geriatric Services Conference in Vancouver, BC. The participants were presented with different portrayals of robotic companions in popular culture and answered …questions about perceptions, expectations, and ethical concerns about the implementation of robotic technology. Our results reveal that the most pressing ethical concerns with robotic technology, such as issues related to privacy, are critical potential barriers to technology adoption. We also found that most participants agree on the types of tasks that robots should help with, such as domestic chores, communication, and medication reminders. Activities that robots should not help with, according to the stakeholders, included bathing, toileting, and managing finances. The perspectives that were captured contribute to a preliminary outline of the areas of importance for geriatric care stake holders in the process of ethical technology design and development. Show more

Keywords: Aging, engagement, ethics, technology

DOI: 10.3233/JAD-200214

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

Authors: Wang, Si-Yu | Gong, Peng-Yu | Yan, E | Zhang, Ying-Dong | Jiang, Teng

Article Type: Review Article

Abstract: Late-onset Alzheimer’s disease (AD) accounts for most of all AD casesand is currently considered a complex disorder caused by a combination of environmental and genetic factors. As an important family member of triggering receptor expressed on myeloid cells (TREM ), TREM-like transcript 2 gene (TREML2 ) locates on human chromosome 6p21.1, a newly-identified hot zone for AD susceptibility, and encodes atransmembrane immune receptor. Emerging evidence implied a potential role of TREML2 in the susceptibility and pathogenesis of AD. Here, we review the recent literature about the association of TREML2 variants with AD risk and disease endophenotypes. Moreover, we …summarize the latest findings regarding cellular localization and biological functions of TREML2 and speculate its possible role in AD pathogenesis. In addition, we discuss future research directions of TREML2 and AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , genetics, microglia, TREML2

DOI: 10.3233/JAD-200406

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Robillard, Julie M. | Goldman, Ian P. | Prescott, Tony J. | Michaud, François

Article Type: Research Article

Abstract: Portacolone et al.’s Ethics Review highlights the ethical challenges associated with the implementation of telepresence devices and applications in the context of aging and dementia. In this response, we review ethical considerations as they relate to specific modalities of telepresence, with an emphasis on the continuum of potential interaction agents, from known individuals to fully automated and intelligent interlocutors. We further discuss areas in need of empirical evidence to inform regulatory efforts in telepresence. We close with a call for meaningful end-user engagement at all stages of technology development.

Keywords: Alzheimer’s disease, ethics, patient engagement, robotics, telepresence

DOI: 10.3233/JAD-200154

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2020

Authors: Rajji, Tarek K. | Bowie, Christopher R. | Herrmann, Nathan | Pollock, Bruce G. | Bikson, Marom | Blumberger, Daniel M. | Butters, Meryl A. | Daskalakis, Zafiris J. | Fischer, Corinne E. | Flint, Alastair J. | Golas, Angela C. | Graff-Guerrero, Ariel | Kumar, Sanjeev | Lourenco, Lillian | Mah, Linda | Ovaysikia, Shima | Thorpe, Kevin E. | Voineskos, Aristotle N. | Mulsant, Benoit H. | for the PACt-MD Study Group

Article Type: Research Article

Abstract: Background: By the time Alzheimer’s disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. Results: PACt-MD (Prevention of Alzheimer’s dementia with Cognitive …remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) and transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. Primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. Secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of biomarkers collected from the participants. Conclusion: PACt-MD is unique in combining brain stimulation and psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD. Show more

Keywords: Alzheimer’s disease and related disorders, cognitive remediation, major depressive disorder, mild cognitive disorder, PACt-MD, prevention, transcranial direct current stimulation, NCT02386670

DOI: 10.3233/JAD-200141

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

Authors: Lakey-Beitia, Johant | Burillo, Andrea M. | La Penna, Giovanni | Hegde, Muralidhar L. | Rao, K.S.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multi factorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-βprotein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing …its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, copper, iron, metal chelation therapy, metalloproteins, polyphenols, zinc

DOI: 10.3233/JAD-200185

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2020

Authors: van der Willik, Kimberly D. | Schagen, Sanne B. | Ikram, M. Arfan

Article Type: Short Communication

Abstract: There is an ongoing debate about how cancer and dementia relate to each other, and whether their relation is biologically determined or caused by surveillance and survival bias. We aimed to circumvent these biases by determining the relation between the tumor marker carcinoembryonic antigen (CEA) and the risk of dementia in 6,692 participants from the population-based Rotterdam Study. We found that higher levels of CEA were associated with a higher risk of dementia (HR per standard deviation increase in CEA = 1.11, 95% CI 1.04;1.18). This finding may indicate that cancer and dementia are positively associated, but the mechanisms underlying the relation …between CEA and dementia warrant further investigation. Show more

Keywords: Carcinoembryonic antigen, cohort studies, dementia, epidemiology

DOI: 10.3233/JAD-200440

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

Authors: Attademo, Luigi | Bernardini, Francesco

Article Type: Research Article

Abstract: As a global problem that has increasingly been causing worldwide concern, air pollution poses a significant and serious environmental risk to health. Risks of cardiovascular and respiratory diseases, as well as various types of cancer, have been consistently associated with the exposure to air pollutants. More recently, various studies have also shown that the central nervous system is also attacked by air pollution. Air pollution appears to be strongly associated with a higher risk of cognitive defects, neuro developmental (e.g., schizophrenia) and neurodegenerative (e.g., Alzheimer’s disease) disorders. Subjects with schizophrenia, as well as subjects with Alzheimer’s disease, experience a variety …of neuropsychological deficits and cognitive impairments. This determines an adverse effect on social and professional functioning, and it contributes to the long-term disease burden. However, no final conclusions have been drawn on the matter of the direct relationship between schizophrenia and Alzheimer’s disease. In recent years, the topic of urbanicity and mental health has become increasingly important. Urban exposure to environmental toxins and pollution is currently described as a reliable risk factor for schizophrenia and other psychoses, and it has been demonstrated more and more how exposure to air pollutants is associated with increased risk of dementia. Pathways by which air pollution can target and damage the brain, leading to an increased risk for developing schizophrenia and Alzheimer’s disease, are multiple and complex. Results from epidemiological studies suggest potential associations, but are still insufficient to confirm causality. Further studies are needed in order to verify this hypothesis. And if confirmed, the clinical implications could be of substantial relevance for both public and mental health. Show more

Keywords: Air pollution, Alzheimer’s disease, public health, schizophrenia

DOI: 10.3233/JAD-200289

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