Journal of Alzheimer's Disease Reports - Volume 3, issue 1

Authors: Kar, Subrata | Majumder, D. Dutta

Article Type: Research Article

Abstract: This study examined early detection of Alzheimer’s disease (AD) by diffusion tensor visualization-based methodology and neuro-fuzzy tools. Initially, we proposed a model for the early detection of AD using the measurement of apparent diffusion coefficient, fractional anisotropy, and gray matter, which can determine neurological disorder patterns and abnormalities in brain white matter. These are used as input parameters into fuzzy tools, and using fuzzy rules, we evaluate the AD score as an output variable that provides a useful platform to physicians in determining the status of the disease. In the second stage, we present an investigative study on AD and …used the neuro-fuzzy classification system for pattern recognition of either AD or healthy control. The experimental results are from 20 samples (14 for training, 3 for validation, and 3 for testing) used in an artificial neural network classification system. The neural network is trained with a training algorithm and the performance of the training algorithm is obtained by executing a fuzzy expert system. Out of 20 patients, 9 are AD patients and 11 are healthy control patients. We present a neuro-fuzzy tool as a better classifier for early detection of AD and obtain a satisfactory performance with 100% accuracy. Show more

Keywords: Alzheimer’s disease, apparent diffusion coefficient, diffusion tensor imaging, fractional anisotropy, gray matter, neuro-fuzzy classification system

DOI: 10.3233/ADR-180082

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 1-18, 2019

Authors: Gandbhir, Omkar | Sundaram, Pazhani

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia among elderly patients afflicted by neurodegenerative diseases, caused by the accumulation of amyloid-β (Aβ). Therapeutic interventions in targeting and restricting Aβ production resulted in little or no success. However, recent studies have shown signs of success in validating Aβ as a target. Recombinant Technologies LLC (RTL) has developed and studied its proprietary Amytrap peptide to remove Aβ from circulation which in turn depletes brain Aβ in a clinically relevant mouse model of AD. In the current study, this Amytrap peptide (the active pharmacological ingredient, API) has been linked to sepharose …matrix by click chemistry. The derivative namely ‘Amytrapper’ was confirmed to remove Aβ from the surrounding media spiked with Aβ42 . Additional testing performed on Amytrapper with sera and plasma containing Aβ42 showed retention of Aβ42 upon increasing concentrations of biotinylated Aβ42 (bio-Aβ42 ). Specificity of this binding was confirmed via 1) pre-blocking Amytrapper with cold (unbiotinylated) Aβ42 followed by binding experiment with biotinylated Aβ42 , 2) 2-dimensional SDS-PAGE analyses on samples harvested before and after the binding experiment, and 3) reconciling the amounts bound to beads and left over in the flow through. The results provide a proof of concept for our proposed prototype design for an Amytrapper device. The results suggest that extracorporeal clearance of Aβ42 by Amytrapper could be a way to manage accumulation of amyloid in AD and thus could become an added mode of therapy for disease modification. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β peptides, Amytrapper, extracorporeal, plasmapheresis, Alzheimer’s therapy

DOI: 10.3233/ADR-180093

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 19-29, 2019

Authors: Prato, Frank S. | Pavlosky, William F. | Foster, Steven C. | Thiessen, Jonathan D. | Beaujot, Roderic P.

Article Type: Review Article

Abstract: Significant advances in positron emission tomography (PET) and magnetic resonance imaging (MRI) brain imaging in the early detection of dementia indicate that hybrid PET/MRI would be an effective tool to screen for dementia in the population living with lifestyle risk factors. Here we investigate the associated costs and benefits along with the needed imaging infrastructure. A demographic analysis determined the prevalence of dementia and its incidence. The expected value of the screening program was calculated assuming a sensitivity and specificity of 0.9, a prevalence of 0.1, a QALY factor of 0.348, a willingness to pay $114,000 CAD and the cost …per PET/MRI scan of $2,000 CAD. It was assumed that each head PET/MRI could screen 3,000 individuals per year. The prevalence of dementia is increasing by almost two-fold every 20 years due to the increased population at ages where dementia is more prevalent. It has been shown that a five-year delay in the incidence of dementia would decrease the prevalence by some 45%. In Canada, a five-year delay corresponds to a health care savings of $27,000 CAD per subject per year. The expected value for screening was estimated at $23,745 CAD. The number of subjects to be screened per year in Canada, USA, and China between 60 and 79 was 11,405,000. The corresponding number of head-only hybrid PET/MRI systems needed is 3,800. A brain PET/MRI screening program is financially justifiable with respect to health care costs and justifies the continuing development of MRI compatible brain PET technology. Show more

Keywords: Brain PET, dementia demographics, dementia screening, hybrid PET/MRI, lifestyle risks, magnetic resonance imaging, MRI-compatible PET, positron emission tomography

DOI: 10.3233/ADR-180098

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 31-45, 2019

Authors: Gamir-Morralla, Andrea | Sacristán, Sandra | Medina, Miguel | Iglesias, Teresa

Article Type: Research Article

Abstract: The nematode Caenorhabditis elegans (C. elegans) is a powerful model organism to study lifespan and aging, protein aggregation, and neurodegeneration, as well as to carry out drug screenings. The C. elegans strain aex-3 /T337 expresses human pathogenic V337M mutant tau under a pan-neuronal promoter and presents uncoordinated locomotion, accumulation of phosphorylated insoluble tau, and shortened lifespan. Herein we have used this strain to assay two compounds that could affect tau aggregation and/or phosphorylation, and looked for phenotypic changes in their lifespan and motility. The first compound is Thioflavin T (ThT), a member of the tetracycline family with protein …antiaggregant properties, yet to be tested in a tauopathy model. The second is a novel small molecule, NP103, a highly selective inhibitor of glycogen synthase kinase-3 (GSK-3), the main kinase contributing to pathogenic tau hyperphosphorylation. Importantly, we find that ThT extends lifespan of aex-3 /T337 worms as it does with control N2 animals, showing both strains similar locomotion features under this treatment. By contrast, NP103 improves the paralysis phenotype of aex-3 /T337 mutants but not their lifespan. Our results show that both treatments present beneficial effects for this model of tauopathy and encourage pursuing further investigations on their therapeutic potential for AD and other tauopathies. Show more

Keywords: Aging, Alzheimer’s disease, C. elegans, GSK-3, tau, tauopathy, Thioflavin T

DOI: 10.3233/ADR-180087

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 47-57, 2019

Authors: Das, Tushar Kanti | Chakrabarti, Swarup Kumar | Zulkipli, Ihsan Nazurah | Abdul Hamid, Mas R.W.

Article Type: Research Article

Abstract: To date, dysregulation of the insulin signaling pathway in the brain has not been demonstrated unequivocally in Alzheimer’s disease (AD). The purpose of the study was to examine the possible dysregulation of insulin signaling pathway in an AD rat model. Furthermore, the present study investigated the effect of Donepezil and Curcumin on insulin signaling, insulin, and glucose levels in AD rat brain. The rats were induced to develop AD by intraperitoneal administration of Scopolamine. We found that glucose levels in plasma and brain were decreased in AD rats, whereas the insulin levels was increased in plasma but decreased in brain …in AD rats. In addition, insulin signaling proteins IR-β, IGF-1, IRS-1, IRS-2 p-Akt (Ser473), and Akt were markedly reduced in the AD rats. Furthermore, GLUT3 and GLUT4 levels in the brain were markedly reduced in AD rats. All these data were compared to Saline-treated control rats. Curcumin significantly increased glucose levels in plasma and in brain. However, insulin levels was decreased in plasma and was increased in AD rats’ brain. Moreover, GLUT3 and GLUT4 levels were significantly increased in Curcumin-treated AD rats. All these data were compared to Scopolamine– induced AD rats. Thus amelioration of impaired insulin signaling and improved glucose regulation in AD rats by Curcumin may be beneficial in the management of AD. Show more

Keywords: Alzheimer’s disease, curcumin, donepezil, glucose receptors, insulin signaling

DOI: 10.3233/ADR-180091

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 59-70, 2019

Authors: Smalheiser, Neil R.

Article Type: Short Communication

Abstract: Mining the case report literature identified an intriguing, yet neglected finding: Deoxyribonuclease I (DNase I) as a possible treatment for Alzheimer’s disease. This finding is speculative, both because it is based on one patient, and because the underlying mechanism(s) of action remain obscure. However, further literature review revealed that there are several plausible mechanisms by which DNase I might affect the course of Alzheimer’s disease. Given that DNase I is an FDA-approved drug, with extensive studies in both animals and man in the context of other diseases, I suggest that investigation of DNAse I in Alzheimer’s disease is worthwhile.

Keywords: Case reports, Deoxyribonuclease I, incidental findings, literature-based discovery, lucidity, lucid dreaming, drug repurposing

DOI: 10.3233/ADR-190100

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 71-76, 2019

Authors: Gandbhir, Omkar | Sundaram, Pazhani

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. Amyloid-β (Aβ42 ) is implicated in AD pathogenesis. We have designed a non-immune based proprietary therapeutic, called Amytrap, a conjugate containing a retro-inverso peptide, polyethylene glycol, and human serum albumin. Amytrap not only binds Aβ42 but also prevents and dissociates aggregated Aβ42 . Amytrap binds to the region in Aβ42 known to trigger its self-aggregation, thus disrupting aggregation. We have obtained proof of concept on AmyTrap in a clinically relevant mouse model, namely, AD-APPSWE/Tg2576. We synthesized and characterized Amytrap and confirmed its authenticity. Efficacy evaluations were performed on …young (5 months) and old (9 months) model mice. Amytrap was injected biweekly for a period of five months. Pharmacokinetics and safety toxicology were assessed in normal mice and rats, respectively. Post treatment, younger mice showed significant improvements in cognition and Aβ42 levels in plasma, brain, and cerebrospinal fluid, while older mice showed less significant benefits. Immunohistochemistry of brain sections showed similar differences between young and old mice. They all had diminished size and number of plaques in the brain of Amytrap-treated mice. Further, treated mice did not develop antibodies to Amytrap, suggesting Amytrap is non-immunogenic. Safety toxicological studies in rats showed that Amytrap was well tolerated and therefore safe (even at 50 X the efficacy dose). Stability tests showed Amytrap is stable at 4°C for up to one year. Efficacy and safety features make Amytrap a promising candidate for treating or modulating AD. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β binder, Amytrap, efficacy, peptide, retro inverso peptide, therapy, toxicology

DOI: 10.3233/ADR-190107

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 77-94, 2019

Authors: Manzano Palomo, Maria Sagrario | Anaya Caravaca, Belen | Balsa Bretón, Maria Angeles | Castrillo, Sergio Muñiz | Vicente, Asuncion de la Morena | Castro Arce, Eduardo | Alves Prez, María Teresa

Article Type: Research Article

Abstract: Background: Previous studies have shown that Souvenaid (medical food) can have benefits on memory, cognition, and function in early Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Objective: Demonstrate that Souvenaid could improve or maintain cognition and has an effect on neurodegeneration biomarkers. Methods: This cohort study was carried out from June 2015 through December 2016 in the Neurology Department, Infanta Cristina Hospital, Madrid, Spain. MCI-HR-AD were recruited using Petersen criteria, neuropsychology (NPS), and 18 F-FDG PET scans to confirm the high risk of progression to dementia with one year of follow-up. Age, sex, vascular risk …factors (VRF), and NPS values (Barcelona brief version) were analyzed. 18 F-FDG PET scans were analyzed as a visual procedure. The study was approved by the Research Committee of ICH. Statistical analysis was made with SPSS 22.0 version. Results: Subjects included 43 MCI patients (58.5% women; mean age 69.78±7.89): 17 receiving Souvenaid® treatment (ST), 24 receiving no treatment (WT) and 2 who withdrew. No differences were seen in VRF, only hypercholesterolemia, and were less prevalent in the ST group (p  = 0.002). The rate of progression to dementia was 48.8% (no differences between groups, p  = 0.654). A second round of 18 F-FDG PET scans showed a significance worsening of glucose metabolism in WT (p  = 0.001) versus ST, in which it was low (p  = 0.050). For NPS testing, there was a significant worsening in memory performance in the WT group (p  = 0.011) and a stabilization in ST (p  = 0.083), as well as in executive functions and attention (worsening in WT, p  = 0.014). For the Subjective Changing Scale (SCS), caregivers indicated a stabilization/improvement in ST (p  = 0.017). Conclusion: Souvenaid had a significant effect on several cognitive domains, and on SCS in patients with MCI-HR-AD. Its intervention had an impact on preservation on 18 F-FDG PET scans. Show more

Keywords: Alzheimer’s disease, 18F-FDG PET scans, mild cognitive impairment, neuropsychology, Souvenaid®

DOI: 10.3233/ADR-190109

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 95-102, 2019

Authors: Pasquini, Lorenzo | Rahmani, Farzaneh | Maleki-Balajoo, Somayeh | La Joie, Renaud | Zarei, Mojtaba | Sorg, Christian | Drzezga, Alexander | Tahmasian, Masoud

Article Type: Review Article

Abstract:  The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer’s disease (AD). We have reviewed the spatiotemporal patterns of amyloid-β and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-β plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-β …and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-β pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events. Show more

Keywords: Alzheimer’s disease, amyloid-β , default mode network, disconnection, hyperexcitability, medial temporal lobe, mild cognitive impairment, posteromedial cortex, tau

DOI: 10.3233/ADR-190121

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 103-112, 2019

Authors: Guix, Francesc X. | Sartório, Carmem L. | ILL-Raga, Gerard

Article Type: Review Article

Abstract:  Human life unfolds not only in time and space, but also in the recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered under pathological conditions such as Alzheimer’s disease, which affects millions of people worldwide. Unfortunately, no effective cure exists to prevent this disorder, the impact of which will rise alarmingly within the next decades. While Alzheimer’s disease is largely considered to be the outcome of amyloid-β (Aβ) peptide accumulation in the brain, conceiving this complex disorder strictly as the result of Aβ-neurotoxicity is perhaps a …too straight-line simplification. Instead, complementary to this view, the tableau of molecular disarrangements in the Alzheimer’s disease brain may be reflecting, at least in part, a loss of function phenotype in memory processing. Here we take BACE1 translation and degradation as a gateway to study molecular mechanisms putatively involved in the transition between memory and neurodegeneration. BACE1 participates in the excision of Aβ-peptide from its precursor holoprotein, but plays a role in synaptic plasticity too. Its translation is governed by eIF2α phosphorylation: a hub integrating cellular responses to stress, but also a critical switch in memory consolidation. Paralleling these dualities, the eIF2α -kinase HRI has been shown to be a nitric oxide-dependent physiological activator of hippocampal BACE1 translation. Finally, beholding BACE1 as a representative protease active in the CNS, we venture a new perspective on the cellular basis of memory, which may incorporate neurodegeneration in itself as a drift in memory consolidating systems. Show more

Keywords: Alzheimer’s disease, β-secretase, eIF2α, exosomes, heme-regulated eIF-2α kinase, memory, nitric oxide, physiological stress response, proteolysis, translation initiation

DOI: 10.3233/ADR-180089

Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 113-148, 2019