Emerging biology of the cholinergic system across the spectrum of Alzheimer's disease

2006 ◽  
Vol 18 (s1) ◽  
pp. S3-S16 ◽  
Author(s):  
Agneta Nordberg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Imaging Techniques ◽  
Positron Emission Tomography Imaging ◽  
Amyloid Plaques ◽  
Hippocampal Volume ◽  
Brain Morphology

The pathological processes that lead to Alzheimer's disease (AD) begin decades before the onset of dementia. Brain abnormalities in genetically susceptible individuals have been observed even in young adults. Patients with AD differ from normal elderly patients in brain morphology and neurochemistry. Important observations include increasing appearance of amyloid plaques and neurofibrillary tangles, progressive loss of hippocampal volume, reduced cerebral glucose utilization, inflammatory processes, glial activation, and impairment of cholinergic function with losses of nicotinic acetylcholine receptors. These changes appear to begin in the asymptomatic stages and continue as cognition and then function and behavior are disrupted. Mild cognitive impairment (MCI) may be the first cognitive manifestation of this pathogenic process moderated by ongoing compensatory neurochemical mechanisms in the cholinergic system. Recent advances in positron emission tomography imaging techniques, including the development of the Pittsburgh B compound (PIB), allow in vivo visualization of amyloid plaques. These techniques have the potential to enable brain amyloid load to be monitored over time and to be related to brain function. Emerging evidence suggests that β-amyloid may interact with nicotinic receptors. This interaction may have clinically significant downstream effects and may mediate amyloid neurotoxicity. The cholinesterase inhibitors may have multiple actions, depending on the stage of the disease, from very mild to severe.

scholarly journals In vivo multi-parametric manganese-enhanced MRI for detecting amyloid plaques in rodent models of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eugene Kim ◽  
Davide Di Censo ◽  
Mattia Baraldo ◽  
Camilla Simmons ◽  
Ilaria Rosa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Transgenic Animals ◽  
Surrounding Tissue ◽  
Rodent Models ◽  
Enhanced Mri ◽  
5Xfad Mice ◽  
Manganese Enhanced Mri

AbstractAmyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

scholarly journals Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review

2018 ◽  
Vol 19 (12) ◽  
pp. 3702 ◽  
Author(s):  
Grazia Femminella ◽  
Tony Thayanandan ◽  
Valeria Calsolaro ◽  
Klara Komici ◽  
Giuseppe Rengo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Multimodal Imaging ◽  
Molecular Mechanisms ◽  
Imaging Techniques ◽  
Structural Mri ◽  
Imaging Biomarkers ◽  
Significant Burden ◽  
Made In

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice.

In Vivo Magnetic Resonance of Amyloid Plaques in Alzheimer’s Disease Model Mice

2004 ◽  
pp. 47-59 ◽  
Author(s):  
Einar M. Sigurdsson ◽  
Youssef Zaim Wadghiri ◽  
Marcin Sadowski ◽  
James I. Elliott ◽  
Yongsheng Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Magnetic Resonance ◽  
Disease Model ◽  
Amyloid Plaques

scholarly journals Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline

Neurology ◽  
2017 ◽  
Vol 89 (21) ◽  
pp. 2176-2186 ◽  
Author(s):  
Shannon L. Risacher ◽  
Wesley H. Anderson ◽  
Arnaud Charil ◽  
Peter F. Castelluccio ◽  
Sergey Shcherbinin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Function ◽  
Alzheimer Disease ◽  
Volume Ratio ◽  
Hippocampal Volume ◽  
Disease Assessment ◽  
Clinical Dementia Rating ◽  
Categorical Models

Objective:To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline.Methods:Amyloid-positive participants with AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models.Results:When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy.Conclusions:AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.

scholarly journals Association of Carotid and Intracranial Stenosis with Alzheimer’s Disease Biomarkers

2020 ◽  
Author(s):  
Koung Mi Kang ◽  
Min Soo Byun ◽  
Jun Ho Lee ◽  
Dahyun Yi ◽  
Hye Jeong Choi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Volume ◽  
Artery Stenosis ◽  
Intracranial Artery ◽  
Positron Emission ◽  
Intracranial Artery Stenosis ◽  
Intracranial Arteries ◽  
Demographic Covariates

Abstract Background To clarify whether atherosclerosis of the carotid and intracranial arteries is related to Alzheimer’s disease (AD) pathology in vivo, we investigated the associations of carotid and intracranial artery stenosis with cerebral beta-amyloid (Aβ) deposition and neurodegeneration in middle- and old-aged individuals. Given the differential progression of Aβ deposition and neurodegeneration across clinical stages of AD, we focused separately on cognitively normal (CN) and cognitively impaired (CI) groups.Methods A total of 281 CN and 199 CI (mild cognitive impairment and AD dementia) subjects underwent comprehensive clinical assessment, [11C] Pittsburgh Compound B positron emission tomography, and magnetic resonance (MR) imaging including MR angiography. We evaluated extracranial carotid and intracranial arteries for the overall presence, severity (i.e. number and degree of narrowing) and location of stenosis.Results We found no associations between carotid and intracranial artery stenosis and cerebral Aβ burden in either CN or CI group. In terms of AD-related neurodegeneration, exploratory univariate analyses showed associations between the presence and severity of stenosis and neurodegeneration biomarkers of AD (i.e. reduced hippocampal volume [HV] and cortical thickness in the AD-signature regions) in both CN and CI groups. In confirmatory multivariate analyses controlling for demographic covariates and diagnosis, the association between number of stenotic intracranial arteries ≥ 2 and reduced HV in the CI group remained significant.Conclusions Neither carotid nor intracranial artery stenosis appears to be associated with brain Aβ burden, while intracranial artery stenosis is related to amyloid-independent neurodegeneration, particularly hippocampal atrophy. These observations support the importance of proper management of intracranial artery stenosis for delaying the progression of AD neurodegeneration and related cognitive decline.

scholarly journals Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Andrew A. Badachhape ◽  
Peter K. Working ◽  
Mayank Srivastava ◽  
Prajwal Bhandari ◽  
Igor V. Stupin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Contrast Agent ◽  
Amyloid Plaques ◽  
High Sensitivity ◽  
Model Of Alzheimer’S Disease ◽  
Pegylated Nanoparticles ◽  
Dose Ranging ◽  
Dose Levels

Abstract In these preclinical studies, we describe ADx-001, an Aβ-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast agent such as ADx-001 is attractive because of the lack of radioactivity, ease of distribution, long shelf life, and the prevalence of MRI scanners. Dose-ranging efficacy studies were performed on a 1 T MRI scanner using a transgenic APP/PSEN1 mouse model of Alzheimer’s disease. ADx-001 was tested at 0.10, 0.15, and 0.20 mmol Gd/kg. Gold standard post-mortem amyloid immunostaining was used for the determination of sensitivity and specificity. ADx-001 toxicity was evaluated in rats and monkeys at doses up to 0.30 mmol Gd/kg. ADx-001 pharmacokinetics were determined in monkeys and its tissue distribution was evaluated in rats. ADx-001-enhanced MRI demonstrated significantly higher (p < 0.05) brain signal enhancement in transgenic mice relative to wild type mice at all dose levels. ADx-001 demonstrated high sensitivity at 0.20 and 0.15 mmol Gd/kg and excellent specificity at all dose levels for in vivo imaging of β amyloid plaques. ADx-001 was well tolerated in rats and monkeys and exhibited the slow clearance from circulation and tissue biodistribution typical of PEGylated nanoparticles.

A Multifunctional Chemical Agent as an Attenuator of Amyloid and Tau Burden and Neuroinflammation in Alzheimer’s Disease

2019 ◽  
Author(s):  
Hong-Jun Cho ◽  
Anuj K. Sharma ◽  
Ying Zhang ◽  
Michael L. Gross ◽  
Liviu M. Mirica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Binding ◽  
Amyloid Plaques ◽  
Chemical Agent ◽  
Aβ Oligomers ◽  
Neuroinflammatory Response ◽  
Aβ Aggregation ◽  
5Xfad Mice

<div>Alzheimer’s disease (AD) is the most common neurodegenerative degenerative disease, and its main hallmark is the deposition of amyloid beta (Aβ) peptides. However, several clinical trials focusing on Aβ-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein pathology, Aβ-metal induced oxidative stress, and neuroinflammation. To address these different pathological aspects of AD, we have employed a multifunctional compound (MFC) L1 that integrates Aβ-interacting and metal-binding functional groups in a single molecular framework. By perturbing the interactions between the Aβ species and metal ions during the Aβ aggregation process, L1 alleviates the formation of neurotoxic Aβ oligomers and promotes the formation of nontoxic, amorphous Aβ aggregates. Furthermore, the significant antioxidant activity and strong metal chelating ability of L1 are operating cooperatively to rescue neuroblastoma N2A cells from Cu2+-induced Aβ neurotoxicity. Along with in vivo Aβ-binding and favorable BBB permeability properties, the treatment of transgenic 5xFAD mice with L1 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates in the brain by 40–50% versus the vehicle-treated 5xFAD mice. Besides, L1 mitigates the neuroinflammatory response of the activated microglia during the Aβ-induced inflammation process. Overall, these results suggest that L1 not only efficiently attenuates the formation of amyloid plaques and p-tau aggregates in vivo, but also reduces the microgliamediated neuroinflammatory response, which is quite uncommon among the previously reported amyloid-targeting chemical agents, and thus L1 could be envisioned as a lead compound for the development of novel AD therapeutics.</div>

99mTc-labeled Small Molecules for Diagnosis of Alzheimer’s Disease: Past, Recent and Future Perspectives

2019 ◽  
Vol 26 (12) ◽  
pp. 2166-2189 ◽  
Author(s):  
Sajjad Molavipordanjani ◽  
Saeed Emami ◽  
Seyed Jalal Hosseinimehr
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Early Stage ◽  
Amyloid Plaques ◽  
Design Synthesis ◽  
Future Studies ◽  
Age Related ◽  
Derivatives Of

Background: Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease. Its prominent hallmarks are extracellular deposition of β-amyloids (amyloid plaques), intracellular neurofibrillary tangles (NTFs), neurodegeneration and finally loss of cognitive function. Hence, AD diagnosis in the early stage and monitoring of the disease are of great importance. Methods: In this review article, we have reviewed recent efforts for design, synthesis and evaluation of 99mTc labeled small molecule for AD imaging purposes. Results: These small molecules include derivatives of Congo red, benzothiazole, benzofuran, benzoxazole, naphthalene, biphenyl, chalcone, flavone, aurone, stilbene, curcumin, dibenzylideneacetone, quinoxaline, etc. The different aspects of 99mTc-labeled small molecules including chemical structure, their affinity toward amyloid plaques, BBB permeation and in vivo/vitro stability will be discussed. Conclusion: The findings of this review confirm the importance of 99mTc-labeled small molecules for AD imaging. Future studies based on the pharmacophore of these designed compounds are needed for improvement of these molecules for clinical application.

Sign in / Sign up

Export Citation Format

Share Document