scholarly journals The Retinal Inner Plexiform Synaptic Layer Mirrors Grey Matter Thickness of Primary Visual Cortex with Increased Amyloid β Load in Early Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Lília Jorge ◽  
Nádia Canário ◽  
Ricardo Martins ◽  
Beatriz Santiago ◽  
Isabel Santana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Primary Visual Cortex ◽  
Early Stage ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Binding Potential ◽  
Inner Plexiform Layer ◽  
Pet Tracer

The retina may serve as putative window into neuropathology of synaptic loss in Alzheimer’s disease (AD). Here, we investigated synapse-rich layers versus layers composed by nuclei/cell bodies in an early stage of AD. In addition, we examined the associations between retinal changes and molecular and structural markers of cortical damage. We recruited 20 AD patients and 17 healthy controls (HC). Combining optical coherence tomography (OCT), magnetic resonance (MR), and positron emission tomography (PET) imaging, we measured retinal and primary visual cortex (V1) thicknesses, along with V1 amyloid β (Aβ) retention ([11C]-PiB PET tracer) and neuroinflammation ([11C]-PK11195 PET tracer). We found that V1 showed increased amyloid-binding potential, in the absence of neuroinflammation. Although thickness changes were still absent, we identified a positive association between the synapse-rich inner plexiform layer (IPL) and V1 in AD. This retinocortical interplay might reflect changes in synaptic function resulting from Aβ deposition, contributing to early visual loss.

scholarly journals Posterior cortical atrophy: A rare variant of Alzheimer’s disease

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Michael A. Meyer ◽  
Stephen A. Hudock
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Primary Visual Cortex ◽  
Photon Emission ◽  
Occipital Cortex ◽  
Cortical Atrophy ◽  
Emission Computed Tomography ◽  
Posterior Cortical Atrophy ◽  
Homonymous Hemianopsia

Posterior cortical atrophy is a rare condition first described in 1988 involving progressive degeneration and atrophy of the occipital cortex, often recognized after an unexplained homonymous hemianopsia may be discovered. We report a case in association with Alzheimer’s disease in a 77-year-old female, who underwent brain single-photon emission computed tomography as well brain positron emission tomography using Florbetapir to further evaluate progressive cognitive decline. The patient had also been followed in Ophthalmology for glaucoma, where a progressive unexplained change in her visual field maps were noted over one year consistent with a progressive right homonymous hemianopsia. This rare combination of findings in association with her dementia led to a detailed review of all her imaging studies, concluding with the surprising recognition for a clear hemi-atrophy of the primary left occipital cortex was occurring, consistent with Alzheimer’s disease affecting the primary visual cortex. Further awareness of this disease pattern is needed, as Alzheimer’s disease typically does not affect the primary visual cortex; other conditions to consider in general include Lewy Body dementia, cortico-basal degeneration and prion disease.

scholarly journals Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3261
Author(s):  
Xiao Liu ◽  
Qian Zhou ◽  
Jia-He Zhang ◽  
Xiaoying Wang ◽  
Xiumei Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Disease Model ◽  
Amyloid Β ◽  
Brain Lesions ◽  
Synaptic Dysfunction ◽  
Synaptic Loss ◽  
And Function ◽  
The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

scholarly journals Astrocytes and Adenosine A2A Receptors: Active Players in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Cátia R. Lopes ◽  
Rodrigo A. Cunha ◽  
Paula Agostinho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Elderly ◽  
Synaptic Function ◽  
Morphological Alterations ◽  
Functional Changes ◽  
A2a Receptors ◽  
Novel Therapeutic Strategies

Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A1R and A2AR subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A2AR, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A2AR levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A2AR in astrocytes function might shed light on novel therapeutic strategies for AD.

PET Imaging of Tau Pathology and Amyloid-β, and MRI for Alzheimer’s Disease Feature Fusion and Multimodal Classification

2021 ◽  
pp. 1-18
Author(s):  
Mehdi Shojaie ◽  
Solale Tabarestani ◽  
Mercedes Cabrerizo ◽  
Steven T. DeKosky ◽  
David E. Vaillancourt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Feature Selection ◽  
Mutual Information ◽  
Feature Fusion ◽  
Early Stage ◽  
Model Performance ◽  
Amyloid Β ◽  
Feature Ranking ◽  
Promising Tool

Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to capture the redundancy and complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer’s Disease with APP Osaka Mutation

2020 ◽  
Vol 21 (12) ◽  
pp. 4443
Author(s):  
Hiroyuki Shimada ◽  
Shinobu Minatani ◽  
Jun Takeuchi ◽  
Akitoshi Takeda ◽  
Joji Kawabe ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
Neuronal Degeneration ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Familial Alzheimer’S Disease ◽  
Pet Tracer ◽  
Familial Alzheimer's Disease ◽  
Parietal Cortices

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer’s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer’s disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.

scholarly journals Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shorena Janelidze ◽  
Erik Stomrud ◽  
Ruben Smith ◽  
Sebastian Palmqvist ◽  
Niklas Mattsson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Pet Tracer ◽  
Positron Emission ◽  
Diagnostic Work ◽  
Work Up ◽  
The Brain ◽  
Better Than

AbstractCerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

Alzheimer’s Disease Amyloid β-Protein and Synaptic Function

2009 ◽  
Vol 12 (1) ◽  
pp. 13-26 ◽  
Author(s):  
Tomas Ondrejcak ◽  
Igor Klyubin ◽  
Neng-Wei Hu ◽  
Andrew E. Barry ◽  
William K. Cullen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Amyloid Β Protein ◽  
Β Protein

scholarly journals Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow Is Linked to Alzheimer's Pathology

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 637-638
Author(s):  
Feng Han ◽  
Jing Chen ◽  
Aaron Belkin-Rosen ◽  
Yameng Gu ◽  
Liying Luo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Resting State ◽  
Early Stage ◽  
Adult Population ◽  
Critical Role ◽  
Low Frequency ◽  
Amyloid Β ◽  
Blood Oxygenation

Abstract Alzheimer’s disease (AD) is the most common cause of dementia in the old adult population. AD pathogenesis has been linked to the aggregation of toxic proteins, e.g., amyloid-β and tau. The glymphatic system may play an important role in clearing out these proteins via cerebrospinal fluid (CSF) flows through perivascular and interstitial spaces. Recent studies have suggested low-frequency (<0.1 Hz), sleep-dependent global blood-oxygenation-dependent-level (gBOLD; global resting-state functional MRI signal) during resting state is coupled with CSF movements, suggesting their potential link to glymphatic function. Here, we directly investigated whether the coupling between the gBOLD and CSF signals is related to AD-related pathology. By analyzing neuroimaging, neurobiological, and neuropsychological data from 118 human subjects (58-90 years of age; AD, early-stage AD, and control subjects included) collected in the Alzheimer's Disease Neuroimaging Initiative project, we found a strong coupling between the gBOLD and CSF signals. More importantly, the strength of this gBOLD-CSF coupling was significantly correlated with cortical amyloid-β level (p = 0.019), cognitive decline in the subsequent two years (p = 0.013), disease severity (p = 0.035), and several AD-related risk factors, including aging (p = 0.011), and gender (p = 0.026). These findings provide initial evidence for the critical role of resting-state low-frequency (<0.1 Hz) neural/physiological dynamics in AD pathology. They also suggest that the gBOLD-CSF coupling may serve as a non-invasive imaging marker for gauging the glymphatic function.

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