scholarly journals Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease

2018 ◽  
Vol 115 (6) ◽  
pp. E1289-E1298 ◽  
Author(s):  
Rachel E. Bennett ◽  
Ashley B. Robbins ◽  
Miwei Hu ◽  
Xinrui Cao ◽  
Rebecca A. Betensky ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Blood Vessel ◽  
Cell Biology ◽  
The Elderly ◽  
Brain Regions ◽  
Cortical Atrophy ◽  
Vascular Abnormalities ◽  
Alzheimer Pathology

Mixed pathology, with both Alzheimer’s disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer’s disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain’s microvasculature.

scholarly journals Autoregulation of Cerebral Blood Flow to Changes in Arterial Pressure in Mild Alzheimer's Disease

2010 ◽  
Vol 30 (11) ◽  
pp. 1883-1889 ◽  
Author(s):  
Allyson R Zazulia ◽  
Tom O Videen ◽  
John C Morris ◽  
William J Powers
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Arterial Pressure ◽  
The Elderly ◽  
Local Defect ◽  
Clinical Dementia Rating ◽  
Positron Emission ◽  
Before And After

Studies in transgenic mice overexpressing amyloid precursor protein (APP) demonstrate impaired autoregulation of cerebral blood flow (CBF) to changes in arterial pressure and suggest that cerebrovascular dysfunction may be critically important in the development of pathological Alzheimer's disease (AD). Given the relevance of such a finding for guiding hypertension treatment in the elderly, we assessed autoregulation in individuals with AD. Twenty persons aged 75±6 years with very mild or mild symptomatic AD (Clinical Dementia Rating 0.5 or 1.0) underwent 15O-positron emission tomography (PET) CBF measurements before and after mean arterial pressure (MAP) was lowered from 107±13 to 92±9 mm Hg with intravenous nicardipine; 11C-PIB-PET imaging and magnetic resonance imaging (MRI) were also obtained. There were no significant differences in mean CBF before and after MAP reduction in the bilateral hemispheres (−0.9±5.2 mL per 100 g per minute, P=0.4, 95% confidence interval (CI)=−3.4 to 1.5), cortical borderzones (−1.9±5.0 mL per 100 g per minute, P=0.10, 95% CI=−4.3 to 0.4), regions of T2W-MRI-defined leukoaraiosis (−0.3±4.4 mL per 100 g per minute, P=0.85, 95% CI=−3.3 to 3.9), or regions of peak 11C-PIB uptake (−2.5±7.7 mL per 100 g per minute, P=0.30, 95% CI=−7.7 to 2.7). The absence of significant change in CBF with a 10 to 15 mm Hg reduction in MAP within the normal autoregulatory range demonstrates that there is neither a generalized nor local defect of autoregulation in AD.

scholarly journals Cortical Microstructural Alterations in Mild Cognitive Impairment and Alzheimer’s Disease Dementia

2020 ◽  
Vol 30 (5) ◽  
pp. 2948-2960 ◽  
Author(s):  
Nicholas M Vogt ◽  
Jack F Hunt ◽  
Nagesh Adluru ◽  
Douglas C Dean ◽  
Sterling C Johnson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cortical Thickness ◽  
Gray Matter ◽  
Brain Regions ◽  
Cortical Atrophy ◽  
Microstructural Alterations ◽  
Additional Information

Abstract In Alzheimer’s disease (AD), neurodegenerative processes are ongoing for years prior to the time that cortical atrophy can be reliably detected using conventional neuroimaging techniques. Recent advances in diffusion-weighted imaging have provided new techniques to study neural microstructure, which may provide additional information regarding neurodegeneration. In this study, we used neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion model, in order to investigate cortical microstructure along the clinical continuum of mild cognitive impairment (MCI) and AD dementia. Using gray matter-based spatial statistics (GBSS), we demonstrated that neurite density index (NDI) was significantly lower throughout temporal and parietal cortical regions in MCI, while both NDI and orientation dispersion index (ODI) were lower throughout parietal, temporal, and frontal regions in AD dementia. In follow-up ROI analyses comparing microstructure and cortical thickness (derived from T1-weighted MRI) within the same brain regions, differences in NODDI metrics remained, even after controlling for cortical thickness. Moreover, for participants with MCI, gray matter NDI—but not cortical thickness—was lower in temporal, parietal, and posterior cingulate regions. Taken together, our results highlight the utility of NODDI metrics in detecting cortical microstructural degeneration that occurs prior to measurable macrostructural changes and overt clinical dementia.

scholarly journals Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8014
Author(s):  
Sudip Dhakal ◽  
Ian Macreadie
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stress Responses ◽  
Cell Biology ◽  
Neurodegenerative Disorder ◽  
The Elderly ◽  
Yeast Cells ◽  
Yeast Genome ◽  
Protein Homeostasis ◽  
Age Related

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD.

scholarly journals Predicting Brain Regions Related to Alzheimer’s Disease Based on Global Feature

2020 ◽  
Author(s):  
Qi Wang ◽  
Siwei Chen ◽  
He Wang ◽  
Luzeng Chen ◽  
Yongan Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Network Analysis ◽  
Diffusion Tensor ◽  
The Elderly ◽  
Brain Regions ◽  
Imaging Method ◽  
Global Feature ◽  
Objective Monitoring ◽  
The Brain

AbstractAlzheimer’s disease (AD) is a common neurodegenerative disease in the elderly, early diagnosis and timely treatment are very important to delay the course of the disease. In the past, most of the brain regions related to AD were identified based on the imaging method, which can only identify some atrophic brain regions. In this work, we used mathematical models to find out the potential brain regions related to AD. First, diffusion tensor imaging (DTI) was used to construct the brain structural network. Next, we set a new local feature index 2hop-connectivity to measure the correlation among different areas. And for this, we proposed a novel algorithm named 2hopRWR to measure 2hop-connectivity. At last, we proposed a new index GFS (Global Feature Score) based on global feature by combing 5 local features: degree centrality, betweenness centrality, closeness centrality, the number of maximal cliques, and 2hop-connectivity, to judge which brain regions are likely related to Alzheimer’s Disease. As a result, all the top ten brain regions in GFS scoring difference between the AD group and the non-AD group were related to AD by literature verification. Finally, the results of the canonical correlation analysis showed that the GFS was significantly correlated with the scores of the mini-mental state examination (MMSE) scale and montreal cognitive assessment (MoCA) scale. So, we believe the GFS can also be used as a new index to assist in diagnosis and objective monitoring of disease progression. Besides, the method proposed in this paper can be used as a differential network analysis method in other areas of network analysis.

HSV1 in Alzheimer’s disease: Myth or reality?

2011 ◽  
Vol 2 (1) ◽  
Author(s):  
Tea Špeljko ◽  
David Jutric ◽  
Goran Šimić
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex ◽  
The Elderly ◽  
Significant Degree ◽  
Brain Regions ◽  
Protein Accumulation ◽  
Amyloid Beta Protein ◽  
High Prevalence ◽  
Simplex Virus

AbstractAlzheimer’s disease (AD) is the most frequent cause of dementia in the elderly, characterized by the presence of cerebral amyloid plaques and neurofibrillary tangles. The causes of the disease are not well understood, especially considering that more than 95% of AD patients are non-familial. Due to the similarity of brain regions affected in herpes simplex encephalitis to those mainly affected in AD, and owing to the very high prevalence of latent herpes simplex virus type 1 (HSV1) infection, reactivation of HSV1 was proposed as one of the possible causes of AD. The trigeminal ganglion, located only a few millimeters from the entorhinal cortex, is the primary site of HSV1 latency, although other sites including the sensory neurons, the nodose ganglion of the vagus nerve and other regions of the brain may be involved, possibly in relation to very early neurofibrillary AD changes in the dorsal raphe, locus coeruleus and other brainstem nuclei. Novel data obtained upon infection of cultured neuronal cells and mouse brain with HSV1 further show that HSV1 infection causes intracellular amyloid-beta protein accumulation, as well as abnormal phosphorylation of tau protein, the major component of tangles. Another interesting fact is the existence of a significant degree of homology between HSV1 components and AD susceptibility genes. In this review we summarize findings that reveal connections between the two conditions, as well as different suggestions for the mechanisms of HSV1-induced AD. As most of the available results support a connection of AD and HSV1 infection, antiviral therapy should be taken into consideration for AD treatment following early diagnosis.

scholarly journals Regional HmPAO SPECT and CT Measurements in the Diagnosis of Alzheimer's Disease

1997 ◽  
Vol 24 (1) ◽  
pp. 22-28 ◽  
Author(s):  
A. Mattman ◽  
H. Feldman ◽  
B. Forste ◽  
D. Li ◽  
I. Szasz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Diagnostic Test ◽  
Discriminant Function ◽  
Regional Blood Flow ◽  
Cortical Atrophy ◽  
Stepwise Discriminant Analysis ◽  
Emission Computed Tomography ◽  
Hmpao Spect

ABSTRACT:Background:This study investigated the hypothesis that the combination of regional CT brain atrophy measurements and semiquantitative SPECT regional blood flow ratios could produce a diagnostic test for Alzheimer's disease (AD) with an accuracy comparable to that achieved with the present clinical gold standard of the NINCDS-ADRDA criteria.Methods:Single proton emission computed tomography (SPECT) and CT head scans were performed on 122 subjects referred an UBC Alzheimer clinic and diagnosed as either ‘not demented’ (ND-37) or ‘possible/probable AD’ (AD-85) by the NINCDS-ADRDA criteria. Stepwise discriminant analysis (SDA) was performed on the bilateral SPECT regions of interest and compared to bilateral CT qualitative/quantitative assessment in the frontal, parietal and temporal lobes to determine which were most accurate at ND/AD distinction. Receiver operating curves (ROC) were then constructed for these variables individually and for their combined discriminant function.Results:The left temporal qualitative cortical atrophy score (CT) and left temporal perfusion ratio (SPECT) were selected in the SDA. The combined discriminant function was more specific at AD/ND distinction than either of CT or SPECT alone. The accuracy of AD/ND distinction with the combined discriminant function was below that achieved by clinical diagnosis according to the NINCDS-ADRDA criteria and was not significantly different from that achieved with SPECT or CT alone as defined by ROC curve analysis.Conclusion:The measurements of left temporal cortical atrophy and regional cerebral blood flow were most indicative of AD; however they lacked the sensitivity and specificity to recommend their use as a diagnostic test for AD.

Quantitative Study of the Changes in Cerebral Blood Flow and Iron Deposition During Progression of Alzheimer’s Disease

2020 ◽  
Vol 78 (1) ◽  
pp. 439-452
Author(s):  
Dongxue Li ◽  
Yuancheng Liu ◽  
Xianchun Zeng ◽  
Zhenliang Xiong ◽  
Yuanrong Yao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Early Diagnosis ◽  
Time Window ◽  
Brain Regions ◽  
Iron Deposition ◽  
Imaging Biomarker ◽  
Subjective Cognitive Decline

Background: Advanced Alzheimer’s disease (AD) has no effective treatment, and identifying early diagnosis markers can provide a time window for treatment. Objective: To quantify the changes in cerebral blood flow (CBF) and iron deposition during progression of AD. Methods: 94 subjects underwent brain imaging on a 3.0-T MRI scanner with techniques of three-dimensional arterial spin labeling (3D-ASL) and quantitative susceptibility mapping (QSM). The subjects included 22 patients with probable AD, 22 patients with mild cognitive impairment (MCI), 25 patients with subjective cognitive decline (SCD), and 25 normal controls (NC). The CBF and QSM values were obtained using a standardized brain region method based on the Brainnetome Atlas. The differences in CBF and QSM values were analyzed between and within groups using variance analysis and correlation analysis. Results: CBF and QSM identified several abnormal brain regions of interest (ROIs) at different stages of AD (p < 0.05). Regionally, the CBF values in several ROIs of the AD and MCI subjects were lower than for NC subjects (p < 0.001). Higher QSM values were observed in the globus pallidus. The CBF and QSM values in multiple ROI were negatively correlated, while the putamen was the common ROI of the three study groups (p < 0.05). The CBF and QSM values in hippocampus were cross-correlated with scale scores during the progression of AD (p < 0.05). Conclusion: Iron deposition in the basal ganglia and reduction in blood perfusion in multiple regions existed during the progression of AD. The QSM values in putamen can be used as an imaging biomarker for early diagnosis of AD.

scholarly journals Cerebral Blood Flow is an Earlier Indicator of Perfusion Abnormalities than Cerebral Blood Volume in Alzheimer's Disease

2014 ◽  
Vol 34 (4) ◽  
pp. 654-659 ◽  
Author(s):  
María Lacalle-Aurioles ◽  
José M Mateos-Pérez ◽  
Juan A Guzmán-De-Villoria ◽  
Javier Olazarán ◽  
Isabel Cruz-Orduña ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Blood Volume ◽  
Cortical Thickness ◽  
Cerebral Blood Volume ◽  
Magnetic Resonance Images ◽  
Cortical Atrophy ◽  
Parahippocampal Gyrus

The purpose of this study was to elucidate whether cerebral blood flow (CBF) can better characterize perfusion abnormalities in predementia stages of Alzheimer's disease (AD) than cerebral blood volume (CBV) and whether cortical atrophy is more associated with decreased CBV or with decreased CBF. We compared measurements of CBV, CBF, and mean cortical thickness obtained from magnetic resonance images in a group of healthy controls, patients with mild cognitive impairment (MCI) who converted to AD after 2 years of clinical follow-up (MCI-c), and patients with mild AD. A significant decrease in perfusion was detected in the parietal lobes of the MCI-c patients with CBF parametric maps but not with CBV maps. In the MCI-c group, a negative correlation between CBF values and cortical thickness in the right parahippocampal gyrus suggests an increase in CBF that depends on cortical atrophy in predementia stages of AD. Our study also suggests that CBF deficits appear before CBV deficits in the progression of AD, as CBV abnormalities were only detected at the AD stage, whereas CBF changes were already detected in the MCI stage. These results confirm the hypothesis that CBF is a more sensitive parameter than CBV for perfusion abnormalities in MCI-c patients.

scholarly journals Frontal presentation of Alzheimer's disease: A series of patients with biological evidence by CSF biomarkers

2013 ◽  
Vol 7 (1) ◽  
pp. 66-74 ◽  
Author(s):  
Leonardo Cruz de Souza ◽  
Maxime Bertoux ◽  
Aurélie Funkiewiez ◽  
Dalila Samri ◽  
Carole Azuar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Atrophy ◽  
Csf Biomarkers ◽  
Post Mortem ◽  
Posterior Cortical Atrophy ◽  
Biological Profile ◽  
Atypical Presentations ◽  
Alzheimer Pathology

ABSTRACT Besides its typical amnesic presentation, focal atypical presentations of Alzheimer's disease (AD) have been described in neuropathological studies. These phenotypical variants of AD (so-called "atypical AD") do not follow the typical amnestic pattern and include non-amnestic focal cortical syndromes, such as posterior cortical atrophy and frontal variant AD. These variants exhibit characteristic histological lesions of Alzheimer pathology at post-mortem exam. By using physiopathological markers, such as cerebrospinal fluid markers, it is now possible to establish in vivo a biological diagnosis of AD in these focal cortical syndromes. We report a series of eight patients who were diagnosed with behavioural variant frontotemporal dementia based on their clinical, neuropsychological and neuroimaging findings, while CSF biomarkers showed an AD biological profile, thus supporting a diagnosis of frontal variant of AD.

scholarly journals Matrix Metalloproteinases and Their Multiple Roles in Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Xiang-Xiang Wang ◽  
Meng-Shan Tan ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Matrix Metalloproteinases ◽  
Senile Plaque ◽  
The Elderly ◽  
Brain Regions ◽  
Protective Role ◽  
Multiple Roles ◽  
Tau Aggregation ◽  
T Tau

Alzheimer’s disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include amyloid-β(Aβ) plaques and neurofibrillary tangles (NFTs), as well as neuronal death and synaptic loss. Matrix metalloproteinases (MMPs) play an important role as inflammatory components in the pathogenesis of AD. MMP-2 might be assumed to have a protective role in AD and is the major MMP which is directly linked to Aβin the brain. Synthesis of MMP-9 can be induced by Aβ, and the enzymes appear to exert multiple effects in AD in senile plaque homoeostasis. The proaggregatory influence on tau oligomer formation in strategic brain regions may be a potential neurotoxic side effect of MMP-9. MMP-3 levels are correlated to the duration of AD and correlate with the CSF T-tau and P-tau levels in the elderly controls. Elevated brain levels of MMP-3 might result in increased MMP-9 activity and indirectly facilitate tau aggregation. At present, the clinical utility of these proteins, particularly in plasma or serum, as potential early diagnostic biomarkers for AD remains to be established. More research is needed to understand the diverse roles of these proteases to design specific drugs and devise therapeutic strategies for AD.

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