scholarly journals Amyloid-beta, p-tau, and reactive microglia load are correlates of MRI cortical atrophy in Alzheimer's disease

2021 ◽  
Author(s):  
Irene Frigerio ◽  
Baayla DC Boon ◽  
Chen-Pei Lin ◽  
Yvon Galis-de Graaf ◽  
John GJM Bol ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Amyloid Beta ◽  
Brain Regions ◽  
Cortical Atrophy ◽  
Strongly Correlated ◽  
Phosphorylated Tau ◽  
Post Mortem ◽  
Reactive Microglia

INTRODUCTION: The aim of this study was to identify the histopathological correlates of MRI cortical atrophy in (a)typical Alzheimer's disease (AD) donors. METHODS: 19 AD and 10 control donors underwent post-mortem in-situ 3T-3DT1-MRI, from which cortical thickness was calculated. Upon subsequent autopsy, 21 cortical brain regions were selected and immunostained for amyloid-beta, phosphorylated-tau, and reactive microglia. MRI-pathology associations were assessed using linear mixed models. Post-mortem MRI was compared to ante-mortem MRI when available. RESULTS: Higher amyloid-beta load weakly correlated with a higher cortical thickness globally. Phosphorylated-tau strongly correlated with cortical atrophy in temporo-frontal regions. Reactive microglia load strongly correlated with cortical atrophy in the parietal region. Post-mortem scans showed high concordance with ante-mortem scans acquired <1 year before death. DISCUSSION: Distinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegenerative process. This study contributes in understanding the pathological underpinnings of MRI atrophy patterns.

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 Amyloid-beta and phosphorylated tau in post-mortem Alzheimer’s disease retinas

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Jurre den Haan ◽  
Tjado H. J. Morrema ◽  
Frank D. Verbraak ◽  
Johannes F. de Boer ◽  
Philip Scheltens ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Phosphorylated Tau ◽  
Post Mortem

Amyloid Beta-Weighted Cortical Thickness: A New Imaging Biomarker in Alzheimer's Disease

2015 ◽  
Vol 12 (6) ◽  
pp. 563-571 ◽  
Author(s):  
Chan Kim ◽  
Jihye Hwang ◽  
Jong-Min Lee ◽  
Jee Hoon Roh ◽  
Jae-Hong Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Amyloid Beta ◽  
Imaging Biomarker

scholarly journals Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Boris Guennewig ◽  
Julia Lim ◽  
Lee Marshall ◽  
Andrew N. McCorkindale ◽  
Patrick J. Paasila ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Sequencing ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Post Mortem ◽  
Tau Pathology ◽  
Membrane Spanning ◽  
Immune Related Genes ◽  
Vesicle Secretion

AbstractTau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

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 Platelet phosphorylated TDP-43: An exploratory study for a peripheral surrogate biomarker development for Alzheimer’s disease

2017 ◽  
Author(s):  
Rodger Wilhite ◽  
Jessica Sage ◽  
Abdurrahman Bouzid ◽  
Tyler Primavera ◽  
Abdulbaki Agbas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Clinical Signs ◽  
Brain Regions ◽  
Post Mortem ◽  
Disease Prognosis ◽  
Post Mortem Brain ◽  
And Control ◽  
Lateral Sclerosis

AbstractAim: Alzheimer’s disease (AD) and other forms of dementia create a non-curable disease population in World’s societies. To develop a blood-based biomarker is important so that the remedial or disease-altering therapeutic intervention for AD patients would be available at the early stage. Materials & Methods: TDP-43 levels were analyzed in post-mortem brain tissue and platelets of AD and control subjects. Results: We observed an increased TDP-43 (<60%) in post-mortem AD brain regions and similar trends were also observed in patient’s platelets. Conclusion: Platelet TDP-43 could be used as a surrogate biomarker that is measurable, reproducible, and sensitive for screening the patients with some early clinical signs of AD and can be used to monitor disease prognosis.Lay abstractIn this study, we explore to identify an Alzheimer’s disease-selective phospho-specific antibody that recognizes the diseased form of TDP-43 protein in patient’s blood-derived platelets. Our results suggest that selective anti-phosphorylated TDP-43 antibody discriminates Alzheimer’s disease from non-demented controls and patients with amyotrophic lateral sclerosis. Therefore, platelet screening with a selective antibody could potentially be a useful tool for diagnostic purposes for Alzheimer’s disease.

scholarly journals Distribution of pathological hallmarks and association with post‐mortem MRI cortical thickness in typical and atypical Alzheimer’s disease

2020 ◽  
Vol 16 (S1) ◽  
Author(s):  
Laura E. Jonkman ◽  
Baayla D.C. Boon ◽  
Irene Frigerio ◽  
Martijn D. Steenwijk ◽  
Paolo Preziosa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Post Mortem ◽  
Atypical Alzheimer’S Disease

scholarly journals Visit-to-visit Blood Pressure Variability and Regional Cerebral Perfusion Decline in Older Adults

2020 ◽  
Author(s):  
Isabel Sible ◽  
Belinda Yew ◽  
Shubir Dutt ◽  
Katherine J. Bangen ◽  
Yanrong Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Blood Pressure ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Blood Pressure Variability ◽  
Cerebral Perfusion ◽  
Cerebral Spinal Fluid ◽  
Spinal Fluid ◽  
Phosphorylated Tau

Abstract Background: Blood pressure variability has been linked to dementia risk, independent of average blood pressure levels. It has been hypothesized that dysregulated blood pressure may challenge autoregulatory mechanisms and risk cerebral hypoperfusion. The current study examined whether visit-to-visit blood pressure variability over one year is related to concurrent regional cerebral perfusion decline over the same period in older adults.Methods: Sixty-three older adults without history of dementia or stroke underwent repeated blood pressure measurement and arterial spin-labelling magnetic resonance imaging over the same one year period. Fluorodeoxyglucose-positron emission tomography determined cerebral metabolism at baseline. A subset underwent lumbar puncture to detect cerebral spinal fluid amyloid-beta (n=18) and phosphorylated tau (n=21) abnormalities. Visit-to-visit blood pressure variability and change in regional cerebral perfusion were both calculated over 12 months. Multiple linear regression examined relationships between blood pressure variability and change in regional perfusion after controlling for age, sex, average blood pressure, antihypertensive medication use and cerebral metabolism. Exploratory analyses were repeated in participant subsets with abnormal cerebral spinal fluid amyloid-beta and phosphorylated tau.Results: Elevated blood pressure variability was related to perfusion decline in medial orbitofrontal cortex (ß = -.36; p = .008), hippocampus (ß = -.37; p = .005), entorhinal cortex (ß = -.48; p < .001), precuneus (ß = -.31; p = .02), inferior parietal cortex (ß = -.44; p < .001) and inferior temporal cortex (ß = -.46; p < .001). Elevated blood pressure variability was similarly related to perfusion decline in some regions among participant subsets showing abnormal cerebral spinal fluid amyloid-beta and phosphorylated tau.Conclusions: Older adults with elevated visit-to-visit blood pressure variability exhibit concurrent regional cerebral perfusion decline in areas vulnerable to cerebrovascular dysfunction in Alzheimer’s disease, independent of cerebral hypometabolism. Similar findings are observed in exploratory analyses of older adults with Alzheimer’s disease biomarker abnormalities. The study is limited by the small sample size, particularly the subset of participants with Alzheimer’s disease biomarker abnormalities. Findings may have therapeutic implications, given that certain antihypertensive medications have differential effects on variability of blood pressure independent of average levels.

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