scholarly journals Heterogeneity of Tau Deposition and Microvascular Involvement in MCI and AD

2021 ◽  
Vol 18 ◽  
Author(s):  
Annie G. Bryant ◽  
Mary K. Manhard ◽  
David H. Salat ◽  
Bruce R. Rosen ◽  
Bradley T. Hyman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Amyloid Β ◽  
Microvascular Perfusion ◽  
Therapeutic Interventions ◽  
Cortical Atrophy ◽  
Periventricular White Matter ◽  
Dynamic Susceptibility ◽  
Tau Pathology ◽  
Cerebrovascular Function ◽  
Tau Pet

Background: Reduced cerebrovascular function and accumulation of tau pathology are key components of cognitive decline in Alzheimer’s disease (AD). Recent multimodal neuroimag- ing studies show a correlation between cortical tau accumulation and reduced cerebral perfusion. However, animal models predict that tau exerts capillary-level changes that may not be fully cap- tured by standard imaging protocols. Objective: Using newly-developed magnetic resonance imaging (MRI) technology to measure cap- illary-specific perfusion parameters, we examined a series of mild cognitive impairment (MCI) and AD patients with tau positron emission tomography (PET) to observe whole-brain capillary perfu- sion alterations and their association with tau deposition. Methods: Seven subjects with MCI or AD received Flortaucipir PET to measure tau deposition and spin-echo dynamic susceptibility contrast (SE-DSC) MRI to measure microvascular perfusion (<10μm radius vessels). Gradient-echo (GE) DSC and pseudocontinuous arterial spin labeling (P- CASL) MRI were also acquired to assess macrovascular perfusion. Tau PET, microvascular perfu- sion, and cortical thickness maps were visually inspected in volumetric slices and on cortical sur- face projections. Results: High tau PET signal was generally observed in the lateral temporal and parietal cortices, with uptake in the occipital cortex in one subject. Global blood flow measured by PCASL was re- duced with increasing tau burden, which was consistent with previous studies. Tau accumulation was spatially associated with variable patterns of microvascular cerebral blood flow (CBF) and oxy- gen extraction fraction (OEF) in the cortex and with increased capillary transit heterogeneity (C- TH) in adjacent periventricular white matter, independent of amyloid-β status. Conclusions: Although macrovascular perfusion generally correlated with tau deposition at the whole-cortex level, regional changes in microvascular perfusion were not uniformly associated with either tau pathology or cortical atrophy. This work highlights the heterogeneity of AD-related brain changes and the challenges of implementing therapeutic interventions to improve cerebrovas- cular function.

scholarly journals Association of amyloid-β CSF/PET discordance and tau load 5 years later

Neurology ◽  
2020 ◽  
Vol 95 (19) ◽  
pp. e2648-e2657 ◽  
Author(s):  
Juhan Reimand ◽  
Lyduine Collij ◽  
Philip Scheltens ◽  
Femke Bouwman ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tau Pet

ObjectiveTo investigate the association between discordant β-amyloid (Aβ) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.MethodsWe included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aβ42 available. Aβ CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aβ) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aβ CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET− participants who during follow-up (1) progressed to Aβ CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET.ResultsAβ CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET− (n = 80) participants were overall similar to the CSF−/PET− (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET− group (1.20 ± 0.13) did not differ from CSF−/PET− (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET− participants, 21/64 (33%) progressed to Aβ CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET.ConclusionsAβ load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aβ levels on both PET and CSF, the CSF+/PET− group has a distinctly better prognosis.

scholarly journals Relationship between cortical iron and tau aggregation in Alzheimer’s disease

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1341-1349 ◽  
Author(s):  
Nicola Spotorno ◽  
Julio Acosta-Cabronero ◽  
Erik Stomrud ◽  
Björn Lampinen ◽  
Olof T Strandberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Disease Process ◽  
Amyloid Β ◽  
Cortical Atrophy ◽  
Tau Pet ◽  
Tau Aggregation ◽  
The Relationship

Abstract A growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer’s disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer’s disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer’s disease aetiology.

scholarly journals Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer’s disease

2021 ◽  
pp. jnnp-2020-325497
Author(s):  
Ellen Singleton ◽  
Oskar Hansson ◽  
Yolande A. L. Pijnenburg ◽  
Renaud La Joie ◽  
William G Mantyh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Clinical Phenotype ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Tau Pathology ◽  
Heterogeneous Distribution ◽  
Tau Pet

ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

PET Amyloid and Tau Status Are Differently Affected by Patient Features

2020 ◽  
Vol 78 (3) ◽  
pp. 1129-1136
Author(s):  
Meng-Shan Tan ◽  
Yu-Xiang Yang ◽  
Hui-Fu Wang ◽  
Wei Xu ◽  
Chen-Chen Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Clinical Genetic ◽  
Multivariable Logistic Regression Model ◽  
Tau Pet ◽  
Pet Amyloid

Background: Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer’s disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms. Objective: Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status. Methods: We included 372 nondemented elderly from the Alzheimer’s Disease Neuroimaging Initiative cohort. All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels. Results: Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42, APOE ɛ4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels. Conclusion: Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis.

scholarly journals Heterogeneous distribution of tau pathology in the behavioral variant of Alzheimer's disease

2020 ◽  
Author(s):  
Ellen H. Singleton ◽  
Oskar Hansson ◽  
Anke A. Dijkstra ◽  
Renaud La Joie ◽  
William G. Mantyh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Clinical Phenotype ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Tau Pathology ◽  
Heterogeneous Distribution ◽  
Tau Pet

Objective: The clinical phenotype of the rare behavioral variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using PET and postmortem examination. Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardized (W-)scores, by adjusting for age, sex and MMSE in a "typical" memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed bvAD (n=8) and typical AD (n=7) patients. Results: Regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, i.e. case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the typical AD group. Postmortem AT8 staining indicated no regional differences in phosphorylated tau levels between bvAD and typical AD (all p>0.05). Conclusion: Both in-vivo and ex-vivo, bvAD patients showed heterogeneous patterns of tau pathology. Since key regions involved in behavioral regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

scholarly journals Neuroanatomical spread of amyloid β and tau in Alzheimer’s disease: implications for primary prevention

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Philip S Insel ◽  
Elizabeth C Mormino ◽  
Paul S Aisen ◽  
Wesley K Thompson ◽  
Michael C Donohue
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Primary Prevention ◽  
Temporal Lobe ◽  
Amyloid Β ◽  
Imaging Biomarker ◽  
Continuous Measure ◽  
Validation Sample ◽  
Tau Pathology ◽  
Tau Pet

Abstract With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer’s disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer’s disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P &lt; 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer’s disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation.

scholarly journals Amyloid-β CSF/PET discordance vs tau load 5 years later: It takes two to tangle

2020 ◽  
Author(s):  
Juhan Reimand ◽  
Lyduine Collij ◽  
Philip Scheltens ◽  
Femke Bouwman ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Performance ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Tau Pet ◽  
Mixed Modelling

AbstractOBJECTIVETo investigate the association between discordant amyloid-β PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.METHODSWe included 730 ADNI participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]Florbetapir PET and CSF Aβ42 available. Amyloid-β CSF/PET status was determined at baseline using established cut-offs. Longitudinal data was available for [18F]florbetapir (Aβ) PET (baseline to 4.3±1.9 years), CSF (p)tau (baseline to 2.0±0.1 years), cognition (baseline to 4.3±2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2±1.2 years after baseline to 1.6±0.7 years later). We used linear mixed modelling to study the association between amyloid-β CSF/PET status and tau pathology measured in CSF or using PET. Additionally, we calculated the proportion of CSF+/PET-participants who during follow-up (i) progressed to amyloid-β CSF+/PET+, and/or (ii) became tau-positive based on [18F]flortaucipir PET.RESULTSAmyloid-β CSF+/PET+ (N=318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET-(N=80) participants were overall similar to the CSF-/PET-(N=306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET-group (1.20±0.13) did not differ from CSF-/PET-(1.18±0.08, p=0.69), but was substantially lower than CSF+/PET+ (1.48±0.44, p<0.001). Of the CSF+/PET-subjects, 21/64 (33%) progressed to amyloid-β CSF+/PET+, whereas only one (3%, difference p<0.05) became tau-positive based on [18F]flortaucipir PET.CONCLUSIONSSufficient amyloid-β load detectable by both CSF and PET is required before substantial tau deposition emerges. Compared to participants with abnormal amyloid-β levels on PET and CSF, the CSF+/PET-group has a distinctly better prognosis.

scholarly journals Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer’s disease mice with presenilin-1 mutation

2020 ◽  
pp. 0271678X2096423
Author(s):  
Dong Liu ◽  
Ismayil Ahmet ◽  
Brandon Griess ◽  
David Tweedie ◽  
Nigel H Greig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Presenilin 1 ◽  
Doppler Flowmetry ◽  
Channel Opener ◽  
Cerebrovascular Function

Local cerebral blood flow (CBF) responses to neuronal activity are essential for cognition and impaired CBF responses occur in Alzheimer’s disease (AD). In this study, regional CBF (rCBF) responses to the KATP channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1M146V) mice from three age groups using Laser-Doppler flowmetry. The rCBF response was reduced early in young 3xTgAD mice and almost absent in old 3xTgAD mice, up to 30%–40% reduction with altered CBF velocity and mean arterial pressure versus WT mice. The impaired rCBF response in 3xTgAD mice was associated with progression of AD pathology, characterized by deposition of intracellular and vascular amyloid-β (Aβ) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine abolished rCBF response to diazoxide suggesting NO was involved in the mediation of vasorelaxation. Levels of phosphor-eNOS (Ser1177) diminished in 3xTgAD brains with age, while the rCBF response to the NO donor sodium nitroprusside remained. In PS1M146V mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1M146V contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aβ oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1M146V mutation.

Depression of Collateral Blood Flow Following Arterial Thrombosis

1977 ◽  
Vol 38 (04) ◽  
pp. 0850-0862 ◽  
Author(s):  
Robert G. Schaub ◽  
Ronald Sande ◽  
Kenneth M. Meyers
Keyword(s):  
Blood Flow ◽  
Arterial Thrombosis ◽  
Hind Limb ◽  
Therapeutic Interventions ◽  
Collateral Blood Flow ◽  
Serotonin Antagonist ◽  
Limb Perfusion ◽  
Clinical Consequences ◽  
Collateral Vessels ◽  
Iliac Bifurcation

SummaryPermanent ligation of the feline aorta at the iliac bifurcation is followed by rapid opening of pre-existing collateral blood vessels. However, if ligation is combined with formation of a clot, these protective collateral vessels do not function. This study was undertaken to determine if drugs which alter serotonin function can improve collateral blood flow after arterial thrombosis. Permanent ligations were placed at the iliac bifurcation, circumflex iliac and sixth lumbar arteries in all cats. A clot was produced in the aorta of 27 cats by injection of 0.1 ml of thromboplastin. Ligated clot-occluded cats were untreated (10); had blood serotonin depleted using a single dose of reserpine (0.1 mg/kg i. m.) followed by para-chlorophenylanine (p-CPA) (100 mg/kg orally) every 3 days (9) ; or were treated prior to surgery with a serotonin antagonist cinanserin HC1 (4 mg/kg i. v.) (8). Control cats (18) were acutely ligated. 9 of these cats were untreated, 5 were cinanserin HC1-treated, and 4 were reserpine/p-CPA-treated. Extent of collateral development was assessed by aortograms 3 days after occlusion and by neurologic rating. Aortograms of acutely ligated cats indicated a significant collateral blood flow around the segment of ligated aorta, while ligated clot-occluded cats had a severely depressed hind-limb perfusion. Reserpine/p-CPA-treated ligation clot-occluded cats had aortograms similar to acutely ligated cats. The cinanserin HC1-treated ligation clot-occluded cats had aortograms which indicated hind-limb perfusion was not as adequate as the acutely ligated cats. However, the perfusion of these animals was improved over untreated ligation clot-occluded cats. Neurologic rating correlated with aortograms. These results suggest: 1) the clinical consequences of arterial thrombosis cannot be entirely attributed to mechanical occlusion of an artery, but may be due to depression of protective collateral blood flow induced by thrombosis, 2) serotonin is an important factor in this depression of collateral blood flow, and 3) isolation of the factors responsible for collateral inhibition could permit the development of therapeutic interventions.

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