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Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer's disease.

ABSTRACT: PURPOSE:We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer's disease (AD), by using a single dynamic [18F]flortaucipir positron emission tomography (PET) scan. METHODS:Seventy-one subjects with AD (66?±?8 years, mini-mental state examination (MMSE) 23?±?4) underwent a dynamic 130-min [18F]flortaucipir PET scan. Cognitive assessment consisted of composite scores of four cognitive domains. For tau pathology and rCBF, receptor parametric mapping (cerebellar gray matter reference region) was used to create uncorrected and partial volume-corrected parametric images of non-displaceable binding potential (BPND) and R1, respectively. (Voxel-wise) linear regressions were used to investigate associations between BPND and/or R1 and cognition. RESULTS: Higher [18F]flortaucipir BPND was associated with lower R1 in the lateral temporal, parietal and occipital regions. Higher medial temporal BPND was associated with worse memory, and higher lateral temporal BPND with worse executive functioning and language. Higher parietal BPND was associated with worse executive functioning, language and attention, and higher occipital BPND with lower cognitive scores across all domains. Higher frontal BPND was associated with worse executive function and attention. For [18F]flortaucipir R1, lower values in the lateral temporal and parietal ROIs were associated with worse executive functioning, language and attention, and lower occipital R1 with lower language and attention scores. When [18F]flortaucipir BPND and R1 were modelled simultaneously, associations between lower R1 in the lateral temporal ROI and worse attention remained, as well as for lower parietal R1 and worse executive functioning and attention. CONCLUSION:Tau pathology was associated with locally reduced rCBF. Tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. These findings indicate that each biomarker may independently contribute to cognitive impairment in AD.

SUBMITTER: Visser D

PROVIDER: S-EPMC7680306 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer's disease.

Visser Denise D Wolters Emma E EE Verfaillie Sander C J SCJ Coomans Emma M EM Timmers Tessa T Tuncel Hayel H Reimand Juhan J Boellaard Ronald R Windhorst Albert D AD Scheltens Philip P van der Flier Wiesje M WM Ossenkoppele Rik R van Berckel Bart N M BNM

European journal of nuclear medicine and molecular imaging 20200527 13

<h4>Purpose</h4>We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer's disease (AD), by using a single dynamic [<sup>18</sup>F]flortaucipir positron emission tomography (PET) scan.<h4>Methods</h4>Seventy-one subjects with AD (66 ± 8 years, mini-mental state examination (MMSE) 23 ± 4) underwent a dynamic 130-min [<sup>18</sup>F]flortaucipir PET scan. Cognitive assessment consisted of composite scores ...[more]

PMID: 32462397

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Project description:PurposeAlpha-synuclein often co-occurs with Alzheimer's disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB.MethodsEighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests.ResultsRegional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p < 0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stβ = 0.72) and category fluency (stβ = 0.69) tests. Lower parietal R1 was related to lower delayed (stβ = 0.50) and immediate (stβ = 0.48) recall, VOSP number location (stβ = 0.70) and fragmented letters (stβ = 0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stβ = 0.61), all p < 0.05.ConclusionThe amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.

Project description:PurposeTau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF.MethodsWe included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aβ- cognitively normal (CN) individuals and Aβ+ (CN and CI) individuals separately.ResultsIn Aβ+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ- individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals.ConclusionWe showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.

Project description:Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95% CI 0.370 to 0.990, p < 0.05). This was accompanied by an increase in neutrophil elastase expression by α-SMA-positive cells in the vessel wall. Small and medium-sized arteries exhibited significant CAA-independent α-SMA loss starting between Braak stage I and II-III, along with accumulation of phosphorylated paired helical filament (PHF) tau in the perivascular space of intraparenchymal vessels. α-SMA remained at the decreased level throughout the later Braak stages. In contrast, arterioles exhibited significant α-SMA loss only at Braak stage V and VI/in AD subjects, which was CAA-dependent/correlated with CAA burden (ρ = -0.422, 95% CI -0.557 to -0.265, p < 0.0001). Collagen content was only significantly changed in small arteries. Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD.

Project description:Neuropathological studies have shown that the typical neurofibrillary pathology of hyperphosphorylated tau protein in Alzheimer's disease (AD) preferentially affects specific brain regions whereas others remain relatively spared. It has been suggested that the distinct regional distribution profile of tau pathology in AD may be a consequence of the intrinsic network structure of the human brain. The spatially distributed brain regions that are most affected by the spread of tau pathology may hence reflect an interconnected neuronal system. Here, we characterized the brain-wide regional distribution profile of tau pathology in AD using 18F-AV 1451 tau-sensitive positron emission tomography (PET) imaging, and studied this pattern in relation to the functional network organization of the human brain. Specifically, we quantified the spatial correspondence of the regional distribution pattern of PET-evidenced tau pathology in AD with functional brain networks characterized by large-scale resting state functional magnetic resonance imaging (rs-fMRI) data in healthy subjects. Regional distribution patterns of increased PET-evidenced tau pathology in AD compared to controls were characterized in two independent samples of prodromal and manifest AD cases (the Swedish BioFINDER study, n = 44; the ADNI study, n = 35). In the BioFINDER study we found that the typical AD tau pattern involved predominantly inferior, medial, and lateral temporal cortical areas, as well as the precuneus/posterior cingulate, and lateral parts of the parietal and occipital cortex. This pattern overlapped primarily with the dorsal attention, and to some extent with higher visual, limbic and parts of the default-mode network. PET-evidenced tau pathology in the ADNI replication sample, which represented a more prodromal group of AD cases, was less pronounced but showed a highly similar spatial distribution profile, suggesting an earlier-stage snapshot of a consistently progressing regional pattern. In conclusion, the present study indicates that the regional deposition of tau aggregates in AD predominantly affects higher-order cognitive over primary sensory-motor networks, but does not appear to be specific for the default-mode or related limbic networks.

Project description:Background Hypertension has been associated with Alzheimer’s disease (AD) dementia as well as vascular dementia. However, the underlying neuropathological changes that link hypertension to AD remain poorly understood. In our study, we examined the relationships of a history of hypertension and high current blood pressure (BP) with in vivo AD pathologies including β-amyloid (Aβ) and tau and also investigated whether a history of hypertension and current BP respectively affect the association between Aβ and tau deposition. Methods This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, a prospective cohort study. Cognitively normal older adults who underwent both Aβ and tau positron emission tomography (PET) (i.e., [11C]-Pittsburgh compound B and [18F] AV-1451 PET) were selected. History of hypertension and current BP were evaluated and cerebral Aβ and tau deposition measured by PET were used as main outcomes. Generalized linear regression models were used to estimate associations. Results A total of 68 cognitively normal older adults (mean [SD] age, 71.5 [7.4] years; 40 women [59%]) were included in the study. Neither a history of hypertension nor the current BP exhibited a direct association with Aβ or tau deposition. However, the synergistic interaction effects of high current systolic (β, 0.359; SE, 0.141; p = 0.014) and diastolic (β, 0.696; SE, 0.158; p < 0.001) BP state with Aβ deposition on tau deposition were significant, whereas there was no such effect for a history of hypertension (β, 0.186; SE, 0.152; p = 0.224). Conclusions The findings suggest that high current BP, but not a history of hypertension, synergistically modulate the relationship between cerebral Aβ and tau deposition in late-life. In terms of AD prevention, the results support the importance of strict BP control in cognitively normal older adults with hypertension. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-022-01149-7.

Dataset Information

Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer's disease.

Publications

Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer's disease.

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