Functional brain architecture is associated with the rate of tau accumulation in Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Franzmeier N
PROVIDER: S-EPMC6969065 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every ∼5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD.
| S-EPMC8555892 | biostudies-literature
Project description:In Alzheimer's disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity. We therefore tested whether Aβ-related GAP-43 increases, as a marker of synaptic changes, drive tau spreading in 93 patients across the aging and Alzheimer's spectrum with available CSF GAP-43, amyloid-PET and longitudinal tau-PET assessments. We found that (1) higher GAP-43 was associated with faster Aβ-related tau accumulation, specifically in brain regions connected closest to subject-specific tau epicenters and (2) that higher GAP-43 strengthened the association between Aβ and connectivity-associated tau spread. This suggests that GAP-43-related synaptic changes are linked to faster Aβ-related tau spread across connected regions and that synapses could be key targets for preventing tau spreading in Alzheimer's disease.
| S-EPMC10764818 | biostudies-literature
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.
| S-EPMC5374886 | biostudies-literature
Project description:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.
| S-EPMC5928393 | biostudies-literature
Project description:BACKGROUND:We aimed to investigate the clinical correlates of principal components (PCs) of tau positron emission tomography (PET) and their predictability for longitudinal changes in tau accumulation in Alzheimer's disease (AD). METHODS:We enrolled 272 participants who underwent two PET scans [18F-flortaucipir for tau and 18F-florbetaben for amyloid-? (A?)], brain magnetic resonance imaging, and neuropsychological tests as baseline assessments. Among them, 187 participants underwent the same follow-up assessments after an average of 2 years. Using A?-positive AD dementia-specific PCs obtained from the baseline scans of 56 A?-positive patients with AD dementia, we determined the expression of the first two PCs (PC1 and PC2) in all participants. We assessed the correlation of PC expression with baseline clinical characteristics and tau accumulation rates. Moreover, we investigated the predictability of PCs for the longitudinal tau accumulation in training and test sets. RESULTS:PC1 corresponded to the tau distribution pattern in AD, while the two PC2 extremes reflected the parietal or temporal predominance of tau distribution. PC1 expression increased with tau burden and decreased with cognitive impairment, while PC2 expression decreased with advanced age and visuospatial and attention function deterioration. The tau accumulation rate was positively correlated with PC1 expression (greater tau burden) and negatively correlated with PC2 expression (temporal predominance). A regression model using both PCs could predict longitudinal changes in the tau burden (intraclass correlation coefficient?=?0.775, R2?=?0.456 in test set). CONCLUSIONS:PC analysis of tau PET could be useful for evaluating disease progression, characterizing the tau distribution pattern, and predicting longitudinal tau accumulation.
| S-EPMC7513482 | biostudies-literature
Project description:In Alzheimer's disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/BioFINDER, n = 240/57). Consistent across both samples, we found that younger symptomatic AD patients showed stronger tau-PET in globally connected fronto-parietal hubs, i.e., regions that are critical for maintaining cognition in AD. Stronger tau-PET in hubs predicted faster subsequent tau accumulation, suggesting that tau in globally connected regions facilitates connectivity-mediated tau spreading. Further, stronger tau-PET in hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients, which predicted faster cognitive decline. These independently validated findings suggest that younger AD symptom onset is associated with stronger tau pathology in brain hubs, and accelerated tau spreading throughout connected brain regions and cognitive decline.
| S-EPMC9392750 | biostudies-literature
Project description:Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF A?(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF A?(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.
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Project description:Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.
| S-EPMC10995141 | biostudies-literature
Project description:In Alzheimer's disease, tau pathology spreads hierarchically from the inferior temporal lobe throughout the cortex, ensuing cognitive decline and dementia. Similarly, circumscribed patterns of pathological tau have been observed in normal ageing and small vessel disease, suggesting a spatially ordered distribution of tau pathology across normal ageing and different diseases. In vitro findings suggest that pathological tau may spread 'prion-like' across neuronal connections in an activity-dependent manner. Supporting this notion, functional brain networks show a spatial correspondence to tau deposition patterns. However, it remains unclear whether higher network-connectivity facilitates tau propagation. To address this, we included 55 normal aged elderly (i.e. cognitively normal, amyloid-negative), 50 Alzheimer's disease patients (i.e. amyloid-positive) covering the preclinical to dementia spectrum, as well as 36 patients with pure (i.e. amyloid-negative) vascular cognitive impairment due to small vessel disease. All subjects were assessed with AV1451 tau-PET and resting-state functional MRI. Within each group, we computed atlas-based resting-state functional MRI functional connectivity across 400 regions of interest covering the entire neocortex. Using the same atlas, we also assessed within each group the covariance of tau-PET levels among the 400 regions of interest. We found that higher resting-state functional MRI assessed functional connectivity between any given region of interest pair was associated with higher covariance in tau-PET binding in corresponding regions of interest. This result was consistently found in normal ageing, Alzheimer's disease and vascular cognitive impairment. In particular, inferior temporal tau-hotspots, as defined by highest tau-PET uptake, showed high predictive value of tau-PET levels in functionally closely connected regions of interest. These associations between functional connectivity and tau-PET uptake were detected regardless of presence of dementia symptoms (mild cognitive impairment or dementia), amyloid deposition (as assessed by amyloid-PET) or small vessel disease. Our findings suggest that higher functional connectivity between brain regions is associated with shared tau-levels, supporting the view of prion-like tau spreading facilitated by neural activity.
| S-EPMC6439332 | biostudies-literature
Project description:Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer's disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.
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