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Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Introduction: Lower network segregation is associated with accelerated cognitive decline in Alzheimer's disease (AD), yet it is unclear whether less segregated brain networks facilitate connectivity‐mediated tau spreading. Methods: We combined resting state functional magnetic resonance imaging (fMRI) with longitudinal tau positron emission tomography (PET) in 42 betamyloid‐negative controls and 81 amyloid beta positive individuals across the AD spectrum. Network segregation was determined using resting‐state fMRI–assessed connectivity among 400 cortical regions belonging to seven networks. Results: AD subjects with higher network segregation exhibited slower brain‐wide tau accumulation relative to their baseline entorhinal tau PET burden (typical onset site of tau pathology). Second, by identifying patient‐specific tau epicenters with highest baseline tau PET we found that stronger epicenter segregation was associated with a slower rate of tau accumulation in the rest of the brain in relation to baseline epicenter tau burden. Discussion: Our results indicate that tau spreading is facilitated by a more diffusely organized connectome, suggesting that brain network topology modulates tau spreading in AD. Highlights: Higher brain network segregation is associated with attenuated tau pathology accumulation in Alzheimer's disease (AD).A patient‐tailored approach allows for the more precise localization of tau epicenters.The functional segregation of subject‐specific tau epicenters predicts the rate of future tau accumulation. [ABSTRACT FROM AUTHOR]

Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta‐amyloid (CSF Aβ1‐42) and late‐stage fibrillary Aβ pathology (amyloid‐PET centiloid), as well as sTREM2, p‐tau181, and FDG‐PET. To determine disease stage, we stratified participants into early Aβ‐accumulators (Aβ CSF+/PET−; n = 70) or late Aβ‐accumulators (Aβ CSF+/PET+; n = 201) plus 131 controls. In early Aβ‐accumulators, higher centiloid was associated with cross‐sectional/longitudinal sTREM2 and p‐tau181 increases. Further, higher sTREM2 mediated the association between centiloid and cross‐sectional/longitudinal p‐tau181 increases and higher sTREM2 was associated with FDG‐PET hypermetabolism. In late Aβ‐accumulators, we found no association between centiloid and sTREM2 but a cross‐sectional association between higher sTREM2, higher p‐tau181 and glucose hypometabolism. Our findings suggest that a TREM2‐related microglial response follows earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p‐tau181 increases in earliest AD. Synopsis: In Alzheimer's disease (AD), microglial activation has been linked to both detrimental and protective effects on disease progression. This study used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. In participants with early beta‐amyloid (Aβ) accumulation, higher amyloid‐PET was associated with higher cross sectional/longitudinal CSF sTREM2 and CSF p‐tau181 levels.In participants with early Aβ accumulation, sTREM2 mediated the association between amyloid‐PET and CSF p‐tau181 increases.Higher CSF sTREM2 levels were associated with FDG‐PET glucose hypermetabolism in early Aβ accumulation but with glucose hypometabolism in late Aβ accumulation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and coexist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer's and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fibre population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows derivation of measures of both white matter microstructure, measured by fibre density, and macrostructure, measured by fibre-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer's disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer's disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer's disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that (i) fibre density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks; (ii) fibre-bundle cross-section was mainly associated with brain volume; and (iii) both fibre density and fibre-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abnormal tau deposition. Fixel metrics were only weakly associated with amyloid- and tau-PET. Taken together, our results in three independent samples suggest that fibre density captures the effect of cerebral small vessel disease, while fibre-bundle cross-section is largely determined by neurodegeneration. The ability of fixel-based imaging markers to capture distinct effects on white matter integrity can propel future applications in the context of precision medicine. [ABSTRACT FROM AUTHOR]

Background: The development of in vivo amyloid (Aβ) and tau biomarkers has greatly facilitated diagnosing AD (Jack et al., 2018), however, reliable prognosis of AD‐related cognitive decline remains a critical yet unmet challenge. Here, especially tau biomarkers may offer great potential for individualized risk prediction of clinical AD progression, since the progressive spread of tau tracks clinical status more closely than Aβ deposition (Ossenkoppele et al., 2016; Wang et al., 2016). Thus, positron emission tomography (PET) of tau may be a better predictor for future cognitive decline and clinical progression than amyloid‐PET. Here, we examined whether tau‐PET‐based Braak‐staging outperforms amyloid‐PET as a predictor of future cognitive decline and clinical progression in older adults with and without cognitive impairment. Method: We included 396 cognitively normal to AD dementia subjects with Flutemetamol/Florbetapir‐amyloid‐PET, Flortaucipir‐tau‐PET and longitudinal cognitive assessments. Annual change rates in global cognition (i.e. MMSE, ADAS13) and episodic memory (i.e. ADNI‐MEM) were calculated via linear mixed models. We determined global amyloid‐PET (i.e. Centiloid) plus global and Braak‐stage‐specific tau‐PET SUVRs, which were stratified as positive(+)/negative(‐) at pre‐established cut‐offs. Using Braak‐stage‐specific binarized tau‐PET SUVRs, we classified subjects as BraakI+/BraakI‐IV+/BraakI‐VI+/Braakatypical+. In bootstrapped linear regression, we assessed whether global tau‐PET explained more variance in subsequent cognitive decline than Centiloid. Using ANCOVAs, we tested whether advanced Braak‐stage predicted faster future cognitive decline. All models were controlled for age, sex, education, clinical diagnosis, and baseline cognition. Lastly, we determined Braak‐stage‐specific conversion risk to mild cognitive impairment (MCI) or dementia. Result: Higher global tau‐PET SUVR at baseline explained more variance in subsequent cognitive decline across ∼2 years of follow up compared to baseline amyloid‐PET, consistently for MMSE, ADAS13, and memory (all p<0.001; Fig. 1). The association between global tau‐PET and subsequent cognitive changes remained consistent when additionally controlling for baseline amyloid‐PET. Advancing Braak‐stage was associated with gradually worsening future cognitive decline, independent of Centiloid (p<0.001; Fig. 2), and elevated clinical conversion risk to MCI or AD dementia (e.g. 15.38% for BraakI+, 23.81% for BraakI‐IV+, 45.45% for BraakI‐VI+; Fig. 3). Conclusion: Tau‐PET clearly outperforms amyloid‐PET in predicting future cognitive decline, where tau‐PET‐based Braak‐staging may be used for estimating patient‐specific risk for clinical AD progression. [ABSTRACT FROM AUTHOR]

Background: To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods: In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(−) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI–IV+/BraakI–VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results: Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen's d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion: Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4‐repeat (4R) tauopathies and its role in accelerating disease progression.We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading.We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F‐PI‐2620 PET and 18F‐GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3‐T resting‐state functional magnetic resonance imaging template derived from age‐matched healthy elderly controls.In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO‐PET across brain regions that are functionally connected to each other (β = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient‐specific tau epicenters (β = −0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F‐PI‐2620 PET.Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease‐modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Lower network segregation is associated with accelerated cognitive decline in Alzheimer's disease (AD), yet it is unclear whether less segregated brain networks facilitate connectivity-mediated tau spreading., Methods: We combined resting state functional magnetic resonance imaging (fMRI) with longitudinal tau positron emission tomography (PET) in 42 betamyloid-negative controls and 81 amyloid beta positive individuals across the AD spectrum. Network segregation was determined using resting-state fMRI-assessed connectivity among 400 cortical regions belonging to seven networks., Results: AD subjects with higher network segregation exhibited slower brain-wide tau accumulation relative to their baseline entorhinal tau PET burden (typical onset site of tau pathology). Second, by identifying patient-specific tau epicenters with highest baseline tau PET we found that stronger epicenter segregation was associated with a slower rate of tau accumulation in the rest of the brain in relation to baseline epicenter tau burden., Discussion: Our results indicate that tau spreading is facilitated by a more diffusely organized connectome, suggesting that brain network topology modulates tau spreading in AD., Highlights: Higher brain network segregation is associated with attenuated tau pathology accumulation in Alzheimer's disease (AD). A patient-tailored approach allows for the more precise localization of tau epicenters. The functional segregation of subject-specific tau epicenters predicts the rate of future tau accumulation., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)