The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive decline

Boccalini, Cecilia; Ribaldi, Federica; Hristovska, Inès; Arnone, Annachiara; Peretti, Débora E; Mu, Linjing; Scheffler, Max; Perani, Daniela; Frisoni, Giovanni B.; Garibotto, Valentina

doi:10.1002/alz.13355

Cited by 25 publications

(15 citation statements)

References 82 publications

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“…We next examined the coupling-thickness association, as tau is closely associated with cortical atrophy and ultimately leads to cognitive decline ( 12, 54 ). Similar to the coupling-tau links above, gBOLD-CSF coupling was also significantly related to cortical thickness in widespread cortical regions, including the Braak V-VI ROI, Braak III-IV ROI, and temporal meta-ROI, across the entire group of subjects, and more specifically among the impaired Aβ+ subjects ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

Han,

Lee,

Chen

et al. 2023

Preprint

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Amyloid-β (Aβ) and tau deposition constitute Alzheimer’s disease (AD) neuropathology. Cortical tau deposits first in the entorhinal cortex and hippocampus and then propagates to neocortex in an Aβ-dependent manner. Tau also tends to accumulate earlier in higher-order association cortex than in lower-order primary sensory-motor cortex. While previous research has examined the production and spread of tau, little attention has been paid to its clearance. Low-frequency (<0.1 Hz) global brain activity during the resting state is coupled with cerebrospinal fluid (CSF) flow and potentially reflects glymphatic clearance. Here we report that tau deposition in subjects with evaluated Aβ, accompanied by cortical thinning and cognitive decline, is strongly associated with decreased coupling between CSF flow and global brain activity. Substantial modulation of global brain activity is also manifested as propagating waves of brain activation between higher- and lower-order regions, resembling tau spreading. Together, the findings suggest an important role of resting-state global brain activity in AD tau pathology.One Sentence SummaryResting-state global brain activity affects tau deposition through the potential involvement of a glymphatic clearance function.

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Section: Resultsmentioning

confidence: 99%

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

Han,

Lee,

Chen

et al. 2023

Preprint

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“…Our findings are consistent with results from other studies, demonstrating high regional variance of tau-deposition patterns in AD and symptom-dependent association with tau-deposition in function-related brain regions (Bejanin et al, 2017; Brier et al, 2016; Vogel et al, 2021). First, an association has been shown between the overall severity of cognitive decline (as assessed by the Mini Mental Status Examination/MMSE) and tau burden, as measured in a large cortical meta-ROI as well as in the lateral temporal cortex (Bejanin et al, 2017; Boccalini et al, 2024; Brier et al, 2016). Importantly, pronounced tau-deposition in individual brain regions has been associated not only with overall cognitive impairment but also with specific decline of different cognitive functions associated with the respective brain areas (Dronse et al, 2016; Ossenkoppele et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the detected clusters do not overlap with brain regions where tau deposition has been associated with overall severity of cognitive decline, such as the lateral temporal cortex (Boccalini et al, 2024). Also, the parts of the praxis network involved are not among the brain regions affected by tau pathology early in the disease course (such as entorhinal cortex, Brodman area 35, neocortical temporal cortex (Berron et al, 2021)).…”

Section: Discussionmentioning

confidence: 99%

Cortical Tau Aggregation Patterns associated with Apraxia in Alzheimer‘s Disease

Bischof,

Jaeger,

Giehl

et al. 2024

Preprint

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ObjectivesApraxia is a core feature of Alzheimer’s disease, but the pathomechanism of this characteristic symptom is not well understood. Here, we systematically investigated apraxia profiles in a well-defined group of patients with Alzheimer’s disease (AD; N=32) who additionally underwent PET imaging with the second-generation tau PET tracer [18F]PI-2620. We hypothesized that specific patterns of tau pathology might be related to apraxic deficits.MethodsPatients (N=32) with a biomarker-confirmed diagnosis of Alzheimer’s disease were recruited in addition to a sample cognitively unimpaired controls (CU1; N=41). Both groups underwent in-depth neuropsychological assessment of apraxia (Dementia Apraxia Screening Test; DATE and the Cologne Apraxia Screening; KAS). In addition, static PET imaging with [18F]PI-2620 was performed to assess tau pathology in the AD patients. To specifically investigate the association of apraxia with regional tau-pathology, we compared the PET-data from this group with an independent sample of amyloid-negative cognitively intact participants (CU2;N=54) by generation of z-score-deviation maps as well as voxel- based multiple regression analyses.ResultsWe identified significant clusters of tau-aggregation in praxis-related regions (e.g., supramarginal gyrus, angular gyrus, temporal, parietal and occipital regions) that were associated with apraxia. These regions were similar between the two apraxia assessments. No correlations between tau-tracer uptake in primary motor cortical or subcortical brain regions and apraxia were observed.ConclusionsThese results suggest that tau deposition in specific cortical brain regions may induce local neuronal dysfunction leading to a dose-dependent functional decline in praxis performance.

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“…Of the 3 broad categories of biomarkers in both 2018 initial and 2023 updated A/T/N research frameworks by the National Institute on Aging and the Alzheimer’s Association (NIA-AA), the detection of the misfolded proteins including Aβ and tau through the brain molecular imaging and body fluid examination was at the core of the framework [22, 60]. A new study evaluating the importance of various brain imaging modalities in monitoring cognition and predicting cognitive decline in memory clinics has observed that neocortical tau pathology is the main determinant of cognitive decline over time and the prognostic value of tau-PET surpassed all other neuroimaging measures [7]. One of the significant advances in the updated 2023 research framework is the addition of plasma biomarkers developed recently to the new version, while the 2018 version mainly depended on biomarkers from CSF and brain imaging [22, 60].…”

Section: Discussionmentioning

confidence: 99%

Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

Wang,

Wu,

Gerasimenko

et al. 2023

Preprint

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Tauopathies are a group of age-related neurodegenerative diseases with a molecular hallmark of the prion-like propagation and accumulation of pathologically phosphorylated tau protein in the brain. They include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Currently, in the peripheral tissues and body fluids there are no reliable diagnostic biomarkers available that are able to directly reflect the capability of propagation and spreading of the misfolded tau aggregates. Here, we revealed significantly increased amounts of phosphorylated tau in the skin of AD patients compared to those in other tauopathies and normal controls. Moreover, the seed-amplification assay (SAA) by the ultrasensitive real-time quaking-induced conversion (RT-QuIC) displayed that the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies including AD, PSP, CBD, PiD was dramatically higher than that in normal controls, yielding 75-80% sensitivity and 95-100% specificity, respectively, depending on different tau substrates used. The increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients. Moreover, analysis of the end products of skin-tau SAA confirmed that the increased seeding activity is accompanied with formation of tau aggregates that are of different physicochemical properties determined by the different tau-substrates used. Our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of the skin misfolded tau can serve as an accurate diagnostic biomarker of tauopathies.

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The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive decline

Cited by 25 publications

References 82 publications

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

Cortical Tau Aggregation Patterns associated with Apraxia in Alzheimer‘s Disease

Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

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