Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology

Peet, Bradley; Spina, Salvatore; Mundada, Nidhi S.; Joie, Renaud La

doi:10.1007/s13311-021-01101-x

Cited by 39 publications

(31 citation statements)

References 263 publications

(427 reference statements)

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“…Increasing evidence suggests that disrupted energy metabolism in CNS is involved in the development of ALS/FTD. Reduced glucose metabolism is observed in the motor-sensory cortex of ALS patients and in the frontal lobes, striatum, and thalamus of FTD patients, including in asymptomatic carriers of the ALS/FTD-linked C9orf72 mutation [32][33][34] . Glycogen, the storage form of glucose, is elevated in ALS mice and in patients' spinal cord tissues 35,36 .…”

Section: Introductionmentioning

confidence: 99%

Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules

Wang

Tian

Jang

et al. 2022

Preprint

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Energy metabolism and membraneless organelles have been implicated in human diseases including neurodegeneration. How energy stress regulates ribonucleoprotein particles such as stress granules (SGs) is still unclear. Here we identified a unique type of granules formed under energy stress and uncovered the mechanisms by which the dynamics of diverse stress-induced granules are regulated. Severe energy stress induced the rapid formation of energy-associated stress granules (eSGs), whereas moderate energy stress delayed the clearance of conventional SGs. The formation of eSGs or the clearance of conventional SGs was regulated by the mTOR-4EBP1-eIF4E pathway or eIF4A1, involving eIF4F complex assembly or RNA condensation, respectively. In ALS patients' neurons or cortical organoids, the eSG formation was enhanced, and conventional SG clearance was impaired. These results reveal a critical role for intracellular energy in the regulation of diverse granules and suggest that an imbalance in these dynamics may contribute to the pathogenesis of relevant diseases.

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Section: Introductionmentioning

confidence: 99%

Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules

Wang

Tian

Jang

et al. 2022

Preprint

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“…The use of positron emission tomography (PET) imaging, in particular, with radiotracers that bind to aggregated forms of tau has facilitated the in vivo detection of tau neuropathology in individuals with AD (reviewed in [19,100,101]). However, tau-PET tracers do not bind strongly to most forms of FTLD-tau pathology and may exhibit off-target binding in individuals with FTLD-TDP pathology [100,101]. Alternatively, the use of CSF- and blood-based protein biomarkers holds great promise for AD [19,20,102] and FTD [21,103], although in the case of FTD, we still cannot discriminate between underlying FTLD-tau and -TDP pathology.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-seq reveals alterations in peripheralCX3CR1and nonclassical monocytes in familial tauopathy

Sirkis

Makarious

Johnson

et al. 2022

Preprint

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Background: Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. Methods: To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau. Results: Analysis of ~181,000 individual PBMC transcriptomes from MAPT pathogenic variant carriers (n = 8) and healthy non-carrier controls (n = 8) demonstrated striking differential expression in monocytes and natural killer (NK) cells. We observed a marked reduction in the expression of CX3CR1 - the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models - in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia. We confirmed differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using droplet digital PCR as an orthogonal technique for quantitative validation. Conclusions: Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

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“…Noteworthy, the patterns of neurodegenerations in bvFTD are often heterogeneous, and structural and metabolic abnormalities vary considerably ( 100 ). Distinctive patterns may be dominantly frontal or frontotemporal, with atrophy broadly restricting these regions, despite the possibility of mild parietal findings.…”

Section: Neuroimaging Evidence and Differential Diagnosis Of Ftd And Bdmentioning

confidence: 99%

Frontotemporal Dementia and Late-Onset Bipolar Disorder: The Many Directions of a Busy Road

Silva¹,

Porto

Lopes

et al. 2021

Front. Psychiatry

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It is a common pathway for patients with the behavioral variant of frontotemporal dementia (bvFTD) to be first misdiagnosed with a primary psychiatric disorder, a considerable proportion of them being diagnosed with bipolar disorder (BD). Conversely, not rarely patients presenting in late life with a first episode of mania or atypically severe depression are initially considered to have dementia before the diagnosis of late-onset BD is reached. Beyond some shared features that make these conditions particularly prone to confusion, especially in the elderly, the relationship between bvFTD and BD is far from simple. Patients with BD often have cognitive complaints as part of their psychiatric disorder but are at an increased risk of developing dementia, including FTD. Likewise, apathy and disinhibition, common features of depression and mania, respectively, are among the core features of the bvFTD syndrome, not to mention that depression may coexist with dementia. In this article, we take advantage of the current knowledge on the neurobiology of these two nosologic entities to review their historical and conceptual interplay, highlighting the clinical, genetic and neuroimaging features that may be shared by both disorders or unique to each of them.

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Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology

Cited by 39 publications

References 263 publications

Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules

Intracellular Energy Controls Dynamics of Stress-induced Ribonucleoprotein Granules

Single-cell RNA-seq reveals alterations in peripheralCX3CR1and nonclassical monocytes in familial tauopathy

Frontotemporal Dementia and Late-Onset Bipolar Disorder: The Many Directions of a Busy Road

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