Propagation of TDP-43 proteinopathy in neurodegenerative disorders

Geula, Changiz; Jamshidi, Pouya; Kawles, Allegra; Minogue, Grace; Zaccard, Colleen R.; Mesulam, Marsel

doi:10.4103/1673-5374.330609

Cited by 4 publications

(5 citation statements)

References 13 publications

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“…Our results showed the highest balanced accuracy of classification for svPPA at 0.89. svPPA is commonly associated with striking asymmetric atrophy of the dominant hemisphere temporal pole ( Rogalski et al, 2011 ). This distinctive atrophy pattern is usually due to the presence of TDP-43 Type C neuropathology in these regions ( Kawles et al, 2022 ; Keszycki et al, 2022 ). The high discriminative accuracy found in the present study is, therefore, unsurprising given this distinctive neuropathological profile and resultant neuroanatomical pattern of atrophy.…”

Section: Discussionmentioning

confidence: 99%

Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI

Ma,

Stocks,

Rosen

et al. 2024

Front. Neurosci.

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BackgroundFrontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN).MethodsData from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach.ResultsThe proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping.ConclusionIn this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.

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Section: Discussionmentioning

confidence: 99%

Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI

Ma,

Stocks,

Rosen

et al. 2024

Front. Neurosci.

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“…Mexican urbanites exposed to complex mixtures of air pollutants, including PM 2.5 above current EPA US standards and highly toxic UFPM have CSF TDP-43 concentrations exponentially increasing with age. TDP-43 is the target protein associated with ALS and fronto-temporal dementia (FTD) [ 39 , 40 , 41 , 42 , 43 , 44 , 66 , 67 , 68 ]. Remarkably, concentrations of TDP-43 in cisternal CSF with averages of 572 ± 208 pg/mL forecasted cortical and subcortical TDP-43 pathology, while averages of 232 ± 130 pg/mL were associated with no TDP-43 brain pathology in any of the study subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Research regarding TDP-43, including novel nuclear pore articles, muscle TDP-43 involvement and the anatomical targets [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ], must be revisited in the context of potential early involvement in pollution-exposed populations. For example, it could be particularly intriguing to look for nuclear NPs in motor neurons of highly exposed city dwellers [ 107 ] and hypothalamic TDP-43 lesions [ 111 ].…”

Section: Discussionmentioning

confidence: 99%

“…There is a strong association between TAR DNA-binding protein 43, frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) [ 39 , 40 , 41 , 42 , 43 , 44 , 51 , 52 ]; thus, our findings in young, highly PM-exposed megacity residents are highly relevant for the global medical community, from both the neuropathology and clinical viewpoints.…”

Section: Introductionmentioning

confidence: 92%

“…TDP-43 nuclear depletion and aggregation are hallmarks of ALS and frontotemporal dementia (FTD) [ 39 , 40 , 41 , 42 ]. TDP-43 immunocytochemical profiles in children and young MMC adults have shown loss of nuclear expression and powdery cytoplasmic particles in the substantia nigrae pars compacta and non-motor neurons, as well as significant involvement of mesencephalic, pontine and medullary reticular formation [ 2 , 41 , 42 , 43 , 44 ]. Of particular concern, we have reported sleep disorders in MMC residents [ 45 ] along key brainstem sleep and arousal hubs, showing solid UFPM from anthropogenic combustion, mainly diesel exhaust, as well as non-exhaust sources coming from tire and brake wearing and from engineered NPs [ 46 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

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TDP-43 CSF Concentrations Increase Exponentially with Age in Metropolitan Mexico City Young Urbanites Highly Exposed to PM2.5 and Ultrafine Particles and Historically Showing Alzheimer and Parkinson’s Hallmarks. Brain TDP-43 Pathology in MMC Residents Is Associated with High Cisternal CSF TDP-43 Concentrations

Calderón‐Garcidueñas

Stommel

Lachmann³

et al. 2022

Toxics

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Environmental exposures to fine particulate matter (PM2.5) and ultrafine particle matter (UFPM) are associated with overlapping Alzheimer’s, Parkinson’s and TAR DNA-binding protein 43 (TDP-43) hallmark protein pathologies in young Metropolitan Mexico City (MMC) urbanites. We measured CSF concentrations of TDP-43 in 194 urban residents, including 92 MMC children aged 10.2 ± 4.7 y exposed to PM2.5 levels above the USEPA annual standard and to high UFPM and 26 low pollution controls (11.5 ± 4.4 y); 43 MMC adults (42.3 ± 15.9 y) and 14 low pollution adult controls (33.1 ± 12.0 y); and 19 amyotrophic lateral sclerosis (ALS) patients (52.4 ± 14.1 y). TDP-43 neuropathology and cisternal CSF data from 20 subjects—15 MMC (41.1 ± 18.9 y) and 5 low pollution controls (46 ± 16.01 y)—were included. CSF TDP-43 exponentially increased with age (p < 0.0001) and it was higher for MMC residents. TDP-43 cisternal CSF levels of 572 ± 208 pg/mL in 6/15 MMC autopsy cases forecasted TDP-43 in the olfactory bulb, medulla and pons, reticular formation and motor nuclei neurons. A 16 y old with TDP-43 cisternal levels of 1030 pg/mL exhibited TDP-43 pathology and all 15 MMC autopsy cases exhibited AD and PD hallmarks. Overlapping TDP-43, AD and PD pathologies start in childhood in urbanites with high exposures to PM2.5 and UFPM. Early, sustained exposures to PM air pollution represent a high risk for developing brains and MMC UFPM emissions sources ought to be clearly identified, regulated, monitored and controlled. Prevention of deadly neurologic diseases associated with air pollution ought to be a public health priority and preventive medicine is key.

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The role of TDP-43 protein in amyotrophic lateral sclerosis

Włodarczyk

Witczak

Gajewska

et al. 2022

JMS

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease where both upper and lower motoneurons are damaged. Even though the pathogenesis of ALS is unclear, the TDP-43 aggregations and non-nuclear localization may be crucial to understanding this process. Despite intensive research on ALS therapies, only two lifespan-prolonging medications have been approved: Riluzole and Edaravone. Unravelling the TDP-43 pathology could help develop new ALS therapies using mechanisms such as inhibition of nuclear export, autophagy, chaperones, or antisense oligonucleotides. Selective inhibitors of nuclear export (SINEs) are drugs that block Exportin 1 (XPO1) and cause the accumulation of not exported molecules inside the nucleus. SINEs that target XPO1 are shown to slightly extend the survival of neurons and soften motor symptoms. Dysfunctional proteins, including TDP-43, can be eliminated through autophagocytosis, which is regulated by the mTOR kinase. Stimulating the elimination of protein deposits may be an effective ALS therapy. Antisense oligonucleotides (ASO) are single-stranded, synthetic oligonucleotides that can bind and modulate specific RNA: via ribonuclease H, inducing their degradation or inducing alternative splicing via blocking primary RNA transcripts. Current ASOs therapies used in ALS focus on SOD1, C9ORF72, FUS, and ATXN2, and they may be used to slow the ALS progression. Reversing the aggregation is a promising therapeutic strategy. Chaperones control other proteins' quality and protect them against stress factors. Due to the irreversible character of ALS, it is essential to understand its complicated pathology better and to seek new therapies.

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Propagation of TDP-43 proteinopathy in neurodegenerative disorders

Cited by 4 publications

References 13 publications

Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI

Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI

The role of TDP-43 protein in amyotrophic lateral sclerosis

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