Frequency and distribution of TAR DNA-binding protein 43 (TDP-43) pathology increase linearly with age in a large cohort of older adults with and without dementia

Carlos, Arenn Faye; Tosakulwong, Nirubol; Weigand, Stephen D.; Boeve, Bradley F.; Knopman, David S.; Petersen, Ronald C.; Nguyen, Aivi T.; Reichard, R. Ross; Murray, Melissa E.; Dickson, Dennis W.; Josephs, Keith A.

doi:10.1007/s00401-022-02434-3

Cited by 15 publications

(23 citation statements)

References 4 publications

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“…The CSF TDP-43 results identify logarithmic increases related to age across young megacity urbanites, crucial information in view of the 18% TDP-43 pathology reported in 202 forensic MMC autopsies aged 27.29 ± 11.8 y and the overlap of aberrant hyperphosphorylated tau, beta amyloid, α synuclein and TDP-43. These data are striking in view of the work of Karanth et al [ 71 ] and Carlos et al [ 113 ]. Karanth and coworkers pointed out that quadruple misfolded proteins, including tau neurofibrillary tangles, amyloid-β [Aβ], α-synuclein and TDP-43, in the same brain are relatively common in aging.…”

Section: Discussionmentioning

confidence: 67%

“…There is an urgent need for noninvasive, reliable fluid biomarkers to diagnose early TDP-43 pathology to improve the differential diagnosis with overlapping neurodegenerative diseases that undoubtedly exhibit an extreme variability in clinical phenotypes, as described by Virgilio et al, for tau [ 112 ]. Since TDP-43 pathology increases linearly with age in older adults with and without dementia [ 113 ], the issue of prevention at early ages is certainly crucial. Identifying the individuals at highest risk of MMC TDP-43 pathology is one of our goals, and to the exploration of cognitive behavioral function tests we could add lipid metabolic traits and body complexions causally associated with the risk of FTD, as in the work of Esteban-García et al [ 114 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, dementia frequency was highest among those with quadruple misfolded proteins [ 71 ]. Carlos et al [ 113 ] made a calculation of the frequency and distribution of TDP-43 pathology in 1072 cases, average age 87 years, with AD and TDP-43 pathology and antemortem cognitive studies, including 58% with dementia, 15% with mild cognitive impairment and 27% who were cognitively intact. Carlos and colleagues showed a linear increase in TDP-43 pathology with age: 30% of subjects aged 70 had TDP-43 pathology, 42% by age 80 y and 49% by age 90.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…For example, in an attributable risk analysis based on all observed pathologic changes that may contribute to cognitive impairment in a large community cohort, LATE-NC accounted for more than 15% of identified amnestic dementia risk [ 16 , 114 ]. Similar to other age-related neurodegenerative disease processes, it is not possible to confidently predict clinical implications of LATE-NC in a given individual, especially if there are multiple concurrent pathologies [ 24 , 98 , 108 , 109 , 112 , 143 , 146 ].…”

Section: Guidance In Autopsy Reportsmentioning

confidence: 99%

LATE-NC staging in routine neuropathologic diagnosis: an update

et al. 2022

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An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

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“…The identification of the initial neuropathological stages of Alzheimer's disease (hyperphosphorylated tau and amyloid beta) (24) in 202/203 Metropolitan Mexico City forensic autopsies, with an average age of 25.4 ± 9.2 years, including 44 children with an average age of 12.89 ± 4.9 years, and the progression of the disease by the second and third decades of life, along with the concomitant development of PD and TDP-43 pathology in young urbanites, are at the core of our research efforts and our deep interest in comparing sleep disorders in patients with AD, PD, FLTD, and ALS, the involvement of aberrant neural proteins, and the presence of UFPM and NPs in sleep hubs in young highly exposed to air pollution cohorts (9)(10)(11)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

Calderón‐Garcidueñas

Torres‐Jardón²,

Greenough³

et al. 2023

Front. Neurol.

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Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aβ1 − 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.

show abstract

Frequency and distribution of TAR DNA-binding protein 43 (TDP-43) pathology increase linearly with age in a large cohort of older adults with and without dementia

Cited by 15 publications

References 4 publications

LATE-NC staging in routine neuropathologic diagnosis: an update

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

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