Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Iida, Megan A.; Farrell, Kurt; Walker, Jamie M.; Richardson, Timothy E.; Marx, Gabe; Bryce, Clare; Purohit, Dushyant P.; Ayalon, Gai; Beach, Thomas G.; Bigio, Eileen H.; Cortés, Etty; Gearing, Marla; Haroutunian, Vahram; McMillan, Corey T.; Lee, Eddie B.; Dickson, Dennis W.; McKee, Ann C.; Stein, Thor D.; Trojanowski, John Q.; Woltjer, Randall L.; Kovács, Gábor G.; Kofler, Julia; Kaye, Jeffrey; White, Charles L.; Crary, John F.

doi:10.1101/2021.06.08.447553

Cited by 7 publications

(21 citation statements)

References 65 publications

(92 reference statements)

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“…Cerebrovascular pathology such as infarcts, microinfarcts, and hemorrhages also increase with age and may contribute to cognitive decline, particularly executive dysfunction, in ADNC and PART. 11,26 The severity of cognitive impairment often observed in individuals with PART is surprising given the low level and localized nature of the tangle pathology, even considering greater than expected hippocampal CA2 region involvement 27 or medial temporal left-right asymmetry. 28 We therefore hypothesized that other age-related copathologies such as LATE-NC or vascular pathology may play a significant role in the cognitive decline of these patients.…”

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confidence: 99%

TDP‐43 Pathology Exacerbates Cognitive Decline in Primary Age‐Related Tauopathy

Smirnov

Salmon

Galasko

et al. 2022

Annals of Neurology

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Objective Primary age‐related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta‐amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) are underappreciated. Methods We compare prevalence of LATE‐NC and vascular copathologies in age‐ and Braak‐matched patients with PART (n = 45, Braak stage I–IV, Thal phase 0–2) or early stage Alzheimer disease neuropathologic change (ADNC; n = 51, Braak I–IV, Thal 3–5), and examine their influence on clinical and cognitive decline. Results Concomitant LATE‐NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini‐Mental State Examination [MMSE] = 24.8 ± 6.9) and ADNC (MMSE = 24.2 ± 6.0). Patients with LATE‐NC were more impaired than those without LATE‐NC on the MMSE (by 5.8 points, 95% confidence interval [CI] = 3.0–8.6), Mattis Dementia Rating Scale (DRS; 17.5 points, 95% CI = 7.1–27.9), Clinical Dementia Rating, sum of boxes scale (CDR‐sob; 5.2 points, 95% CI = 2.1–8.2), memory composite (0.8 standard deviations [SD], 95% CI = 0.1–1.6), and language composite (1.1 SD, 95% CI = 0.2–2.0), and more likely to receive a dementia diagnosis (odds ratio = 4.8, 95% CI = 1.5–18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI = 0.1–20.3) and executive composite (1.3 SD, 95% CI = 0.3–2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death; however, LATE‐NC was associated with more rapid decline on the MMSE (β = 1.9, 95% CI = 0.9–3.0), DRS (β = 7.8, 95% CI = 3.4–12.7), CDR‐sob (β = 1.9, 95% CI = 0.4–3.7), language composite (β = 0.5 SD, 95% CI = 0.1–0.8), and vascular pathology with more rapid decline on the DRS (β = 5.2, 95% CI = 0.6–10.2). Interpretation LATE‐NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 2022;92:425–438

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confidence: 99%

TDP‐43 Pathology Exacerbates Cognitive Decline in Primary Age‐Related Tauopathy

Smirnov

Salmon

Galasko

et al. 2022

Annals of Neurology

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“…While Braak staging is highly reproducible, with one report showing that across brains and raters the kappa score was greater than 0.90 108 , it is a semiquantitative (ordinal) variable. Further studies using a more quantitative approach to measuring tau burden that we have shown more closely align with functional clinical measures in PART may reveal additional candidates 109 . Additional follow-up studies in experimental models are necessary further to validate our findings.…”

Section: Discussionmentioning

confidence: 73%

Genome-wide association study and functional validation implicates JADE1 in tauopathy

Farrell¹,

Kim²,

Han³

et al. 2021

Preprint

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Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

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“…2b, online resource). Comorbid cerebrovascular disease, which is common in this cohort, is likely responsible for the variation in cognitive impairment [39]. In summary, our cohort consists of older individuals, with a range of dementia severity, restricted regional tau distribution and varying severity of burden, demonstrating the diversity of both the clinical and neuropathological features of the condition.…”

Section: Resultsmentioning

confidence: 89%

“…Braak NFT staging is also modeled after a subset of AD cases with patterns of NFT formation that may differ somewhat from the pattern seen in PART. Furture studies using a more quantitative approach to measuring tau burden that we have shown more closely aligns with functional clinical measures in PART may reveal additional candidates [39].…”

mentioning

confidence: 68%

Genome-wide association study and functional validation implicates JADE1 in tauopathy

et al. 2021

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View full text Add to dashboard Cite

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Coimmunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

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Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Cited by 7 publications

References 65 publications

TDP‐43 Pathology Exacerbates Cognitive Decline in Primary Age‐Related Tauopathy

TDP‐43 Pathology Exacerbates Cognitive Decline in Primary Age‐Related Tauopathy

Genome-wide association study and functional validation implicates JADE1 in tauopathy

Genome-wide association study and functional validation implicates JADE1 in tauopathy

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