“New Old Pathologies”: AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS)

Nelson, Peter T.; Trojanowski, John Q.; Abner, Erin L.; Al‐Janabi, Omar; Jicha, Gregory A.; Schmitt, Frederick A.; Smith, Charles D.; Fardo, David W.; Wang, Wang‐Xia; Neltner, Janna H.; Kukull, Walter A.; Cykowski, Matthew D.; Eldik, Linda J. Van; Ighodaro, Eseosa T.

doi:10.1093/jnen/nlw033

Cited by 137 publications

(155 citation statements)

References 274 publications

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“…This further emphasizes that TDP-43 is not an epiphenomenon across the AD spectrum. In line with the idea that co-pathologies increase with age [19], these patients were older than those without TDP-43, more likely to have hippocampal sclerosis, and tended to have more cardiovascular disease. Future studies could further assess the differential effect of these pathologies in middle-aged and older adults.…”

Section: Discussionsupporting

confidence: 72%

TDP-43 and Alzheimer’s Disease Pathologic Subtype in Non-Amnestic Alzheimer’s Disease Dementia

Sahoo

Bejanin

Murray

et al. 2018

JAD

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Background: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer’s disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with a non-amnestic phenotype is unknown. Objective: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. Methods: All cases with pathologically confirmed intermediate-high probability AD from 1996–2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. Results: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p=0.02) and age at death (p=0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. Conclusion: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

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Section: Discussionsupporting

confidence: 72%

TDP-43 and Alzheimer’s Disease Pathologic Subtype in Non-Amnestic Alzheimer’s Disease Dementia

Sahoo

Bejanin

Murray

et al. 2018

JAD

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“…TDP-43 pathology is a key component of the pathologic phenotype [3, 66]. Although TDP-43 pathology in CARTS is conspicuous within neurons and neurites [2, 34, 65], astrocytes may play an active role in the pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…We proposed a descriptive designation, “Cerebral age-related TDP-43 with sclerosis” (CARTS) [66]. The new terminology reflects that there is a distinct disease that preferentially affects persons in advanced old age and TDP-43 pathology is a relatively specific marker.…”

Section: Introductionmentioning

confidence: 99%

“…The new terminology reflects that there is a distinct disease that preferentially affects persons in advanced old age and TDP-43 pathology is a relatively specific marker. These characterizations were based on clinical-pathologic correlation, neuroimaging, and genetic data [66]. …”

Section: Introductionmentioning

confidence: 99%

“…CARTS has a large impact on public health according to studies from multiple high-quality autopsy series [65, 66, 100]. The disease affects approximately 20% of persons in advanced old age [47, 64, 69, 101], and is associated with substantial cognitive impairment [11, 58, 60].…”

Section: Introductionmentioning

confidence: 99%

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Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

et al. 2016

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We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data; n=2,113, including 241 autopsy-confirmed HS cases). Further, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer’s Disease Neuroimaging Initiative data; n=1,239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p<0.04 in two separately analyzed groups), but not in Alzheimer’s disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.

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Prediction of neuropathologic lesions from clinical data

Phongpreecha

Cholerton

Bhukari

et al. 2023

Alzheimer's & Dementia

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INTRODUCTION:Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS:This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS:Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.Thomas J. Montine and Nima Aghaeepour contributed equally to this work.

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“New Old Pathologies”: AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS)

Cited by 137 publications

References 274 publications

TDP-43 and Alzheimer’s Disease Pathologic Subtype in Non-Amnestic Alzheimer’s Disease Dementia

TDP-43 and Alzheimer’s Disease Pathologic Subtype in Non-Amnestic Alzheimer’s Disease Dementia

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

Prediction of neuropathologic lesions from clinical data

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