Research Report Titled “Comprehensive Evaluation of TDP-43 Neuropathology Data in the National Alzheimer’s Coordinating Center Database”

Research Background

TDP-43 proteinopathy is a significant neuropathological feature in frontotemporal lobar degeneration (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and age-related limbic TDP-43 encephalopathy neuropathological changes (LATE-NC). These diseases are closely associated with hippocampal sclerosis of aging (HS-A). Studies have shown that TDP-43 proteinopathy appears in up to 95% of ALS patients and about 50% of FTLD patients. Therefore, the role of TDP-43 in these conditions has become a focus of research. To further understand the role of TDP-43 proteinopathy in different types of neurodegenerative diseases, this study conducted a comprehensive evaluation using data from the National Alzheimer’s Coordinating Center (NACC).

Research Source

This study was jointly completed by researchers from academic institutions such as the University of California, Irvine, and the University of Kentucky. The authors include Davis C. Woodworth, Katelynn M. Nguyen, Lorena Sordo, Kiana A. Scambray, Elizabeth Head, Claudia H. Kawas, María M. Corrada, Peter T. Nelson, and S. Ahmad Sajjadi. The paper was published in the journal “Acta Neuropathologica” in 2024.

Research Objectives and Methods

The study was divided into two parts: The first part recorded the availability of TDP-43-related pathological data in the NACC, while the second part assessed the regional distribution, demographic characteristics, clinical symptoms, and co-existing neuropathological conditions of TDP-43 in participants with comprehensive TDP-43-related measurement data.

Step 1: Data Availability

1. The study included a total of 4,326 participants, with TDP-43-related data included in the neuropathological forms used.
2. The data showed the highest availability for HS-A related data (97%), followed by ALS (94%), and FTLD-TDP (83%).
3. Regional TDP-43 pathology assessments were available for 77% of the participants, with the hippocampus being the most commonly assessed region.

Step 2: Detailed Assessment

1. Among the 2,142 participants with all TDP-43-related measurement data, 27% were diagnosed with LATE-NC, 9% with ALS-TDP or FTLD-TDP, and 2% had other types of TDP-43 pathology.
2. HS-A appeared in 14% of the participants, with 55% having LATE-NC, 20% belonging to ALS/FTLD-TDP, 3% having other TDP-43 pathology, and 23% without TDP-43 proteinopathy.

Research Results

TDP-43 Data Availability

1. Centers with a higher proportion of clinical FTLD had greater availability of TDP-43-related measurement data, and the availability of these measurements gradually increased over time.
2. ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) were associated with a higher probability of dementia, HS-A, and hippocampal atrophy.

Regional TDP-43 Pathology Assessment

In the regional TDP-43 pathology assessment: 1. ALS/FTLD-TDP patients typically had TDP-43 inclusions visible in all brain regions (78%). Specifically, TDP-43 pathology characteristics were more common in the entorhinal cortex/inferior temporal cortex (95%), hippocampus (91%), neocortex (89%), and amygdala (88%). 2. The regional distribution of TDP-43 inclusions in LATE-NC patients showed significant differences. The most common TDP-43 inclusion distribution characteristic in LATE-NC patients was visibility in two regions (53%) or three regions (13%).

Clinical Characteristics and Co-Existing Pathologies

1. All TDP-43 categories (LATE-NC, ALS/FTLD-TDP, other TDP-43) were significantly associated with a higher incidence of dementia and HS-A.
2. LATE-NC patients were highly associated with clinical Alzheimer’s disease (AD) diagnosis, AD neuropathological changes (ADNC), Lewy bodies (LB), arteriolosclerosis, and cortical atrophy.
3. ALS/FTLD-TDP patients were associated with primary progressive aphasia (PPA), behavioral variant FTD (bvFTD) diagnosis, and frontotemporal atrophy, but were less related to AD clinical diagnosis, ADNC, and LB.

Conclusion

Through a thorough neuropathological assessment, this study revealed the distribution characteristics of TDP-43 in various neurodegenerative conditions and its relationship with other neuropathological changes. The results have significant scientific value, providing extensive data support for further understanding the role of TDP-43 in neurodegenerative diseases. Additionally, they hold practical application value, offering reference points for the formulation of future clinical diagnosis and treatment plans.

Research Highlights

1. This study records for the first time the distribution characteristics of TDP-43 on a national scale, particularly its presence in different brain regions.
2. It explores the co-occurrence relationship between TDP-43 and other neuropathological features, providing a new perspective for understanding the role of TDP-43 in neurodegenerative conditions.
3. It developed new classification methods to identify different types of TDP-43 pathology and proposed insights into late-stage TDP-43 proteinopathy (LATE-NC) and FTLD-TDP based on regional distribution.

Other Valuable Information

1. The study results suggest differences and similarities in TDP-43 protein pathology characteristics among various neurodegenerative diseases, emphasizing the necessity of classification based on pathological characteristics rather than solely clinical diagnosis.
2. Suggestions for future research, such as using more types of TDP-43 antibodies to improve detection sensitivity of pathological features, are provided.

This study not only enriches the understanding of the role of TDP-43 in neurodegenerative diseases but also offers valuable reference data and practical suggestions for future research and clinical practice.