Shahidehpour Ryan K, Katsumata Yuriko, Dickson Dennis W, Ghayal Nikhil B, Aung Khine Zin, Wu Xian, Phe Panhavuth, Jicha Gregory A, Neltner Allison M, Archer Jessalin R C, Corrada Maria M, Kawas Claudia H, Ahmad Sajjadi S, Woodworth Davis C, Bukhari Syed A, Montine Thomas J, Fardo David W, Nelson Peter T
Sanders-Brown Center On Aging, University of Kentucky, Rm 575 Lee Todd Jr Bldg/U. Kentucky, 789 S. Limestone Ave, Lexington, KY, 40536, USA.
Department of Neuroscience, University of Kentucky, Lexington, KY, USA.
Acta Neuropathol. 2025 Apr 28;149(1):38. doi: 10.1007/s00401-025-02876-5.
A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In LATE-NC Stage 3, TDP-43 proteinopathy is present in the middle frontal gyrus (MFG), thus posing a potential diagnostic challenge in differentiating these severe LATE-NC cases from FTLD-TDP. LATE-NC Stage 3 cases and other TDP-43 proteinopathies were analyzed from the University of Kentucky (total n = 514 with TDP-43 pathology assessed), The 90+ Study at the University of California Irvine (n = 458), and the Mayo Clinic (n = 5067) brain banks. Digital pathology was used to quantify pathology burden in a select subset of cases (n = 51), complemented by a previously-described manual counting method and expert neuropathologic examinations to evaluate qualitative features such as FTLD-TDP types and subtypes of neuronal cytoplasmic inclusions (NCIs). To evaluate clinical and genetic characteristics of LATE-NC Stage 3, data were analyzed from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data set and correlated with findings from the Alzheimer's Disease Genetics Consortium (ADGC). When using TDP-43 proteinopathy quantification in the MFG as a diagnostic criterion, more than 90% of cases could be classified as either LATE-NC Stage 3 or FTLD-TDP. Diagnostically challenging scenarios included a subset of FTLD-TDP Type B cases with relatively mild MFG TDP-43 pathology and a novel non-LATE-NC, non-FTLD-TDP pathologic subtype with severe MFG TDP-43 pathology. Taking these potential pitfalls into account, a classification schema was developed that could correctly diagnose all included cases. There was no difference in the Alzheimer's disease pathological load in LATE-NC Stages 2 versus 3. In genetic analyses, the GRN (rs5848) risk allele was preferentially associated with LATE-NC Stage 3, whereas TMEM106B and APOE risk-associated variants were not. In conclusion, LATE-NC Stage 3 could be differentiated reliably from FTLD-TDP and other TDP-43-opathies, based on a data-driven diagnostic rubric.
需要一种诊断标准来区分以边缘系统为主的年龄相关性TDP-43脑病神经病理改变（LATE-NC）和伴有TDP-43包涵体的额颞叶变性（FTLD-TDP）。在LATE-NC 3期，TDP-43蛋白病存在于额中回（MFG），因此在将这些严重的LATE-NC病例与FTLD-TDP区分开来时面临潜在的诊断挑战。对肯塔基大学（共514例评估了TDP-43病理）、加利福尼亚大学欧文分校的90+研究（458例）以及梅奥诊所（5067例）脑库中的LATE-NC 3期病例和其他TDP-43蛋白病进行了分析。使用数字病理学对部分病例（51例）的病理负担进行量化，并辅以先前描述的手动计数方法和专家神经病理学检查，以评估定性特征，如FTLD-TDP类型和神经元胞质包涵体（NCI）的亚型。为了评估LATE-NC 3期的临床和遗传特征，对国家阿尔茨海默病协调中心（NACC）神经病理学数据集的数据进行了分析，并与阿尔茨海默病遗传学联盟（ADGC）的研究结果进行了关联。当将MFG中TDP-43蛋白病的量化用作诊断标准时，超过90%的病例可被分类为LATE-NC 3期或FTLD-TDP。诊断具有挑战性的情况包括一部分MFG中TDP-43病理相对较轻的B型FTLD-TDP病例，以及一种新的非LATE-NC、非FTLD-TDP病理亚型，其MFG中TDP-43病理严重。考虑到这些潜在的陷阱，制定了一种分类方案，该方案可以正确诊断所有纳入的病例。LATE-NC 2期和3期的阿尔茨海默病病理负担没有差异。在基因分析中，GRN（rs5848）风险等位基因优先与LATE-NC 3期相关，而TMEM106B和APOE风险相关变体则不然。总之，基于数据驱动的诊断标准，LATE-NC 3期可以与FTLD-TDP和其他TDP-43蛋白病可靠区分。
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