Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Department of Psychology and Psychiatry, Mayo Clinic, Rochester, MN, USA.
J Alzheimers Dis. 2023;93(4):1521-1535. doi: 10.3233/JAD-221094.
Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer's disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications.
To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP.
363 participants from the Mayo Clinic Study of Aging, Alzheimer's Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1-3 were classified as Limbic, those 4-6 as Diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology.
The cohort was 61% female and old at onset (median: 76 years [IQR:70-82]) and death (median: 88 years [IQR:82-92]). Fifty-four percent were Limbic and 46% Diffuse. Clinically, ∼10-20% increases in odds of being Diffuse associated with 5-year increments in age at onset (p = 0.04), 1-year longer disease duration (p = 0.02), and higher Neuropsychiatric Inventory scores (p = 0.03), while 15-second longer Trailmaking Test-B times (p = 0.02) and higher Block Design Test scores (p = 0.02) independently decreased the odds by ~ 10-15%. There was evidence for association of APOEɛ4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3-5) decreased the odds of diffuse TDP-43 pathology by 80-90%, while hippocampal sclerosis increased it sixfold (p < 0.001).
Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP.
越来越多的证据表明，阿尔茨海默病（AD）中的 TAR DNA 结合蛋白 43（TDP-43）病理学（AD-TDP）可能是弥散性或边缘性为主。了解弥散性 AD-TDP 是否具有与边缘性 AD-TDP 不同的遗传、临床和病理学特征，可能具有临床和研究意义。
更好地描述弥散性 AD-TDP 的临床和病理学特征，并将其与边缘性 AD-TDP 区分开来。
纳入了来自 Mayo 诊所衰老研究、阿尔茨海默病研究中心和神经退行性研究组的 363 名尸检证实为 AD 和 TDP-43 病理学的参与者。所有参与者均接受了遗传、临床、神经心理学和神经病理学评估。使用 Josephs 6 级量表评估 AD-TDP 病理学分布。第 1-3 期被归类为边缘性，第 4-6 期为弥散性。多变量逻辑回归用于确定独立预测弥散性病理学的临床病理学特征。
该队列中 61%为女性，发病年龄（中位数：76 岁 [IQR：70-82]）和死亡年龄（中位数：88 岁 [IQR：82-92]）较大。54%为边缘性，46%为弥散性。临床方面，发病年龄每增加 5 年（p=0.04）、疾病持续时间增加 1 年（p=0.02）和神经精神病学评分增加（p=0.03），出现弥散性 AD-TDP 的几率增加约 10-20%，而 15 秒 Trailmaking Test-B 时间延长（p=0.02）和 Block Design Test 评分升高（p=0.02）则使几率降低约 10-15%。APOEɛ4 等位基因与边缘性 AD-TDP 相关，TMEM106B rs3173615C 等位基因与弥散性 AD-TDP 相关。病理上，广泛的淀粉样β斑块（Thal 分期：3-5）使弥散性 TDP-43 病理学的几率降低 80-90%，而海马硬化则使几率增加 6 倍（p<0.001）。
弥散性 AD-TDP 具有与边缘性 AD-TDP 不同的临床病理学和遗传学特征。
