Higher Prevalence of TDP‐43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample

Abstract

Transactive response DNA binding-protein 43 (TDP-43) proteinopathy is the major hallmark of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. It is also present in a subset of Alzheimer’s disease cases. Recently, few reports showed TDP-43 changes in cognitively normal elderly. In Caucasians, TDP-43 proteinopathy independently correlate with cognitive decline. However, it is challenging to establish direct links between cognitive and/or neuropsychiatric symptoms and protein inclusions in neurodegenerative diseases because individual cognitive reserves modify the threshold for clinical disease expression. Cognitive reserve is influenced by demographic, environmental and genetic factors. We investigated the relationships between demographic, clinical, and neuropathological variables and TDP-43 proteinopathy in a large multiethnic sample of cognitively normal elderly. TDP-43 proteinopathy were identified in 10.5%, independently associated with older age (p = 0.03) and Asian ethnicity (p = 0.002). Asians showed a higher prevalence of TDP-43 proteinopathy than Caucasians, even after adjustment for sex, age, Braak stage, and schooling (odds ratio = 3.50, confidence interval 1.41–8.69, p = 0.007). These findings suggested Asians older adults may be protected from the clinical manifestation of brain TDP-43 proteinopathy. Future studies are needed to identify possible race-related protective factors against clinical expression of TDP-43 proteinopathies.

Prevalence of transactive response DNA‐binding protein 43 (TDP‐43) proteinopathy in cognitively normal older adults: systematic review and meta‐analysis

“…Ethnicity also impacts the prevalence of age-related diseases, such as hypertension, cardiovascular disease [65,66], and dementia [67]. Interestingly, our recently published data showed that cognitively normal Asians were more prone to exhibit TDP-43 proteinopathy, when compared to Caucasians, even after we controlled for age, sex and education [16].…”

Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

“…The Brazilian population is highly mixed genetically, mainly due to historical waves of immigration from Africa, Europe, and Asia. We have shown before that African and Japanese ancestry may modify the risk for specific neurodegenerative lesions [36,63]. Quantitative studies are necessary to investigate if the same is true for cerebrovascular lesions.…”

“…All sections were stained with hematoxylin and eosin. Immunohistochemistry with antibodies against β-amyloid (4G8, 1:10.000; Signet Pathology Systems, Dedham, Massachusetts), phosphorylated tau (PHF-1, 1:2.000; gift from Peter Davies, New York), TDP-43 (1:500, Proteintech, Chicago, Illinois), and α-synuclein (EQV-1, 1:10.000; gift from Kenji Ueda, Tokyo, Japan) were performed in selected sections [22,36,37]. Internationally accepted neuropathological criteria were used to stage and diagnose the brain pathologies [38–42].…”

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype

“…TDP-43 pathology has been frequently shown in cognitively normal elderly individuals, and this pathology increased with age [15,3,47]. In contrast, a recent study demonstrated that advanced age at death was associated with prevalence of TDP-43 pathology in cognitively normal individuals, but not in patients with AD, DLB, or those with mixed AD and DLB [43].…”