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

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Abnormal accumulation of transactive response DNA‐binding protein 43 (TDP‐43) is found in several age‐related diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) 1. Indeed, expression of clinical symptoms during disease progression follows regional and cell‐specific patterns of pathological TDP‐43 accumulation 3. For example, in FTD behavioural variant, TDP‐43 inclusions are present in brain regions that play a central role in emotional control, such as in the orbitofrontal cortex and the amygdala, while in ALS the encephalic regions responsible for motor control are primarily affected 4. In the semantic variant of FTD, left lateral temporal cortex atrophy is associated with frontotemporal lobar degeneration with accumulation of TDP‐43 (FTLD‐TDP). TDP‐43 pathology has been also associated with aggravated memory loss and medial temporal atrophy in AD, which are major features of the disease 6. Furthermore, TDP‐43 proteinopathy have been independently associated with more rapid cognitive decline and impairment of episodic memory in older adults 7.
Pathological changes in the brain may be present decades before the onset of clinical symptoms 8. Early detection of neurodegenerative diseases is crucial to better understand their pathophysiology and improve the diagnosis and treatment of these diseases. Tools to assess pathological accumulation of proteins related to other neurodegenerative diseases in patients, such as tau and β‐amyloid 10, are now possible to be used in patients. However, approaches to detect TDP‐43 accumulation in vivo in humans are not yet available 13. A way to better understand the early changes in TDP‐43 protein is studying its prevalence through post mortem neuropathological evaluation in cognitively normal older adults. These studies have shown a wide variation in TDP‐43 frequency, ranging from 8% to 52% 14. In this study, we performed a systematic review of the literature on the prevalence of TDP‐43 proteinopathy in cognitively normal older adults.
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