Synaptic injury is an important pathological feature of Alzheimer disease (AD) which is present in even the earliest pre-symptomatic stages and continues with further disease progression. Synaptic loss in AD is thought to result from various pathological α-substrates including synaptic toxicity of abnormal protein aggregates, such as amyloid-β oligomers and various forms of hyperphosphorylated tau, abnormal α-synuclein and TDP-43 aggregation, and other mechanisms such as microglial and astrocytic dysregulation, oxidative stress, mitochondrial damage, and vascular or endothelial injury. Brain expression of several pre-synaptic and post-synaptic proteins is reduced in AD. Cortical and hippocampal synaptic density is reduced by 30% and 50%, respectively, in even the early symptomatic stages which is thought to result from both neuronal loss and reduced synaptic density per neuron. Recent evidence suggests that, while common mechanisms of synaptic injury are shared across different neurodegenerative disorders, other mechanisms of synaptic injury may be relatively specific to AD. Clinicopathological studies converge on the notion that synaptic loss is the best surrogate for cognitive impairment and is more closely associated with cognitive outcomes than amyloid or tau pathologies. Therefore, there has been increasing interest in identifying novel fluid and imaging markers of synaptic injury as these may provide important prognostic information regarding clinical disease progression. Further, synaptic markers that reflect disease-specific mechanisms may improve early diagnosis and complement other diagnostic tools. Importantly, there has been an interest in integrating synaptic injury markers as biomarker surrogate endpoints to demonstrate disease modification in clinical trials of emerging therapies in AD and related dementias. The last few years have witnessed considerable progress in identifying and validating new markers of synaptic injury in the cerebrospinal fluid (CSF). Some of these markers, such as neurogranin, offer great promise as dynamic measures that correlate with clinical progression in longitudinal studies. However, there remains a need to identify new proteins that can be measured in the blood and serve as useful surrogates for synaptic injury in AD-vulnerable brain regions or identify new methods to reliably quantify synaptic markers, which have already been established in the CSF, in the periphery. This chapter summarizes the current state of the most promising fluid and imaging markers of synaptic injury in AD and highlights important areas for future research.

Fluid and Imaging Markers of Synaptic Injury

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发表日期：

2025年

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Rawan Tarawneh

摘要

Synaptic injury is an important pathological feature of Alzheimer disease (AD) which is present in even the earliest pre-symptomatic stages and continues with further disease progression. Synaptic loss in AD is thought to result from various pathological α-substrates including synaptic toxicity of abnormal protein aggregates, such as amyloid-β oligomers and various forms of hyperphosphorylated tau, abnormal α-synuclein and TDP-43 aggregation, and other mechanisms such as microglial and astrocytic dysregulation, oxidative stress, mitochondrial damage, and vascular or endothelial injury. Brain expression of several pre-synaptic and post-synaptic proteins is reduced in AD. Cortical and hippocampal synaptic density is reduced by 30% and 50%, respectively, in even the early symptomatic stages which is thought to result from both neuronal loss and reduced synaptic density per neuron. Recent evidence suggests that, while common mechanisms of synaptic injury are shared across different neurodegenerative disorders, other mechanisms of synaptic injury may be relatively specific to AD. Clinicopathological studies converge on the notion that synaptic loss is the best surrogate for cognitive impairment and is more closely associated with cognitive outcomes than amyloid or tau pathologies. Therefore, there has been increasing interest in identifying novel fluid and imaging markers of synaptic injury as these may provide important prognostic information regarding clinical disease progression. Further, synaptic markers that reflect disease-specific mechanisms may improve early diagnosis and complement other diagnostic tools. Importantly, there has been an interest in integrating synaptic injury markers as biomarker surrogate endpoints to demonstrate disease modification in clinical trials of emerging therapies in AD and related dementias. The last few years have witnessed considerable progress in identifying and validating new markers of synaptic injury in the cerebrospinal fluid (CSF). Some of these markers, such as neurogranin, offer great promise as dynamic measures that correlate with clinical progression in longitudinal studies. However, there remains a need to identify new proteins that can be measured in the blood and serve as useful surrogates for synaptic injury in AD-vulnerable brain regions or identify new methods to reliably quantify synaptic markers, which have already been established in the CSF, in the periphery. This chapter summarizes the current state of the most promising fluid and imaging markers of synaptic injury in AD and highlights important areas for future research.