SYNAPSE: Synaptic plasticity, synapse loss, and proteinopathy in mild neurocognitive disorder
Short description
In this study, we aim to measure the concentration of synapses in the brain, changes in the concentration of synapses during learning (plasticity), and blood markers for Alzheimer's disease in older individuals with mild neurocognitive impairment. Measurements of synaptic concentration have recently become possible through the development of a new tracer for positron emission tomography (PET). Our goal is to unravel several mysteries surrounding the physiological processes behind cognitive impairment and Alzheimer's disease, and for the first time, investigate whether learning-related synaptic restructuring can be measured in humans.
Background
Alzheimer’s disease (AD) has immense effects on the well-being of the patient and relatives, and comes with increasing societal costs. According to the leading hypothesis, the etiology of dementia due to AD involves accumulation of amyloid-b (Ab) plaques and aggregation of phosphorylated tau protein, which in turn lead to loss of synaptic plasticity, synaptic density, and neurodegeneration. However, the etiology, especially the hypothesized sequence of events, is debated. In contrast, there is consensus that cognitive symptoms in AD are likely to be a consequence of loss of synaptic plasticity and reduction of synaptic density. This state of the field is growingly recognized, causing stakeholders and funding agencies to note the absence of research on synaptic changes in AD and call for such efforts.
The SYNAPSE study combines measurements of synaptic density in the living human brain, assessments of learning-related synaptic plasticity, and measurements of proteinopathy in older adults with mild neurocognitive impairment (mild NCD). Mild NCD is characterized by subjective and objective cognitive disturbances that do not impair independence in functional abilities. We will employ a recently developed radiotracer for positron emission tomography (PET) to estimate synaptic density, in combination with magnetic resonance imaging (MRI), clinical and neuropsychological assessments, state-of-the-art assessment of cognitive performance, and novel blood biomarkers for Ab and tau proteinopathy.
Aims
The main purpose of this study is to clarify the physiology of the early phases of cognitive impairment in older age. Specifically, we aim to (1) clarify the associations among synaptic density, learning-related synaptic plasticity, blood-based biomarkers of AD-related proteinopathy, and cognitive performance in mild NCD; (2) clarify these associations early in development of major NCD/dementia and investigate whether synaptic density, learning-related synaptic plasticity, or proteinopathy best predict impending major NCD/dementia; and (3) investigate whether synaptic density and synaptic plasticity predict the development of proteinopathy.
The results will break new ground in the understanding of the early physiological changes leading to major NCD/dementia and pave the way for future larger-scale research honing in on clinical applications, such as early diagnosis of AD and related treatment. The novel assessment of learning-related synaptic plasticity is a key feature of the study that will be of groundbreaking importance not only for the understanding of the early etiology of major NCD/dementia, but also for basic cognitive neuroscience. We can, for the first time, establish learning-related plasticity of synaptic density in humans, which is likely to be a core neural correlate of learning and memory in both healthy aging and AD, and we may study whether learning-related changes in synaptic density are related to Ab and tau pathology.
This study will provide crucial knowledge on the early etiology of cognitive impairment in older age, elucidating the associations among learning-related synaptic plasticity, synaptic density, proteinopathy, and cognitive impairment in mild NCD. The understanding of this physiology in early stage of cognitive impairment will pave the way for a next generation of clinical studies improving early diagnosis of AD, which is of great importance for appropriate referral, planning of care, and introduction of treatment. With our intervention design, we can, for the first time, factor in measurements of the plasticity of synapses, which is likely to be a core neural correlate of cognitive performance in both healthy aging and AD, and we may study whether experimentally induced changes in synaptic density are related to cognitive performance and to Ab and tau pathology.
Members
Martin Lövdén
Toms Voits
Gaia Olivo
Freja Erikson
Saga Sandkvist Studsare
Michael Schöll
Silke Kern
Ulman Lindenberger
