Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern

Vanderlinden, Greet; Ceccarini, Jenny; Michiels, Laura; Lemmens, Robin; Triau, Eric; Serdons, Kim; Tournoy, Jos; Vandenbulcke, Mathieu; Laere, Koen Van

doi:10.1038/s41380-022-01672-x

Cited by 22 publications

(18 citation statements)

References 70 publications

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“…12 In a 2-year follow-up study, Vanderlinden et al observed the synaptic loss followed the specific tau build-up pattern, indicating that the accumulation of tau might drive synaptic vulnerability. 17 Our results justify further studies to clarify the relationship between synapse loss, tau deposition and network dysfunction.…”

Section: Discussionsupporting

confidence: 59%

“…The outcome measure for SV2A was standardized uptake value ratios (SUVR), 12,17,19 and we employed an automatic pipeline implemented in FreeSurfer 7.1.1 (https://surfer.nmr.mgh.harvard.edu/fswiki/PetSurfer) to extract cortical and subcortical SUVR. In detail, structural T1 images were used to create a high-resolution segmentation to run the partial volume correction (PVC) methods.…”

Section: Pet Image Analysismentioning

confidence: 99%

“…11 11 C-UCB-J was developed as a PET tracer for SV2A and was widely used in a variety of neuropsychiatric diseases. [11][12][13][14][15][16][17] The 18 F-labeled SV2A PET imaging was developed partly due to its longer radioactive half-life compared to 11 C-UCB-J, which will improve the accessibility, enable multicenter studies, and accelerate their potential clinical applications. 18 As an 18 F-labeled difluoro-analog of UCB-J, 18 F-SynVesT-1 has good properties similar to 11 C-UCB-J, which include high brain uptake, fast and reversible kinetics, and high specific binding.…”

Section: Introductionmentioning

confidence: 99%

“…23 Moreover, Vanderlinden et al demonstrated that the spatial decrease of synaptic density follows the specific tau build-up pattern in amnestic MCI patients in the two-year follow-up study. 17 However, whether and how synapse loss relates to functional and structural connectivity dysfunction, which may contribute to the neurobiology underlying cognitive impairment in AD, is unclear.…”

Section: Introductionmentioning

confidence: 99%

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In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

Zhang

Wang

et al. 2023

J Cereb Blood Flow Metab

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Synapse loss has been considered as a major pathological change in Alzheimer’s disease (AD). It remains unclear about whether and how synapse loss relates to functional and structural connectivity dysfunction in AD. We measured synaptic vesicle glycoprotein 2 A (SV2A) binding using 18F-SynVesT-1 PET to evaluate synaptic alterations in 33 participants with AD, 31 with mild cognitive impairment (MCI), and 30 controls. We examined the correlation between synaptic density and cognitive function. Functional MRI was performed to analyze functional connectivity in lower synaptic density regions. We tracked the white matter tracts between impaired functional connectivity regions using Diffusion MRI. In AD group, lower synaptic density in bilateral cortex and hippocampus was found when compared with controls. The synaptic density changes in right insular cortex and bilateral caudal middle frontal gyrus (MFG) were correlated with cognitive decline. Among them, right MFG synaptic density was positively associated with right MFG - bilateral superior frontal gyrus (SFG) functional connectivity. AD had lower probability of tract (POT) between right MFG and SFG than controls, which was significantly associated with global cognition. These findings provide evidence supporting synapse loss contributes to functional and related structural connectivity alterations underlying cognitive impairment of AD.

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Section: Discussionsupporting

confidence: 59%

Section: Pet Image Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

Zhang

Wang

et al. 2023

J Cereb Blood Flow Metab

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“…The evidence for progressive in vivo synaptic loss, as measured with longitudinal [ 11 C]UCB-J PET imaging, is however limited. Vanderlinden and colleagues 40 have recently reported significant progressive reductions (6%-9%) in patients with amnestic mild cognitive impairment, over 2 years, correlating with cognitive decline. Venkataraman and colleagues 41 observed reduced baseline [ 11 C]UCB-J binding potential in disease-specific areas in eight patients with Alzheimer's disease, but they did not find significant progressive loss over 12 to 18 months of follow-up.…”

Section: Discussionmentioning

confidence: 97%

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [¹¹C]UCB‐J Positron Emission Tomography Study

et al. 2023

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Background Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. Objective In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. Methods Our cross‐sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid‐negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex‐ and age‐matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11C]UCB‐J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11C]UCB‐J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty‐two participants with PSP/CBD had a follow‐up [11C]UCB‐J positron emission tomography scan after 1 year. We calculated the annualized change in [11C]UCB‐J nondisplaceable binding potential and correlated this with the change in clinical severity. Results We found significant annual synaptic loss within the frontal lobe (−3.5%, P = 0.03) and the right caudate (−3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination–Revised, R = −0.62, P = 0.003). Conclusions We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early‐phase clinical trials of disease‐modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Tracing synaptic loss in Alzheimer's brain with SV2A PET‐tracer UCB‐J

Kumar,

Scarpa,

Nordberg

2024

Alzheimer's & Dementia

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INTRODUCTIONSynaptic loss is an early prominent feature of Alzheimer's disease (AD). The recently developed novel synaptic vesicle 2A protein (SV2A) PET‐tracer UCB‐J has shown great promise in tracking synaptic loss in AD. However, there have been discrepancies between the findings and a lack of mechanistic insight.METHODSHere we report the first extensive pre‐clinical validation studies for UCB‐J in control (CN; n = 11) and AD (n = 11) brains using a multidimensional approach of post‐mortem brain imaging techniques, radioligand binding, and biochemical studies.RESULTS AND DISCUSSIONWe demonstrate that UCB‐J could target SV2A protein with high specificity and depict synaptic loss at synaptosome levels in AD brain regions compared to CNs. UCB‐J showed highest synaptic loss in AD hippocampus followed in descending order by frontal cortex, temporal cortex, parietal cortex, and cerebellum. 3H‐UCB‐J large brain‐section autoradiography and cellular/subcellular fractions binding studies indicated potential off‐target interaction with phosphorylated tau (p‐tau) species in AD brains, which could have subsequent clinical implications for imaging studies.Highlights Synaptic positron emission tomography (PET)–tracer UCB‐J could target synaptic vesicle 2A protein (SV2A) with high specificity in Alzheimer's disease (AD) and control brains. Synaptic PET‐tracer UCB‐J could depict synaptic loss at synaptosome levels in AD brain regions compared to control. Potential off‐target interaction of UCB‐J with phosphorylated tau (p‐tau) species at cellular/subcellular levels could have subsequent clinical implications for imaging studies, warranting further investigations.

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Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern

Cited by 22 publications

References 70 publications

In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [¹¹C]UCB‐J Positron Emission Tomography Study

Tracing synaptic loss in Alzheimer's brain with SV2A PET‐tracer UCB‐J

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Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern

Cited by 22 publications

References 70 publications

In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11C]UCB‐J Positron Emission Tomography Study

Tracing synaptic loss in Alzheimer's brain with SV2A PET‐tracer UCB‐J

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Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [¹¹C]UCB‐J Positron Emission Tomography Study