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Salardini, E.

Publications and source records attributed to Salardini, E..

3 recordsLinked to original sources

Associations between fluid biomarkers and PET imaging (UCB-J) of synaptic pathology in Alzheimer's disease

INTRODUCTIONPositron Emission Tomography (PET) imaging with ligands for synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising methodology for measuring synaptic density in Alzheimers disease (AD). We investigate the relationship between SV2A PET and CSF synaptic protein changes of AD patients. METHODTwenty-one participants with early AD and 7 cognitively normal (CN) individuals underwent [11C]UCB-J PET. We used mass spectrometry to measure a panel of synaptic proteins in CSF. RESULTSIn the AD group, higher levels of syntaxin-7 and PEBP-1 were associated with lower global synaptic density. In the total sample, lower global synaptic density was associated with higher levels of AP2B1, neurogranin, {gamma}-synuclein, GDI-1, PEBP-1, syntaxin-1B, and syntaxin-7 but not with the levels of the neuronal pentraxins or 14-3-3 zeta/delta. CONCLUSIONReductions of synaptic density found in AD compared to CN participants using [11C]UCB-J PET were observed to be associated with CSF biomarker levels of synaptic proteins.

neuroscience↗

Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study

BackgroundThe pathological effects of amyloid {beta} oligomers (A{beta}o) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimers disease (AD). Positron emission tomography (PET) studies of mGluR5 using [18F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [11C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [18F]FPEB and [11C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD. MethodsFifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [18F]FPEB to measure mGluR5 and [11C]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [18F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [11C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region. ResultA strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic in the AD group (r = 0.85, p <0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions. ConclusionMedial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated A{beta}o toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss.

pathology↗

Widespread brain activity increases in frontal lobe seizures with impaired consciousness

Impaired consciousness is a serious clinical manifestation of epilepsy with negative consequences on quality of life. Little work has investigated impaired consciousness in frontal lobe seizures, a common form of focal epilepsy. In temporal lobe seizures, previous studies showed widespread cortical slow waves associated with depressed subcortical arousal and impaired consciousness. However, in frontal lobe epilepsy, it is not known whether cortical slow waves are present, or whether a very different cortical activity pattern may be related to impaired consciousness. We used intracranial EEG recordings of 65 frontal lobe seizures in 30 patients for quantitative analysis of ictal cortical activity and its relationship to impaired consciousness. Behavioral changes based on blinded review of seizure videos were used to classify focal aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures. Changes in intracranial EEG power from preictal baseline were analyzed in different cortical regions and across frequency ranges in these three categories. We found that frontal lobe focal aware seizures showed approximately 40% increases in intracranial EEG power localized to the frontal lobe of seizure onset across frequency ranges, with relatively smaller changes in other cortical regions. Frontal lobe focal impaired awareness seizures showed approximately 50% increases in intracranial EEG power, not significantly different from focal aware seizures in the frontal lobe of seizure onset (P = 1.038), but significantly greater than focal aware seizures in other broad cortical regions (P < 0.001). Importantly, the widespread cortical increases in EEG power observed in focal impaired awareness versus focal aware seizures were seen not just in the frequency range of slow waves, but were also observed across other frequencies including fast activity. However, the widespread cortical increases in focal impaired awareness seizures differed from focal to bilateral tonic-clonic seizures where intracranial EEG power increased to a much higher level by approximately 600%. The large power increases in focal to bilateral tonic-clonic were significantly greater than in focal impaired awareness seizures both in the frontal lobe of seizure onset and in other cortical regions (P < 0.001). Our findings contrast with focal temporal lobe epilepsy, where impaired consciousness is associated with cortical slow waves. We can speculate that different focal seizure types produce impaired consciousness by impacting widespread cortical regions but through different physiological mechanisms. Insights gained by studying mechanisms of impaired consciousness may be the first step towards developing novel treatments to prevent this important negative consequence of epilepsy.

neuroscience↗