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2021/04/28: Endothelin-1 impairs the mind

Disrupted metabolic connectivity in dopaminergic and cholinergic networks at diferent stages of dementia from 18F‑FDG PET brain persistent homology network

cite: Hsu TW, Fuh JL, Wang DW, et al. Disrupted metabolic connectivity in dopaminergic and cholinergic networks at different stages of dementia from ¹⁸F-FDG PET brain persistent homology network. Scientific Reports. 2021 Mar;11(1):5396. DOI: 10.1038/s41598-021-84722-8.

Abstract

• Dementia is related to
  • the cellular accumulation of β‑amyloid plaques
  • tau aggregates
  • α‑synuclein aggregates
  • neurotransmitter defciencies in the dopaminergic and cholinergic pathways
• Cause: Cellular and neurochemical changes
• Challenge: the role of dopaminergic and cholinergic networks in metabolic connectivity at diferent stages of dementia remains unclear
• Methods:
  • 18F‑fuorodeoxyglucose positron emission tomography (18F‑FDG PET) imaging data to construct dopaminergic and cholinergic metabolism network
  • and used PHN analysis to track the evolution of these networks in patients with diferent stages of dementia.
• Result: The sums of the network distances in the Alzheimer’s disease and mild cognitive impairment cohorts is diferences
• Conclusion:
  1. A larger distance between brain regions can indicate poorer efciency in the integration of information.
  2. PHN analysis revealed the structural properties of and changes in the dopaminergic and cholinergic metabolism networks in patients with diferent stages of dementia at a range of thresholds.
  3. This method was able to identify dysregulation of dopaminergic and cholinergic networks in the pathology of dementia.

Introduction

Dementia

Dementia is a neurodegenerative disease^[1]:

• a progressive and chronic loss of function in
  1. cognitive
  2. motor
  3. sensory
     Caused by:
• β-amyloid plaques
• tau aggregates
• α-synuclein aggregates
• neurotransmitter deficiencies in the dopaminergic and cholinergic systems.
• Cholinergic circuity affects attention and cognition, memory and reward dysfunction,
  Else:
• Dopamine, α-synuclein werer related.

18F-FDG PET

Advantage: The main advantage of 18F-FDG PET is its high sensitivity in detecting pathologies at the molecular level, due to the transportation of 18F-fluorodeoxyglucose into the intracellular space by glucose-1 transporters and its subsequent phosphorylation through the hexokinase reaction… Each brain region can be assumed to exchange information directly or indirectly with other parts of the network through synchronized fluctuations in glucose uptake… Using the 18F-FDG PET metabolic network, local neural activity, disconnection, and neuropathology effects can be observed.

Result

striatocortical pathways in Dopaminergic

1. The SLD (single linkage distance) represents the functional distance between two brain regions

• SLD is higher in the AD and MCI groups compared with the SCD and HC groups.

2. When λ increased, the dendrogram indicated that modularity occurred from the dorsal striatum to the prefrontal and sensorimotor cortices and that the supplementary motor regions had large delays in connectivity in patients with AD and MCI, but most markedly for MCI.

• When λ increased, the clustering of brain connections occurred more slowly and at a longer distance (less efficiency in the network): MCI > AD > SCD > HC.

3. The CPL and SIP AUC values is variety among all groups.

mesolimbic pathways in Dopaminergic

2021/04/20: Endothelin-1 impairs the mind

Endothelin-1 mediated vasoconstriction leads to memory impairment and synaptic dysfunction

cite: Diwakar, L., Gowaikar, R., Chithanathan, K. et al. Endothelin-1 mediated vasoconstriction leads to memory impairment and synaptic dysfunction. Sci Rep 11, 4868 (2021). https://doi.org/10.1038/s41598-021-84258-x

Abstract

Cerebrovascular lesions are seen as white matter hyperintensity in MRI. It could be caused by micro-infracts and micro-bleeds and changing the blood flow to impair the cognitive deficits.
We developed a model to study related impact by injecting ET-1 into C57 mice.
The impediment in cerebral blood flow decreased CD31 expression around the hippocampal region, leading to memory deficits after 7 days.

• AKT-mTOR signaling cascade was downregulated but reversed after 30 days.
• activities depending on protein translation in the hippocampus were decreased.

Introduction

Dementia covers Alzheimer’s Disease (AD), Lewy body dementia, and Vascular Dementia (VD). The diagnosis of those diseases is relied on neuroimaging, neuropsychological, and pathological confirmation.

Vasoconstriction over time contributes to VD, and cerebral small vessel disease (SVD) is being recognized as a major factor leading to cognitive impairment.

We developed a mouse model of vasoconstriction predominantly in small vessels by intracerebroventricular (ICV) injection of ET-1 into lateral ventricles, bilaterally, which allowing ET-1 to spread through cerebrospinal fluid.

Result

• Decreased expression of CD31 after 3 days injection
• Vasoconstriction leads to learning and memory deficits 7 days after injection
• Activation of microglia and increase in Iba1 expression after injection
• Activity-dependent protein translation is curtailed in synaptoneurosomes from the hippocampus of mice injected with ET-1
• Akt‑1 and GSK phosphorylation are downregulated during the transient ischemia caused by ET‑1 injection.
• Memory impairment and synaptic function caused by a single dose of ET‑1 were reversed in 30 days.

Discussion

1. The model is successful and it led to significant effects on the mouse.
2. ET-1 injection (2 µg) produces irreversible, focal lesion in locomotion and or memory depending on site of injection^[2][3][4], low doses of ET-1 (0.5–1 μg) produces infarct induced lesion that is largely resolved by 3 days^[5]. A higher dose (4 µg/ mouse) into the cortex results in mortality^[6]

3. CSF (cerebrospinal fluid) subsequently flows through the ventricular system of the brain, which consists of the two lateral ventricles and the third ventricle, which finally connects to the subarachnoid space… It has been shown that active transport can be bi-directional over the epithelial cells
   of the choroid plexus^[7]. The direction of flow, the anatomical structures involved, and the driving forces that are involved in interstitial fluid and CSF flow are controversial^[8][9]… Thus, the model was able to deliver a sufficient dose of ET-1.
4. Synaptic plasticity is an important attribute for learning and memory and activity-dependent protein translation at the synapse is essential for synaptic plasticity… S35 methionine incorporation increased significantly in vehicle injected mice upon stimulation with KCl this was not observed in ET-1 treated mice indicating that activity dependent protein translation was non-existent following ET-1 treatment.
5. Our results indicate for the first time the commonality between vasoconstriction in brain and early AD in downstream pathways that drive the behavioral abnormalities.

6. Downregulated: Akt1 (Ser473 and Tr308)*, pmTOR, pS6k and p4EBP1
7. The loss of Akt1 kinase leads to downregulation in Akt-mTOR pathway which finally repressed activities dependent on protein translation^[10].
8. ET-1 effects reversed after 30 days, much like that in patients with transient ischemic insults.

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2. Sheng, T. et al. Endothelin-1-induced mini-stroke in the dorsal hippocampus or lateral amygdala results in deficits in learning and memory. J. Biomed. Res. 29, 362–369 (2015). ↩︎

3. Tennant, K. A. & Jones, T. A. Sensorimotor behavioral effects of endothelin-1 induced small cortical infarcts in C57BL/6 mice. J. Neurosci. Methods 181, 18–26 (2009). ↩︎

4. Windle, V. et al. An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat. Exp. Neurol. 201, 324–334 (2006). ↩︎

5. Wang, Y., Jin, K. & Greenberg, D. A. Neurogenesis associated with endothelin-induced cortical infarction in the mouse. Brain Res. 1167, 118–122 (2007). ↩︎

6. Horie, N. et al. Mouse model of focal cerebral ischemia using endothelin 1. J. Neurosci. Methods 173, 286–290 (2008). ↩︎

7. de Lange, E. C. Potential role of ABC transporters as a detoxifcation system at the blood-CSF barrier. Adv Drug Deliv. Rev. 56,
   1793–1809 (2004). ↩︎

8. Strazielle, N. & Ghersi-Egea, J. F. Choroid plexus in the central nervous system: biology and physiopathology. J. Neuropathol. Exp. Neurol. 59, 561–574 (2000). ↩︎

9. Bedussi, B. et al. Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system. Fluids Barriers CNS 12, 23 (2015). ↩︎

10. Ahmad, F. et al. Reactive oxygen species-mediated loss of synaptic Akt1 signaling leads to deficient activity-dependent protein translation early in Alzheimer’s disease. Antioxidants Redox Signal. 27, 1269–1280 (2017). ↩︎