bims-medebr 2022-10-16 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–10–16
fourteen papers selected by
Regina F. Fernández, Johns Hopkins University

Increasing brain glucose metabolism by ligustrazine piperazine ameliorates cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.
A Novel 5-Chloro-N-phenyl-1H-indole-2-carboxamide Derivative as Brain-Type Glycogen Phosphorylase Inhibitor: Potential Therapeutic Effect on Cerebral Ischemia.
Circulating Levels of Short-Chain Fatty Acids during Pregnancy and Infant Neurodevelopment.
Taurine and N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice.
Author Correction: Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance.
Myo-Inositol Moderates Glucose-Induced Effects on Human Placental 13C-Arachidonic Acid Metabolism.
27-Hydroxycholesterol-Induced Dysregulation of Cholesterol Metabolism Impairs Learning and Memory Ability in ApoE ε4 Transgenic Mice.
Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele.
CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons.
Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer's dementia.
Plasma glycocholic acid and linoleic acid identified as potential mediators of mitochondrial bioenergetics in Alzheimer's dementia.
PGC-1α activity and mitochondrial dysfunction in preterm infants.
Clinical relevance of single-subject brain metabolism patterns in amyotrophic lateral sclerosis mutation carriers.
Dynamic proteomic and phosphoproteomic atlas of corticostriatal axons in neurodevelopment.

Alzheimers Res Ther. 2022 Oct 11. 14(1): 150

Increasing brain glucose metabolism by ligustrazine piperazine ameliorates cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

Zongyang Li, Xiangbao Meng, Guoxu Ma, Wenlan Liu, Weiping Li, Qian Cai, Sicen Wang, Guodong Huang, Yuan Zhang.

  PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aβ40 and Aβ42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aβ plaques in APP/PS1 mice and decreased the levels of Aβ40 and Aβ42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain 18F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

Keywords:  Alzheimer’s disease; Mitochondria; Mitophagy; PINK1/Parkin; PPARγ

DOI:  https://doi.org/10.1186/s13195-022-01092-7
Molecules. 2022 Sep 26. pii: 6333. [Epub ahead of print]27(19):

A Novel 5-Chloro-N-phenyl-1H-indole-2-carboxamide Derivative as Brain-Type Glycogen Phosphorylase Inhibitor: Potential Therapeutic Effect on Cerebral Ischemia.

Yatao Huang, Shuai Li, Youde Wang, Zhiwei Yan, Yachun Guo, Liying Zhang.

  Brain-type glycogen phosphorylase inhibitors are potential new drugs for treating ischemic brain injury. In our previous study, we reported compound 1 as a novel brain-type glycogen phosphorylase inhibitor with cardioprotective properties. We also found that compound 1 has high blood-brain barrier permeability through the ADMET prediction website. In this study, we deeply analyzed the protective effect of compound 1 on hypoxic-ischemic brain injury, finding that compound 1 could alleviate the hypoxia/reoxygenation (H/R) injury of astrocytes by improving cell viability and reducing LDH leakage rate, intracellular glucose content, and post-ischemic ROS level. At the same time, compound 1 could reduce the level of ATP in brain cells after ischemia, improve cellular energy metabolism, downregulate the degree of extracellular acidification, and improve metabolic acidosis. It could also increase the level of mitochondrial aerobic energy metabolism during brain cell reperfusion, reduce anaerobic glycolysis, and inhibit apoptosis and the expression of apoptosis-related proteins. The above results indicated that compound 1 is involved in the regulation of glucose metabolism, can control cell apoptosis, and has protective and potential therapeutic effects on cerebral ischemia-reperfusion injury, which provides a new reference and possibility for the development of novel drugs for the treatment of ischemic brain injury.

Keywords:  apoptosis; brain-type glycogen phosphorylase inhibitor; glycolysis; mouse astrocytes; oxidative phosphorylation

DOI:  https://doi.org/10.3390/molecules27196333
Nutrients. 2022 Sep 23. pii: 3946. [Epub ahead of print]14(19):

Circulating Levels of Short-Chain Fatty Acids during Pregnancy and Infant Neurodevelopment.

Carmen Hernández-Martínez, Josefa Canals, Núria Voltas, Francisco Martín-Luján, Victoria Arija.

   BACKGROUND: Short-chain fatty acids (SCFA) play a key role in the gut microbiota-brain crosstalk regulating the main neurodevelopmental processes during pregnancy. The aim of this study is to investigate the longitudinal relationship between prenatal levels of the main SCFAs in maternal serum and infant cognitive development and temperament on day 40 postpartum after adjusting for several pre-, peri- and post-natal confounders.
METHODS: A sample of 357 healthy mother-infant pairs were followed from the beginning of pregnancy to 40 days after birth. Serum SCFA concentrations were assessed in the first and third trimester of pregnancy by LC-MS/MS; and socio-demographic, nutritional, and psychological variables were collected. At 40 days, the Bayley Scales of Infant Development-III and the Early Infancy Temperament Questionnaire were administered.
RESULTS: Lower serum levels of acetic, butyric and isobutyric acid, mainly during the first trimester, were related to better language and psychomotor development and, in the case of butyric acid, better intensity behavior in infants. Medium levels of propionic acid were related to better scores for development, mood and temperament.
CONCLUSIONS: These findings suggest that in a community sample of healthy pregnant women from a Mediterranean region of northern Spain, lower serum levels of SCFAs, especially in the first trimester of pregnancy, seem to be related to better infant neurodevelopment.

Keywords:  acetic acid; butyric acid; cognitive development; infant; isobutyric acid; neurodevelopment; pregnancy; propionic acid; short chain fatty acids

DOI:  https://doi.org/10.3390/nu14193946
Nutr Neurosci. 2022 Oct 12. 1-13

Taurine and N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice.

Alba M Garcia-Serrano, Joao P P Vieira, Veronika Fleischhart, João M N Duarte.

  Background: Obesity constitutes a risk factor for cognitive impairment. In rodent models, long-term exposure to obesogenic diets leads to hippocampal taurine accumulation. Since taurine has putative cyto-protective effects, hippocampal taurine accumulation in obese and diabetic models might constitute a counteracting response to metabolic stress. Objective: We tested the hypothesis that treatment with taurine or with N-acetylcysteine (NAC), which provides cysteine for the synthesis of taurine and glutathione, prevent high-fat diet (HFD)-associated hippocampal alterations and memory impairment. Methods: Female mice were fed either a regular diet or HFD. Some mice had access to 3%(w/v) taurine or 3%(w/v) NAC in the drinking water. After 2 months, magnetic resonance spectroscopy (MRS) was used to measure metabolite profiles. Memory was assessed in novel object and novel location recognition tests. Results: HFD feeding caused memory impairment in both tests, and reduced concentration of lactate, phosphocreatine-to-creatine ratio, and the neuronal marker N-acetylaspartate in the hippocampus. Taurine and NAC prevented HFD-induced memory impairment and N-acetylaspartate reduction. NAC, but not taurine, prevented the reduction of lactate and phosphocreatine-to-creatine ratio. MRS revealed NAC/taurine-induced increase of hippocampal glutamate and GABA levels. Conclusion: NAC and taurine can prevent memory impairment, while only NAC prevents alterations of metabolite concentrations in HFD-exposed female mice.

Keywords:  MRS; N-acetylaspartate; Obesity; diabetes; lactate; metabolism; neurochemical profile; neuroprotection

DOI:  https://doi.org/10.1080/1028415X.2022.2131062
Nat Metab. 2022 Oct 14.

Author Correction: Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance.

Lige Leng, Ziqi Yuan, Ruiyuan Pan, Xiao Su, Han Wang, Jin Xue, Kai Zhuang, Ju Gao, Zhenlei Chen, Hui Lin, Wenting Xie, Huifang Li, Zhenyi Chen, Keke Ren, Xiao Zhang, Wenting Wang, Zi-Bing Jin, Shengxi Wu, Xinglong Wang, Zengqiang Yuan, Huaxi Xu, Hei-Man Chow, Jie Zhang.

DOI: https://doi.org/10.1038/s42255-022-00682-x
Nutrients. 2022 Sep 26. pii: 3988. [Epub ahead of print]14(19):

Myo-Inositol Moderates Glucose-Induced Effects on Human Placental 13C-Arachidonic Acid Metabolism.

Oliver C Watkins, Victoria K B Cracknell-Hazra, Reshma Appukuttan Pillai, Preben Selvam, Hannah E J Yong, Neha Sharma, Sathya Narayanan Patmanathan, Amaury Cazenave-Gassiot, Anne K Bendt, Keith M Godfrey, Rohan M Lewis, Markus R Wenk, Shiao-Yng Chan.

  Maternal hyperglycemia is associated with disrupted transplacental arachidonic acid (AA) supply and eicosanoid synthesis, which contribute to adverse pregnancy outcomes. Since placental inositol is lowered with increasing glycemia, and since myo-inositol appears a promising intervention for gestational diabetes, we hypothesized that myo-inositol might rectify glucose-induced perturbations in placental AA metabolism. Term placental explants (n = 19) from women who underwent a mid-gestation oral glucose-tolerance-test were cultured with 13C-AA for 48 h in media containing glucose (5, 10 or 17 mM) and myo-inositol (0.3 or 60 µM). Newly synthesized 13C-AA-lipids were quantified by liquid-chromatography-mass-spectrometry. Increasing maternal fasting glycemia was associated with decreased proportions of 13C-AA-phosphatidyl-ethanolamines (PE, PE-P), but increased proportions of 13C-AA-triacylglycerides (TGs) relative to total placental 13C-AA lipids. This suggests altered placental AA compartmentalization towards storage and away from pools utilized for eicosanoid production and fetal AA supply. Compared to controls (5 mM glucose), 10 mM glucose treatment decreased the amount of four 13C-AA-phospholipids and eleven 13C-AA-TGs, whilst 17 mM glucose increased 13C-AA-PC-40:8 and 13C-AA-LPC. Glucose-induced alterations in all 13C-AA lipids (except PE-P-38:4) were attenuated by concurrent 60 µM myo-inositol treatment. Myo-inositol therefore rectifies some glucose-induced effects, but further studies are required to determine if maternal myo-inositol supplementation could reduce AA-associated pregnancy complications.

Keywords:  LCMS; diabetes; lipid; metabolism; pregnancy

DOI:  https://doi.org/10.3390/nu14193988
Int J Mol Sci. 2022 Oct 01. pii: 11639. [Epub ahead of print]23(19):

27-Hydroxycholesterol-Induced Dysregulation of Cholesterol Metabolism Impairs Learning and Memory Ability in ApoE ε4 Transgenic Mice.

Yushan Wang, Ling Hao, Tao Wang, Wen Liu, Lijing Wang, Mengwei Ju, Wenjing Feng, Rong Xiao.

  Dysregulated brain cholesterol metabolism is one of the characteristics of Alzheimer's disease (AD). 27-Hydroxycholesterol (27-OHC) is a cholesterol metabolite that plays an essential role in regulating cholesterol metabolism and it is suggested that it contributes to AD-related cognitive deficits. However, the link between 27-OHC and cholesterol homeostasis, and how this relationship relates to AD pathogenesis, remain elusive. Here, 12-month-old ApoE ε4 transgenic mice were injected with saline, 27-OHC, 27-OHC synthetase inhibitor (anastrozole, ANS), and 27-OHC+ANS for 21 consecutive days. C57BL/6J mice injected with saline were used as wild-type controls. The indicators of cholesterol metabolism, synaptic structure, amyloid β 1-42 (Aβ1-42), and learning and memory abilities were measured. Compared with the wild-type mice, ApoE ε4 mice had poor memory and dysregulated cholesterol metabolism. Additionally, damaged brain tissue and synaptic structure, cognitive decline, and higher Aβ1-42 levels were observed in the 27-OHC group. Moreover, cholesterol transport proteins such as ATP-binding cassette transporter A1 (ABCA1), apolipoprotein E (ApoE), low-density lipoprotein receptor (LDLR), and low-density lipoprotein receptor-related protein1 (LRP1) were up-regulated in the cortex after the 27-OHC treatment. The levels of cholesterol metabolism-related indicators in the hippocampus were not consistent with those in the cortex. Additionally, higher serum apolipoprotein A1 (ApoA1) levels and lower serum ApoE levels were observed in the 27-OHC group. Notably, ANS partially reversed the effects of 27-OHC. In conclusion, the altered cholesterol metabolism induced by 27-OHC was involved in Aβ1-42 deposition and abnormalities in both the brain tissue and synaptic structure, ultimately leading to memory loss in the ApoE ε4 transgenic mice.

Keywords:  27-hydroxycholesterol; cholesterol metabolism; homeostasis; learning and memory impairment; transgenic mice

DOI:  https://doi.org/10.3390/ijms231911639
J Nutr Biochem. 2022 Oct 08. pii: S0955-2863(22)00249-2. [Epub ahead of print] 109181

Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele.

Mohammed Amir Husain, Annick Vachon, Raphael Chouinard-Watkins, Milène Vandal, Frédéric Calon, Mélanie Plourde.

  The metabolism of docosahexaenoic acid (DHA), an omega-3 fatty acid, is different in carriers of APOE4, the main genetic risk factor for late-onset Alzheimer's disease. The brain relies on the plasma DHA pool for its need, but the plasma-liver-brain axis in relation to cognition remains obscure. We hypothesized that this relationship is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice. Male and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. There was a significant genotype × diet interaction for DHA concentration in the liver and adipose tissue. In the cortex, a genotype effect was found where APOE4 mice had a higher concentration of DHA than APOE3 mice fed the control diet. There was a significant genotype × diet interaction for the liver and hippocampal arachidonic acid (AA). APOE4 mice had 20-30% lower plasma DHA and AA concentrations than APOE3 mice, independent of diet. Plasma and liver DHA levels were significantly correlated in APOE3 and APOE4 mice. In APOE4 mice, there was a significant correlation between plasma, adipose tissues, and cortex DHA and the Barnes maze and/or with a better recognition index. Moreover, higher AA levels in the liver and the hippocampus of APOE4 mice were correlated with lower cognitive performance. Our results suggest that there is a plasma-liver-brain axis of DHA that is modified in APOE4 mice. Moreover, our data support that APOE4 mice rely more on plasma DHA than APOE3 mice, especially in cognitive performance. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Keywords:  APOE; Alzheimer's disease; Barnes maze; docosahexaenoic acid; omega-3 fatty acid

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109181
Int J Mol Sci. 2022 Sep 30. pii: 11593. [Epub ahead of print]23(19):

CERKL, a Retinal Dystrophy Gene, Regulates Mitochondrial Transport and Dynamics in Hippocampal Neurons.

Rocío García-Arroyo, Gemma Marfany, Serena Mirra.

  Mutations in the Ceramide Kinase-like (CERKL) gene cause retinal dystrophies, characterized by progressive degeneration of retinal neurons, which eventually lead to vision loss. Among other functions, CERKL is involved in the regulation of autophagy, mitochondrial dynamics, and metabolism in the retina. However, CERKL is nearly ubiquitously expressed, and it has been recently described to play a protective role against brain injury. Here we show that Cerkl is expressed in the hippocampus, and we use mouse hippocampal neurons to explore the impact of either overexpression or depletion of CERKL on mitochondrial trafficking and dynamics along axons. We describe that a pool of CERKL localizes at mitochondria in hippocampal axons. Importantly, the depletion of CERKL in the CerklKD/KO mouse model is associated with changes in the expression of fusion/fission molecular regulators, induces mitochondrial fragmentation, and impairs axonal mitochondrial trafficking. Our findings highlight the role of CERKL, a retinal dystrophy gene, in the regulation of mitochondrial health and homeostasis in central nervous system anatomic structures other than the retina.

Keywords:  CERKL; hippocampus; mitochondria; mitochondrial dysfunction; mitochondrial trafficking; neurons

DOI:  https://doi.org/10.3390/ijms231911593
Alzheimers Res Ther. 2022 Oct 11. 14(1): 152

Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer's dementia.

Brandon Ebright, Isaac Assante, Roy A Poblete, Shaowei Wang, Marlon V Duro, David A Bennett, Zoe Arvanitakis, Stan G Louie, Hussein N Yassine.

   BACKGROUND: Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer's disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration.
METHODS: Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype.
RESULTS: Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes.
CONCLUSION: These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.

Keywords:  Alzheimer’s disease; ApoE; Inflammation; Lipidomics

DOI:  https://doi.org/10.1186/s13195-022-01084-7
Front Aging Neurosci. 2022 ;14 954090

Plasma glycocholic acid and linoleic acid identified as potential mediators of mitochondrial bioenergetics in Alzheimer's dementia.

K Allison Amick, Gargi Mahapatra, Zhengrong Gao, Amber Dewitt, Suzanne Craft, Mohit Jain, Anthony J A Molina.

  Mitochondrial bioenergetic alterations occur in the brain and peripheral cells of patients with Alzheimer's disease (AD). This study focuses on plasma circulating factors, namely lipids, as mediators of systemic bioenergetic differences in participants with normal cognition (NC), mild cognitive impairment (MCI), and dementia due to probable AD (DEM). We examined bioenergetic differences across cognitive groups by measuring the mitochondrial respiration of peripheral blood mononuclear cells (PBMCs) from 37 participants (12 NC, 12 MCI, 13 DEM). PBMC bioenergetics were lower in the DEM group compared to the NC group. To determine whether circulating factors can mediate bioenergetic differences according to cognitive status, we exposed naïve neuronal Neuro-2a (N2a) cells to plasma from each participant in vitro. N2a bioenergetics were lower following plasma exposure from DEM compared to NC group participants. Notably, PBMC Max and N2a Max positively correlated, suggesting that circulating factors modulate the bioenergetics of naïve N2a cells according to the bioenergetic capacity of donor primary PBMCs. To identify lipid metabolites that may contribute to bioenergetic differences between cognitive groups, we performed liquid chromatography-mass spectrometry to assess the abundance of individual lipid species and correlated PBMC and N2a bioenergetics. Glycocholic acid (GCA) positively correlated with PBMC and N2a bioenergetics, while linoleic acid (LA) was negatively correlated. These data suggest that GCA and LA may contribute to the stimulatory and inhibitory bioenergetics effects related to cognitive status. Post hoc analyses revealed that GCA abundance was lower by 52.9% in the DEM group compared to the NC group and that LA abundance was higher by 55.7% in the DEM group compared to the NC group. To validate these findings, we examined the abundance of GCA and LA in the larger, more diverse, parent cohort (n = 378) and found similar results; GCA abundance was lower by 29.7% in the DEM group compared to the NC group and LA abundance was higher by 17.8% in the DEM group compared to the NC group. These data demonstrate that circulating factors have a direct effect on mitochondrial bioenergetics and that individual circulating factors identified to be associated with mitochondrial function are differentially expressed in patients with dementia.

Keywords:  Alzheimer’s disease; bioenergetics; glycocholic acid; linoleic acid; metabolomics; mitochondria; neurons; plasma

DOI:  https://doi.org/10.3389/fnagi.2022.954090
Front Physiol. 2022 ;13 997619

PGC-1α activity and mitochondrial dysfunction in preterm infants.

Atefeh Mohammadi, Randa Higazy, Estelle B Gauda.

  Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.

Keywords:  PGC-1α; bronchopulmonary dysplasia; mitochondrial dysfunction; oxidative stress; reactive oxygen species; white matter injury

DOI:  https://doi.org/10.3389/fphys.2022.997619
Neuroimage Clin. 2022 Oct 05. pii: S2213-1582(22)00287-X. [Epub ahead of print]36 103222

Clinical relevance of single-subject brain metabolism patterns in amyotrophic lateral sclerosis mutation carriers.

Giacomo Tondo, Letizia Mazzini, Silvia Paola Caminiti, Maria Francesca Sarnelli, Lucia Corrado, Roberta Matheoud, Sandra D'Alfonso, Roberto Cantello, Gian Mauro Sacchetti, Daniela Perani, Cristoforo Comi, Fabiola De Marchi.

   BACKGROUND AND OBJECTIVES: The ALS diagnosis requires an integrative approach, combining the clinical examination and supporting tests. Nevertheless, in several cases, the diagnosis proves to be suboptimal, and for this reason, new diagnostic methods and novel biomarkers are catching on. The 18F-fluorodeoxyglucose (18F-FDG)-PET could be a helpful method, but it still requires additional research for sensitivity and specificity. We performed an 18F-FDG-PET single-subject analysis in a sample of familial ALS patients carrying different gene mutations, investigating the genotype-phenotype correlations and exploring metabolism correlations with clinical and neuropsychological data.
METHODS: We included ten ALS patients with pathogenic gene mutation who underwent a complete clinical and neuropsychological evaluation and an 18F-FDG-PET scan at baseline. Patients were recruited between 2018 and 2022 at the ALS Tertiary Centre in Novara, Italy. Patients were selected based on the presence of ALS gene mutation (C9orf72, SOD1, TBK1, and KIF5A). Following a validated voxel-based Statistical Parametric Mapping (SPM) procedure, we obtained hypometabolism maps at single-subject level. We extracted regional hypometabolism from the SPM maps, grouping significant hypometabolism regions into three meta-ROIs (motor, prefrontal association and limbic). Then, the corresponding 18F-FDG-PET regional hypometabolism was correlated with clinical and neuropsychological features.
RESULTS: Classifying the patients with C9orf72-ALS based on the rate of disease progression from symptoms onset to the time of scan, we observed two different patterns of brain hypometabolism: an extensive motor and prefrontal hypometabolism in patients classified as fast progressors, and a more limited brain hypometabolism in patients grouped as slow progressors. Patients with SOD1-ALS showed a hypometabolic pattern involving the motor cortex and prefrontal association regions, with a minor involvement of the limbic regions. The patient with TBK1-ALS showed an extended hypometabolism, in limbic systems, along with typical motor involvement, while the hypometabolism in the patient with KIF5A-ALS involved almost exclusively the motor regions, supporting the predominantly motor impairment linked to this gene mutation. Additionally, we observed strong correlations between the hypometabolism in the motor, prefrontal association and limbic meta-ROI and the specific neuropsychological performances.
CONCLUSIONS: To our knowledge, this is the first study investigating brain hypometabolism at the single-subject level in genetic ALS patients carrying different mutations. Our results show high heterogeneity in the hypometabolism maps and some commonalities in groups sharing the same mutation. Specifically, in patients with C9orf72-ALS the brain hypometabolism was larger in patients classified as fast progressors than slow progressors. In addition, in the whole group, the brain metabolism showed specific correlations with clinical and neuropsychological impairment, confirming the ability of 18F-FDG-PET in revealing pattern of neuronal dysfunction, aiding the diagnostic workup in genetic ALS patients.

Keywords:  (18)F-FDG-PET; Amyotrophic lateral sclerosis; Brain metabolism; Genetic; Neurodegenerative diseases; Positron emission tomography

DOI:  https://doi.org/10.1016/j.nicl.2022.103222
Elife. 2022 Oct 14. pii: e78847. [Epub ahead of print]11

Dynamic proteomic and phosphoproteomic atlas of corticostriatal axons in neurodevelopment.

Vasin Dumrongprechachan, Ryan B Salisbury, Lindsey Butler, Matthew L MacDonald, Yevgenia Kozorovitskiy.

  Mammalian axonal development begins in embryonic stages and continues postnatally. After birth, axonal proteomic landscape changes rapidly, coordinated by transcription, protein turnover, and post-translational modifications. Comprehensive profiling of axonal proteomes across neurodevelopment is limited, with most studies lacking cell-type and neural circuit specificity, resulting in substantial information loss. We create a Cre-dependent APEX2 reporter mouse line and map cell-type specific proteome of corticostriatal projections across postnatal development. We synthesize analysis frameworks to define temporal patterns of axonal proteome and phosphoproteome, identifying co-regulated proteins and phosphorylations associated with genetic risk for human brain disorders. We discover proline-directed kinases as major developmental regulators. APEX2 transgenic reporter proximity labeling offers flexible strategies for subcellular proteomics with cell type specificity in early neurodevelopment, a critical period for neuropsychiatric disease.

Keywords:  mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.78847