Study On Early Diagnosis And PET Functional Imaging Of Amyotrophic Lateral Sclerosis

Objective:(1)To Explore the characteristics and differential imaging markers of neck magnetic resonance imaging(MRI)in patients with amyotrophic lateral sclerosis(ALS)and cervical spondylotic myelopathy(CSM).(2)To investigate the characteristics of brain glucose metabolism in patients with ALS in mainland China,and to explore the influence of different clinical manifestations and genetic factors on brain glucose metabolism in patients with ALS.(3)To evaluate whether 18F-SynVesT-1 PET can be used as a potential biomarker for ALS,and to investigate whether ALS patients have specific synaptic density changes.Methods:(1)A total of 130 ALS patients with combined CSM,203 ALS patients without combined CSM,192 CSM patients,and 115 gender and age matched healthy controls were included.All subjects underwent neck MRI examination,and measurements of the C2/3-C6/7 horizontal transverse spinal cord maximum transverse diameter(TCD),minimum anteroposterior cord diameter(APCD),spinal cord area(SCA),and dural sac area(DSA)were performed on all subjects,The spinal cord compression rates(CR),cord eccentricity(CE)and spinal cord occupancy rate(SCOR)were calculated.All subjects were measured for the cervical spinal canal anterior posterior(CSC a-p),anterior posterior diameter of intervertebral disc(intervertebral disc a-p)and anterior posterior diameter of vertebral body(vertebral body a-p)in the C2/3-C7 level midsagittal position,and Pavlov ratio was calculated.Apply Mann Whitney U test or independent sample t-test to compare the TCD,APCD,CR,CE,SCA,DSA,SCOR,CSC a-p,vertebral a-p,intervertebral disc a-p,and Pavlov ratios between all ALS patient groups and CSM+healthy control group,ALS patient group without CSM and healthy control group,as well as ALS patient group with CSM and CSM patient group.The receiver operating characteristic(ROC)was used to analyze the test efficacy of CR,CE,SCOR,and Pavlov ratio parameters between the ALS patient group and CSM patient group with concomitant CSM.(2)A total of 146 ALS patients and 128 gender and age matched healthy controls were included.All ALS patients and healthy controls underwent 18F fluorodeoxy glucose positron emission tomography(18F FDG-PET)examination,with 115 ALS patients undergoing whole exome sequencing.Patients were divided into groups based on the site of onset,upper and lower motor neuron damage,sensory impairment,disease progression rate,and King’s staging.In addition,according to the results of genetic testing,it is divided into groups with and without genetic mutations.Use the two sample t-test model in SPM12 software to compare the differences in brain glucose metabolism between ALS patients and healthy control groups,as well as the differences in brain glucose metabolism between different ALS subgroups.(3)A total of 21 ALS patients and 25 sex-and age-matched healthy controls were recruited.Patients were grouped separately according to ECAS,site of onset,and rate of disease progression.18FSynVesT-1 PET was used to measure the synaptic density of ALS subjects.The differences of synaptic density between ALS and healthy controls and between different ALS subgroups were compared by SPM software.The standardized uptake value ratio(SUVR)of 18F-SynVesT-1 was calculated and correlated with ALSFRS-R and ECAS scores.Results:(1)In the comparison between all ALS patient groups and the CSM+healthy control group,statistical differences were only found in the C4/5-C6/7 levels of SOCR,C2/3-C3/4 levels of intervertebral disc a-p,C5 removed levels of vertebral a-p,and C3 levels of Pavlov ratio;In the comparison between the ALS patient group without CSM and the healthy control group,statistical differences were found in the C3/4-C4/5 levels of APCD,CR,and CE,C4/5-C5/6 and C6/7 levels of CSC a-p,C3/4-C6/7 levels of intervertebral disc a-p,C3-C5 levels of vertebral a-p,and C4/5-C6/7 levels of Pavlov ratio;In the comparison of ALS patients with combined CSM and CSM patients,there were significant differences in APCD,CR,CE,DSA,SCOR,CSC a-p,vertebral a-p,intervertebral disc a-p,and Pavlov ratios.TCD showed significant differences at the C3/4 level,SCA showed significant differences at the C3/4 and C4/5 levels,and the ROC curves of CR,CE,SCOR,and Pavlov ratios showed statistical differences.(2)Compared with healthy controls,ALS patients had decreased glucose metabolism in bilateral temporal lobe,precentral gyrus,basal ganglia,midbrain and cerebellum regions,and increased glucose metabolism in left anterior cingulate gyrus,occipital lobe and bilateral frontal lobe;Grouping according to different onset sites:Compared with healthy controls,ALS patients with medulla oblongata onset mainly have areas with reduced glucose metabolism located in the basal ganglia,thalamus,and brainstem,while areas with increased glucose metabolism are mainly located in the frontal lobe,cingulate gyrus,and temporal lobe;Compared with the normal controls,the areas of decreased glucose metabolism were mainly located in the occipital lobe,temporal lobe and precentral gyrus,while the areas of increased glucose metabolism were mainly located in the frontal lobe and occipital lobe;Compared with patients with spinal cord onset,patients with medulla oblongata onset only have low metabolic areas,including bilateral temporal lobes,left frontal lobe,and left subcortical area;According to the grouping of upper or lower motor neuron damage:The upper motor neuron damage group(UMN group)is mainly due to a significant decrease in glucose metabolism in the cortical motor area compared to the healthy control group;Compared with the healthy control group,the lower motor neurons(LMN group)mainly suffered from impaired glucose metabolism in the basal ganglia and occipital lobe;Compared with LMN group,UMN group had significantly lower glucose metabolism in the precentral gyrus;According to the grouping of sensory disorders:Compared to the healthy control group,the ALS sensory disorder group showed low metabolism in the central posterior gyrus;Compared with the healthy control group,the ALS group showed low metabolism in the subcortical area and temporal lobe,while high metabolism in the frontal and limbic systems;Compared with ALS normal sensory group,ALS sensory disturbance group showed lower metabolism in the posterior central gyrus,precentral gyrus and other frontal parietal lobe regions;According to the rate of disease progression,the ALS slow progression group showed low metabolism in the basal ganglia and inferior parietal lobules compared to the healthy control group,while high metabolism was observed in the frontal lobe,cingulate gyrus,and anterior cuneiform lobe;Compared with the healthy control group,the ALS fast progressing group showed significantly lower metabolism in the basal ganglia,temporal lobe and precentral gyrus,and higher metabolism in the cingulate gyrus and inferior frontal gyrus;There was no significant difference in glucose metabolism between the ALS slow progression group and the ALS fast progression group;According to the grouping of King’s stage:ALS patients in King’s stage 1 have reduced glucose metabolism mainly located in the basal ganglia area,brainstem,and other regions,while areas with increased glucose metabolism mainly located in the parietal lobe,cingulate gyrus,and some frontal lobes;The areas of reduced glucose metabolism in ALS patients with King’s Stage 2 are mainly located in the temporal lobe,cerebellum,and some frontal lobes,while the areas of increased glucose metabolism are mainly located in the cingulate gyrus and some frontal lobes;The areas of decreased metabolism in patients with ALS in King stage 3 were mainly located in the basal ganglia,parahippocampal gyrus and precentral gyrus,and the areas of increased glucose metabolism were located in the cingulate gyrus and a few frontal lobes;There is no difference between patients in King Stage 1 and Stage 2;Compared with ALS patients in King’s stage 1+2,ALS patients in King’s stage 3 have decreased metabolism in the frontal lobe region;Grouping based on whether or not they carry genetic mutations:Compared with healthy controls,ALS patients with genetic mutations have decreased metabolism in the bilateral paracortex,parahippocampal gyrus,occipital lobe,cerebellum,and right temporal region,while increased metabolism in the right frontal lobe and left paracortex.In ALS patients without gene mutation,the metabolism of left temporal lobe,precentral gyrus and bilateral paracortical areas was decreased,and the metabolism of left cingulate gyrus,occipital lobe and bilateral inferior frontal gyrus was increased.Compared with ALS patients without genetic mutations,ALS patients with genetic mutations have reduced metabolism in the right anterior cuneiform lobe,central posterior gyrus,and occipital gyrus.(3)Compared with healthy controls,all ALS patients had decreased synaptic density in frontotemporal and hippocampal-insular regions;Grouping according to different sites of onset:Compared with patients with spinal cord onset,patients with medulla oblongata onset had lower synaptic density in bilateral cingulate gyrus,and higher uptake values of imaging agents in temporal and occipital lobes.Compared with healthy controls,ALS patients with medulla oblongata onset had reduced synaptic density in the temporal,occipital and insular lobes.There was no significant change in synaptic density in patients with spinal cord onset of ALS compared to healthy controls;Grouping according to the presence or absence of cognitive impairment:The synaptic density of bilateral temporal lobe,hippocampal-insular lobe and left frontal lobe in ALS patients with cognitive impairment was lower than that in healthy controls,but there was no significant difference between ALS patients with normal cognitive function and healthy controls.There is no significant difference in synaptic density between ALS patients with cognitive impairment and ALS patients with normal cognitive function;Grouping according to rate of disease progression:Compared with healthy controls,ALS patients with slow disease progression had significantly lower synaptic density in the right insula and temporal lobe.Compared with healthy controls,there was no significant change in synaptic density in ALS patients with rapid disease progression.There was no significant difference in synaptic density between ALS with rapid disease progression and ALS with slow disease progression;Correlation analysis:There was no significant correlation between SUVR of relevant brain regions and ALSFRS-R score,ECAS score or rate of disease progression.Conclusion:(1)ALS patients have more cervical problems compared to their peers.Under the same muscle strength,ALS patients with combinedCSM have less spinal cord compression compared to CSM.CR,CE,SCOR,and Pavlov ratios can distinguish ALS andCSM with merged CSM,but the testing efficiency still needs to be strengthened.(2)This study found that there were characteristic changes in brain glucose metabolism in ALS patients in Chinese Mainland;18F-FDG PET can well detect whether the patient has upper Motor neuron damage;Genetic factors may be a potential factor affecting brain glucose metabolism in ALS;Patients carrying known pathogenic gene mutations are at greater risk of sensory impairment.(3)18F-SynVesT-1-PET can directly measure the synaptic density of ALS patients and is expected to become a potential imaging marker for ALS diagnosis;18F-SynVesT-1-PET has certain value in evaluating cognitive impairment in ALS patients.