Correlation Of Cognitive And Behavioral Impairment And Uric Acid And White Matter Microstructure In Amyotrophic Lateral Sclerosis Patients

Background:Amyotrophic lateral sclerosis(ALS)is a chronic progressive neurodegenerative disease.Although ALS was initially considered only to involve the motor system,cognitive and behavioral impairment has been increasingly recognized as one feature of ALS.Because the occurrence of cognitive and behavioral impairment in ALS can aggravate adverse prognosis and increase caregivers’burden,early identification of cognitive and behavioral impairment in ALS patients is crucial.So far,the mechanism of cognitive and behavioral impairment in ALS patients is unclear.Clinical identification of cognitive and behavioral impairment is still based mainly on comprehensive neuropsychological tests,which are time-consuming.Some scales have not been localized for application in clinical practice.And non-invasive biomarkers to detect cognitive and behavioral decline need to be further investigated and developed.Previous studies have shown that oxidative stress may be involved in the pathological process of neuronal injury of ALS.The antioxidant uric acid has been reported to improve ALS patients’morbidity,progression,and prognosis.However,the relationship between uric acid levels and cognitive and behavioral impairment in ALS patients remains unclear.Furthermore,white matter microstructural changes have increasingly become a research hotspot in ALS.Most of them only group patients based on specific cognitive/behavioral scales to evaluate the correlation between neuroimaging and impairment of cognition or behavior,and do not conduct systematic and accurate research on ALS patients with different degrees of cognitive and behavioral impairment according to the latest revised Strong’s criteria.Different scales used in these studies will also lead to different evaluation results in cognition and behavior,and then influence the interpretation and analysis of imaging results.White matter is susceptible to oxidative stress due to the lower blood flow.The antioxidant uric acid may play a protective role in the microstructural changes of white matter in neurodegenerative diseases,while the effect of uric acid on the white matter microstructure in ALS patients remains unclear.Objective:(1)The Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire(ALS-FTD-Q)developed for ALS patients abroad was translated into Chinese and tested to provide a reliable tool for studying behavioral abnormalities in ALS patients in China.The Chinese version of ALS-FTD-Q was used to explore the features of behavioral impairment in ALS patients,and the relationship between behavioral abnormalities and other clinical symptoms was analyzed;(2)To investigate the relationship between plasma uric acid levels and cognitive and behavioral impairment in ALS patients;(3)Diffusion tensor imaging(DTI)and the revised Strong’s criteria were used to explore the characteristics of white matter microstructural changes in ALS patients with cognitive and/or behavioral impairment;(4)To explore the relationship between plasma uric acid levels and white matter microstructural changes in ALS patients,and whether white matter microstructural changes mediate the protective effect of plasma uric acid on cognitive function in ALS patients.Methods:In the first part of the current study,115 ALS patients,15 ALS-frontotemporal dementia(ALS-FTD)patients,and 51 healthy controls were recruited.The English version of ALS-FTD-Q was translated into Chinese by literal translation and back translation and corrected further.The Chinese version of ALS-FTD-Q was used to evaluate all participants and the reliability and validity of the scale were tested.Behavioral changes were compared in different ALS clinical stages according to the results of ALS-FTD-Q.Correlation analysis was adopted to explore the relationship between behavioral abnormalities and other clinical symptoms in ALS patients.In the second part of the study,plasma uric acid levels were tested in 159 ALS patients.Meanwhile,ALS patients were screened by the Chinese version of Edinburgh Cognitive and Behavioral ALS Screen(ECAS)and classified into ALS with normal cognition(ALSnc),ALS with cognitive impairment(ALSci),ALS with behavioral impairment,ALS with combined cognitive and behavioral impairment(ALScbi)and ALS-FTD according to the revised Strong’s criteria.General and clinical data were compared among the five groups.Parameters with significant differences and uric acid were further included in multivariate linear regression analysis with ECAS total score and ECAS behavioral score as dependent variables,respectively.Hold-out validation was performed to evaluate the fitness of the regression model.In the third part of the study,fractional anisotropy,mean diffusivity,axial diffusivity,and radial diffusivity of 50 parts of the whole brain were measured by DTI in 36 ALS patients with or without cognitive and/or behavior disorders and 18 healthy controls.The differences in DTI parameters between different ALS patient groups and control groups were compared.In the last part of the current study,plasma uric acid test,DTI scan,and cognitive assessment were performed on 34 ALS patients.Multivariate linear regression analysis was used to evaluate the relationship between plasma uric acid,white matter structure,and cognitive function.Mediation analysis was used to evaluate the role of white matter structure in the relationship between uric acid and cognitive function.Results:(1)The Chinese version of ALS-FTD-Q had good reliability and validity(Cronbachα=0.868;r=0.777),which could effectively distinguish ALS patients,ALS-FTD patients,and healthy controls(P<0.001).The results of ALS-FTD-Q showed that 30%of ALS patients had behavioral impairment,and patients in late stage presented more severe behavioral changes.Restlessness and irritability were common behavioral abnormalities in ALS patients,and all patients with severe behavioral disorders showed withdrawal behavior.Behavioral symptoms of ALS patients were weakly correlated with motor function,cognitive function,anxiety,depression,and respiratory function(P<0.05).A strong correlation was found between behavioral impairment and caregiver burden(P<0.001).There was no significant correlation between behavior and sleep;(2)Up to 60%of ALS patients showed cognitive and/or behavioral impairment according to the revised Strong’s criteria.The age of ALSci and ALScbi was older than that of ALSnc(P<0.05),while the education level of ALSci was lower than that of ALSnc(P<0.001).Multivariate analysis showed increased uric acid(β=0.151,P=0.041),lower age at testing(β=-0.408,P<0.001),and higher education level(β=0.393,P<0.001)could predict higher ECAS score(F=24.282,R~2=0.378,P<0.001).Validation analysis showed that the predicted ECAS score was significantly correlated with the raw ECAS score in both the training set and the testing set(P<0.001).No association was found between uric acid and behavioral impairment in ALS patients;(3)Whole-brain DTI revealed extensive white matter degeneration in the bilateral brain regions in ALS patients,especially in the left cerebral hemisphere.In addition to the motor area(corona radiata,external capsule,cerebral peduncle,superior cerebellar peduncle,and inferior cerebellar peduncle)involved,the white matter fiber tracts of the external motor area including the frontotemporal lobe(uncinate fasciculus),frontoparietal lobe(superior longitudinal fasciculus),frontooccipital lobe(inferior fronto-occipital fasciculus)and medial lemniscus were also damaged.ALS in late stage presented more extensive white matter degeneration than ALS in early stage.Compared with healthy controls,the left inferior cerebellar peduncle and left inferior fronto-occipital fasciculus were impaired in ALSnc,while the left superior cerebellar peduncle was involved in ALS with cognitive and/or behavioral disorders;(4)Plasma uric acid levels were positively correlated with extensive white matter microstructural integrity in ALS patients(P<0.05),including the frontoparietal lobe(superior longitudinal fasciculus),frontotemporal lobe(cingulum),fronto-occipital lobe(inferior frontal-occipital fasciculus),corpus callosum,fornix,internal capsule,posterior thalamic radiation,corona radiata,superior cerebellar peduncle,inferior cerebellar peduncle,and cerebral peduncle.Mediating analysis results suggested that axial diffusivity in the right cerebral peduncle had full mediation effects between plasma uric acid levels and executive function in ALS patients(indirect effect=0.017,P=0.02).Conclusions:(1)The Chinese version of ALS-FTD-Q was an effective tool for detecting behavioral symptoms of ALS patients.ALS patients in late stage presented more severe behavioral changes.The unique damage pattern of behavioral impairment provides a reference for further clinical and basic science research;(2)Cognitive and behavioral impairment was not unusual in Chinese ALS patients.Plasma uric acid might help evaluate the risk of cognitive impairment in ALS patients when combined with education level and age;(3)Extensive white matter microstructural changes were observed in motor and extra-motor tracts in ALS patients.The cognitive and behavioral impairment in ALS patients may be associated with damage to the cerebellum-thalamo-cortical pathway;(4)Plasma uric acid could protect extensive white matter microstructure in ALS patients.White matter microstructural changes mediated the relationship between uric acid and executive function in ALS patients.