A Multimodal Magnetic Resonance Imaging Study In Patients With Amyotrophic Lateral Sclerosis-frontotemporal Dementia

Background:Amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD)are increasingly considered part of the same incurable disease continuum.ALS-FTD is rare,especially in China.ALS-FTD exhibited worse prognosis than patients with pure ALS or FTD.Cognitive onset ALS-FTD(ALS-FTD-C)patients have shown significantly longer survival compared to motor onset(ALS-FTD-M)patients.However,the pathophysiological differences between these subgroups are still poorly understood.Objectives:This study aimed to compare clinical prognosis,gray matter structure,cerebral blood flow(CBF)and white matter changes between ALS-FTD-C and ALS-FTD-M.Methods:We enrolled 26 patients diagnosed as ALS-FTD in Peking Union Medical College Hospital from March 2013 to October 2020.Baseline clinical data were collected,and electromyography was performed and documented.Regular telephone follow-ups recorded survival status and the revised ALS functional rating scale(ALSFRS-R).Kaplan-Meier survival analysis was used to compare the median survival of ALS-FTD-C and ALS-FTD-M.Seven ALS-FTD-C,5 ALS-FTD-M and 10 healthy controls(HC)with matching age,gender and education level completed the MRI scan.3D-T1W brain structure imaging,3D-pseudo continuous arterial spin labeled imaging and diffusion tensor imaging of all participants were collected.Gray matter volume(GMV)and CBF of ALS-FTD-C and ALS-FTD-M subgroups were compared using voxel-based analysis.White matter fibers of the two subgroups were compared using tract-based spatial statistics.Correlations between imaging parameters and clinical data were also analyzed.Results:ALS-FTD-C showed a longer median survival than ALS-FTD-M,which was not statistically significant.Median survival of motor symptoms was not different between two subgroups.The brain segmentation results displayed that in ALS-FTD patients and the ALS-FTD-C subgroup,the relative total volume of gray matter and the relative total volume of white matter were significantly lower than those in HC.In the comparison of gray matter structure,ALS-FTD patients had significant GMV reduction in bilateral precentral gyrus,frontotemporal lobe,insula,and anterior cingulate gyrus compared to HC.ALS-FTD-C showed more widespread GMV reduction in these areas while the GMV reduction of ALS-FTD-M was limited to the right inferior frontal gyrus,left temporal lobe,and bilateral insula.Further,direct comparison revealed ALS-FTD-C had significantly lower GMV in right middle temporal gyrus,insula,and angular gyrus than ALS-FTD-M.In the comparison of CBF,ALS-FTD patients presented significant hypoperfusion in bilateral dorsolateral superior frontal gyrus compared to HC.In ALS-FTD-C,hypoperfusion was also found in bilateral temporal lobe,prefrontal cortex and anterior cingulate gyrus.However,there were no significant perfusion differences between HC vs.ALS-FTD-M and ALS-FTD-C vs.ALS-FTD-M.In the comparison of white matter structure,ALS-FTD patients presented damage of white matter fibers in the bilateral corticospinal tract,forceps major,corona radiata,and corpus callosum compared with HC.ALS-FTD-C had more widespread damage of white matter fibers than ALS-FTD-M.Additionally,in ALS-FTD patients,ALSFRS-R scores,disease duration and age at MRI were correlated with GMV reduction in specific brain regions.Conclusions:In this cohort,ALS-FTD-C had a longer median survival than ALS-FTD-M,which was not statistically significant.When ALS-FTD-C patients developed motor symptoms,their survival time was similar to ALS-FTD-M.These results indicated that motor involvement rather than cognitive deficits may be the defining factor in the survival of ALS-FTD.The imaging results displayed that ALS-FTD-C had more widespread cortical atrophy,hypoperfusion and damage of white matter fibers than ALS-FTD-M.Our study preliminarily revealed the pathological differences between these subgroups in upper motor neuron and brain extra-motor regions.