White Matter Hyperintensities Related Cognitive Decline And Its Pattern Of Progression:A Multimodality Imaging Study

White matter hyperintensities(WMH)is a common neuroimaging finding among elderly population and is an important feature of cerebral small vessel disease(CSVD).Due to its high prevalence and close association with cognitive decline,dementia and stroke,understanding the mechanism of WMH development and promote its prevention is a topic of great interest.Recent studies discovered that WMH is associated with cognitive decline,specially in the domains of information processing speed,attention and executive function.Different brain lobes are associated with different cognitive tasks,as such different spatial distribution of WMH can lead to different states of cognitive decline.The distribution and progression of WMH is influenced by APOE genotype and amyloid ?(A?)deposition.Understanding the connection between APOE genotype,A? deposition,WMH development and cognitive decline is of great importance.On the other hand,previous study discovered that the normal appearing white matter around WMH has already deterioratied in metabolism and microstructure.This area is called the “penumbra” and is associated with future conversion to WMH,however their association need to be further studied.Therefore,longitudinal study discovering the metabolism and microstructural changes in the normal appearing white matter can lead to further understanding of the progression of WMH,poteintially aiding future treatment and early intervension.To address these questions,we utilized MR and PET imaging technique and designed the following study,explored the cross-sectional and longitudinal spatial development of WMH,how it is influenced by APOE genotype and A? deposition,and how it affects information process speed,and explored the microstructural and metabolism changes in white matter that is developing into WMH.The detail of each study is as follows:Chapter 1 impact of the spatial distribution of WMH and cortical thickness on the information processing speed among elderly populationAPOE is one of the strongest genetic factors associated with information processing speed(IPS).Herein,we explored the neural substrates underlying APOE-related IPS alteration by measuring lobar distribution of white matter hyperintensities(WMH),cortical grey matter volume(GMV)and thickness.Using the ADNI database,we evaluated 178 cognitively normal elderly individuals including 34 APOE ?2 carriers,54 APOE ?4 carriers and 90 ?3 homozygotes.IPS was determined using Trail Making Tests(TMT).We quantified lobar distribution of WMH,cortical GM lobar volume,cortical thickness among three groups.Finally,we used Pearson's correlation and general linear models to examine structural MRI markers in relation to IPS.There were significant differences of IPS among groups,with ?4 carriers displaying the worst performance.Across groups,significant differences in frontal and parietal WMH load were observed(the highest in ?4 carriers);however,no significant differences in cortical GMV and thickness were found.Pearson's correlation analysis showed parietal WMH volume was significantly related with IPS,especially in ?4 carriers.Subsequently a general linear model demonstrated that parietal WMH volume,age and the interaction between parietal WMH volume and age,were significantly associated with IPS,even after adjusting total intracranial volume(TIV),gender and vascular risk factors.Disruption of WM structure,rather than atrophy of GM,plays a more critical role in APOE ?4 allele-specific IPS.Moreover,specific WMH loci are closely associated with IPS;increased parietal WMH volume,especially in ?4 carriers,was independently contributed to slower IPS.Chapter 2 longitudinal analyses of the differences between WMH location and A? deposition: a multimodality studyTo further understand the relationship between parietal WMH distribution and A? deposition,and how WMH in these area affects information processing speed.In the current study,we retrospectively enrolled 135 healthy elderly subjects,each of them had complete baseline,first year and second year follow-up data.We longitudinally assessed the annual progression rate of WMH in each lobe,and we used the [18F]-Florbetapir PET r SUV to analysis the baseline Abeta accumulation.Based on whether these subjects had significant WMH progression(determined by whether the annual progression was >5% of the baseline WMH volume),we compared the differences in A? deposition in different lobe.and we used Pearson correlation to test the relationship between WMH and annual progression rate of WMH with the annual progression rate of TMT-A,TMT-B and Mo CA.Our results showed that the subjects with the most parietal WMH progression had the highest [18F]-Florbetapir PET r SUV compared to subjects with no parietal WMH progression.And correlation analysis showed that the annual progression rate of WMH is correlated with the annual progression rate of TMT-A.In conclusion,we discovered that subjects with parietal WMH progression had more Abeta deposition than subjects with no WMH progression.Also,parietal WMH volume are related with TMT-A score.Chapter 3 longitudinal analysis of microstructural and metabolism imaging marker in the progress of WMHOur purpose is to evaluate the microstructural and metabolism property in the white matter that later become white matter hyperintensity(WMH),and of WMH that later disappeared.Forty subjects with two-year follow-up were included.Each subject had 3DT1,T2 FLAIR,DTI and [18F]-FDG-PET scans.White matter was classified into: constant WMH,growing WMH,shrinking WMH and normal appearing white matter(NAWM).The average DTI(FA and MD)and [18F]-FDG-PET(standardized [18F]-FDG-PET r SUV)of each of the above-mentioned region were extracted and compared.At baseline,the growing WMH had lower FA and [18F]-FDG-PET r SUV than NAWM but had higher FA than the constant WMH.Longitudinally,in NAWM,there was a more rapid decline in metabolism compared to WMH areas,while in the growing WMH,a progression in diffusion was found.Finally,we discovered that the shrinking WMH had a similar microstructural and metabolism property and progression to the constant WMH.Our results suggest there are dynamic changes in microstructural and metabolism in WMH.The metabolic change was mainly found in NAWM,while the microstructural change was mainly found in WMH region.Besides,the reduced volume in WMH,to a larger extent,is irrelevant to the microstructural or metabolism recovery.