Exploring The Pathological Role And Clinical Diagnostic Value Of Cerebral Small Vessel Disease Imaging Features In Alzheimer’s Disease Based On MRI And Fluid Biomarkers

Alzheimer’s disease(AD)is a progressive syndrome,accounting for about 60%of all dementias.The specific etiology of AD is still unclear and there is no effective treatment.The main hypothesis widely accepted at present is the amyloid(β-amyloid,Aβ)cascade hypothesis.However,clinical trials targeting Aβ have failed so far,suggesting the complexity of AD pathology.In recent years,research on AD biomarkers has progressed rapidly.The National Institute on Aging and Alzheimer’s Association(NIA-AA)proposed a new AT(N)classification diagnostic system in 2018,which provides a clear diagnosis for AD.biological definition.However,clinically,AD is often closely related to other aging-related diseases,especially having common risk factors with cerebrovascular diseases such as stroke.The process of change has been gradually recognized in recent years.Cerebral small vessel disease(CSVD)refers to lesions that occur in perforating arterioles,capillaries,and venules,and can be found by pathological or imaging examinations.CSVD usually manifests as white matter hyperintensities(WMH),Cerebral microbleeds(CMB),lacunae,and Virchow-Robin space(VRSs)on magnetic resonance imaging(MRI)and microinfarcts.CSVD has been shown to be an age-related and slowly progressive disease that affects neural network connections in the brain,leading to decreased concentration and impaired executive function,ultimately affecting memory function.There is a complex correlation between CSVD and AD pathology.A number of studies on the correlation between WMH,lacuna,CMB,VRSs and other CSVD characteristics and AD risk have reached different conclusions.The possible reasons are the change of AD diagnostic criteria,the complexity of CSVD imaging evaluation methods and other factors.relevant,further research is needed.The promoting effect of CSVD on AD may be related to the disruption of the blood-brain barrier(BBB),however,the exact reason and the correlation between BBB disruption and changes in the classic biomarkers of AD remain unclear.In addition,although the AT(N)diagnostic system includes the classic pathological features of AD(Aβ plaques,tau fibrillary tangles,and neurodegeneration),it still does not take into account whether the key factor of vascular disease can further improve the diagnostic accuracy of AD.This study intends to collect AD patients,mild cognitive impairment(MCI)and normal cognition(CN)based on the latest AT(N)diagnostic criteria,to explore and clarify the imaging features of CSVD and AD disease.The correlation of physical markers,and further explore the possible mechanism and clinical diagnostic value of CSVD features in the development of AD.Part Ⅰ:Correlation between imaging features of cerebral small vessel disease and biological markers of Alzheimer’s diseaseBackgroundCerebral small vessel disease(CSVD),which comprises the typical features of white matter hyperintensity(WMH)and Vichor-Robin spaces(VRSs)in the brain,is one of the leading causes of aging-related cognitive decline and,ultimately,contributes to the occurrence of dementia,including Alzheimer’s disease(AD).However,the relationship between CSVD characteristics and AD biomarkers is still unclear.PurposesTo investigate the correlation between CSVD imaging features and AD biomarkers,and explore whether CSVD can promote the pathological process of AD,and could combining CSVD imaging features and AD biomarkers can improve the accuracy of AD diagnosisMethodsAccording to the inclusion criteria,208 people were enrolled.Fluid AD biomarkers were detected using a single-molecule array(Simoa),and cerebral small vessel dysfunction was determined using magnetic resonance imaging.ResultsWMH contributed to AD pathology within the CN and MCI groups(CDR≤0.5),whereas VRSs did not affect AD pathology.The associations between AD biomarkers and cognitive mental status were consistent with CSVD pathology.That is,within individuals without CSVD pathology,the MMSE scores were correlated with AD fluid biomarkers,except for plasma Aβ42 and Aβ40.Increased plasma p-Tau levels were associated with worse cognitive performance in individuals with WMH(β=-0.465,p=0.0016)or VRSs(β=-0.352,p=0.0257)pathology.Plasma AD biomarkers combined with CSVD markers showed higher accuracy in diagnosing dementia.ConclusionsFindings from this cross-sectional cohort study support the notion that CSVD is a risk factor for AD and highlights that vascular pathology can promote AD biomarker levels,especially in the early course of the disease.Moreover,our results suggest that adding a vascular category(V)(i.e.,CSVD imaging features)to the ATN framework improves the diagnostic accuracy of AD.Part Ⅱ:Exploring whether cerebral small vessel injury is involved in the breakdown of the blood-brain barrier in Alzheimer’s diseaseBackgroundCerebral small vessel disease(CSVD)is usually one of the common complications in Alzheimer’s disease(AD)patients.Furthermore,it is acknowledged that blood-brain barrier(BBB)breakdown and vascular dysregulation can be detected before the cognitive decline in AD patients.Meanwhile,a large number of studies also indicated that Aβ accumulation is generally accompanied by cerebral small vessel disease(CSVD),indicating a synergistic effect between BBB damage and CSVD in the occurrence of AD.However,the relationship among cerebellar vascular lesions,especially cerebral microbleeds(CMBs),AD pathology and BBB damage remains unclear.PurposesTo investigate the relationship between cerebral small vessel injury,especially CMB,AD pathology and BBB injury in AD patients,and the relationship between AD pathology and BBB injury.MethodsA total of 139 individuals were divided into the probable AD group(18F-florbetapir PET positive,n=101)and the control group(cognitive normal,n=38).The levels of cerebrospinal fluid(CSF)and plasma t-tau,p-tau181,Aβ40,Aβ42,and albumin were measured with corresponding commercial assay kits,and CSF/plasma albumin ratio(Qalb),the indicator for BBB dysfunction,were calculated.CSVD burden and the number of CMB were defined by magnetic resonance imaging(MRI).ResultsThe mean Qalb value(p=0.0024),CSVD burden(p<0.0001),and CMB numbers(p=0.0348)in the AD group were significantly higher than that in CN.The proportion of AD patients with CSVD was significantly higher than that of CN(p<0.0001).Qalb showed a negative correlation trend with the CSF Aβ42/Aβ40 ratio(r=-0.1830,p=0.0311).An increasing number of CMB was associated with a low level of CSF Aβ40(r=-0.3869,p=0.0347)and Aβ42(r=-0.3670,p=0.0460)in AD patients,CMB was significantly associated with Qalb(r=0.4923,p=0.0057).The tendency of APOE4 carriers to have higher Qalb values than non-carriers in the AD group.ConclusionsOur study demonstrated a higher CSVD burden,especially CMB.Cerebral small vessel disease is associated with Aβ pathology and promotes BBB damage,which may lead to the progression of AD.Part Ⅲ:Exploring the possible mechanism of cerebral small vessel disease promoting blood-brain barrier damage in patients with Alzheimer’s diseaseBackgroundIn addition to two feature pathologic characterizations,Aβ plaques,and hyperphosphorylation tangles,cerebrovascular dysfunction has also been recognized to contribute to AD.Early blood-brain barrier(BBB)breakdown is known to occur before cognitive impairment,and the occurrence of cerebral small vessel damage in patients with AD generally accompanies Aβ accumulation.Pericytes in the brain are an important part of the BBB,and the level of soluble platelet-derived growth factor receptor(sPDGFRβ)in cerebrospinal fluid is an important marker reflecting pericyte damage.However,whether the damaging effect of cerebral small vessel disease(CSVD)on the BBB is partly through pericytes damage is unclear.In addition,in different stages of AD,the change of sPDGFRβ level under CSVD load and its relationship with Qalb,a marker of BBB damage,are not yet clear.PurposesTo investigate the correlation between CSF sPDGFRβ levels and BBB damage in different stages of cognitive impairment and its relationship with CSVD,and further explore the possible mechanism of CSVD regulating BBB damage in AD patients.MethodsIn all,158 individuals were selected,including normal cognitive participants(clinical dementia rating,CDR=0;27cases)and patients with mild cognitive impairment(MCI)(CDR=0.5;48cases)or AD(CDR)≥ 1;83cases).The levels of cerebrospinal fluid(CSF)and plasma t-tau,p-tau181,Aβ40,Aβ42,and albumin were measured with corresponding commercial assay kits,and CSF/plasma albumin ratio(Qalb),the indicator for BBB dysfunction,were calculated.The levels of sPDGFRβin CSF were determined using the ELISA method.CSVD burden was assessed for lacunes,cerebral microbleeds(CMB),white matter hyperintensities(WMH),and perivascular spaces(PVS)in magnetic resonance imaging.ResultsCSF sPDGFRβ reached the highest level in the CDR=0.5 sPDGFRβ was significantly correlated with the CSF/serum albumin ratio(Qalb)in the CDR=0-0.5 group(β=0.31,P=0.008),but not in the CDR 1-2 group(β=-0.12,P=0.317).In the CDR=0-0.5 group,CSF sPDGFRβ levels exhibited a significant mediating effect between Aβ42/Aβ40 levels and Qalb(P=0.038).CSF sPDGFRβ levels did not show substantial differences between individuals with or without CSVD burden.Further,sPDGFRβ levels were higher in subjects with progressive mild cognitive impairment(PMCI)than in those with stable mild cognitive impairment(SMCI)subjects(P=0.001).ConclusionThese results suggest that change in CSF sPDGFRβ level is related to BBB breakdown in the early cognitive impairment stage of AD but not to cerebral small vascular damage;Damage of the blood-brain barrier caused by may not depend on the abnormal function of pericytes;CSF sPDGFRβ may be considered a biomarker for the prognosis of MCI cases.