Lewy Body Diseases:A Clinical,Neuropathological And Neuroimaging Study

The Lewy body diseases(LBD),including dementia with Lewy bodies(DLB),Parkinson disease dementia(PDD),and Parkinson disease(PD),are characterized neuropathologically by neuronal inclusions of α-synuclein in cortical and subcortical regions as well as loss of neuromodulator neuronal populations including dopamine cells of the substantia nigra pars compacta and cholinergic cells of the basal forebrain.The shared clinical features of DLB and PDD,which together comprise the Lewy body dementias,include progressive cognitive impairment in association with parkinsonism,visual hallucinations,rapid eye movement sleep behavior disorder(RBD),and fluctuations in alertness and cognition.Although it has been more than one hundred years after Lewy bodies were discovered,less has been known about the neuropathological and neurophysiological mechanisms underlying the Lewy body diseases.Previous studies indicated that Alzheimer disease(AD)– associated neuropathology including amyloid plaques and neurofibrillary tangles were also common in DLB and PDD,supported by both neuroimaging and postmortem research.However,the interactions between beta-amyloid,tau and α-synuclein remain unclear and the impact of AD neuropathology on Lewy body diseases has not been investigated yet.Therefore,the first goal of my doctoral dissertation is to develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against post-mortem neuropathologic findings.In the second part,my research will focus on the topographic distribution of cortical thinning in the Lewy body diseases,the association of regional thinning with clinical features and the impact of amyloid deposition.The last steps will be taken to explore the complexity of cortical ribbon in the dementia with Lewy bodies.PART I: Neuropathologic Correlates of Amyloid and Dopamine Transporter Imaging in Lewy Body DiseaseObjectiveTo develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against post-mortem neuropathologic findings.MethodsFour cognitively normal Parkinson disease(PD),4 PD with cognitive impairments,and 10 dementia with Lewy bodies(DLB)participants underwent amyloid imaging with [11C]Pi B and dopamine transporter(DAT)imaging with [11C]Altropane.All 18 had annual neurological examinations.All cognitively normal PD participants developed cognitive impairment prior to death.Neuropathological examinations assessed and scored Braak Lewy bodies,Thal distribution of amyloid,CERAD neuritic amyloid plaques,Braak neurofibrillary tangles,and cerebral amyloid angiopathy,as well as total amyloid plaque burden in superior frontal,superior parietal,occipital and inferior temporal cortical regions.PET data were expressed as the standardized uptake value ratio with cerebellar reference.Analyses accounted for the interval between imaging and autopsy.ResultsAll 18 patients met neuropathologic criteria for Lewy body disease;the DAT concentration was low in each case.All patients with elevated [11C]Pi B retention measured in a neocortical aggregate had A amyloid deposits at autopsy.[11C]Pi B retention significantly correlated with neuritic plaque burden and with total plaque burden.[11C]Pi B retention also significantly correlated with the severity of both Braak stages of neurofibrillary tangle and Lewy body scores.Neuritic plaque burden was significantly associated with neurofibrillary tangle pathology.ConclusionAntemortem [11C]Altropane PET is a sensitive measure of substantia nigra degeneration.[11C]Pi B scans accurately reflect cortical amyloid deposits seen at autopsy.These findings support the use of molecular imaging in the evaluation of patients with Lewy body diseases.PART II: Topography of Cortical Thinning in the Lewy Body DiseasesObjective Regional cortical thinning in dementia with Lewy bodies(DLB)and Parkinson disease dementia(PDD)may underlie some aspect of their clinical impairments;cortical atrophy likely reflects extensive Lewy body pathology with alpha-synuclein deposits,as well as associated Alzheimer’s disease co-pathologies,when present.Here we investigated the topographic distribution of cortical thinning in these Lewy body diseases compared to cognitively normal PD and healthy non-PD control subjects,explored the association of regional thinning with clinical features and evaluated the impact of amyloid deposition.Methods Twenty-one participants with dementia with Lewy bodies(DLB),16 with Parkinson disease(PD)-associated cognitive impairment(PD-MCI and PDD),and 24 cognitively normal participants with PD underwent MRI,Pi B PET,and clinical evaluation.Cortical thickness across the brain and in regions of interest(ROIs)was compared across diagnostic groups and across subgroups stratified by amyloid status,and was related to clinical and cognitive measures.Results DLB and PD-impaired groups shared a similar distribution of cortical thinning that included regions characteristic of AD,as well as the fusiform,precentral,and paracentral gyri.Elevated Pi B retention in DLB and PD-impaired but not in PD-normal participants was associated with more extensive and severe cortical thinning,in an overlapping topography that selectively affected the medial temporal lobe in DLB participants.In DLB,greater thinning in AD signature and fusiform regions was associated with greater cognitive impairment.Conclusion The pattern of cortical thinning is similar in DLB and PD-associated cognitive impairment,overlapping with and extending beyond AD signature regions to involve fusiform,precentral,and paracentral regions.Cortical thinning in AD signature and fusiform regions in these diseases reflects cognitive impairment and is markedly accentuated by amyloid co-pathology.Further work will be required to determine whether the distinct topography of cortical thinning in DLB and PD-associated cognitive impairment might have value as a diagnostic and/ or outcome biomarker in clinical trials.PART III: Complexity Analysis of Cortical Surface in Dementia with Lewy BodiesObjective We previously performed exploratory analyses across the entire cortical mantle to determine the topology of cortical thinning in Lewy body diseases.Here we examined the complexity of cortical surface including cortical folding and fractal dimension(FD)in dementia with Lewy bodies(DLB),in order to capture complex process involving transverse forces of neuronal sheets or underlying axonal connectivity.We further investigated whether a greater degree of changes in cortical ribbon would predict DLB better than other cortical measures.Methods Thirty-one participants with DLB and 31 age-matched healthy controls underwent magnetic resonance imaging(MRI)and clinical evaluation.Cortical folding,measured by local gyrification index(l GI),and fractal dimension of cortical ribbon were examined in each subject and were used for following group analysis by general linear model.These structural MRI measures were related to clinical assessments by correlation analysis.Receiver operating characteristic curve was performed to analyze the sensitivity and the specificity of detecting DLB from the healthy controls.Results In this study,DLB had significantly reduced overall gyrification,prominently in bilateral cortex including superior frontal,inferior parietal,posterior temporal,and lateral occipital regions(p < 0.05,FDR corrected).Fractal dimension of cortical ribbon in DLB was decreased across the entire cortex than that in the age-matched controls(p < 0.05).The extent of cortical folding was associated with cognitive impairment(p < 0.05).In DLB,fractal dimension had a better prediction with 84% sensitivity and 71% specificity.Conclusion Loss of cortical gyrification and reduced fractal dimension,which may reflect complex disease process and may capture additional aspects of neurodegeneration,were common in DLB.Future analysis are needed to focus on these structural imaging biomarkers,for detecting patients in early stage of DLB and for differentiating DLB from Alzheimer disease(AD).PART IV: Serum NFL levels predict progression of motor impairment and reduction in dopamine transporter binding ratios in Parkinson’s diseaseObjective Neurofilament light chain(NFL)level in biofluids is a sensitive measure of axonal damage and a promising biomarker in neurodegenerative diseases.In Parkinson’s disease(PD),NFL can distinguish PD from other parkinsonian disorders,and NFL concentration is associated with disease severity,risk of progression,and survival.The aim of this study is to determine whether serum NFL at baseline in de novo PD predicts motor decline,differentially impacts specific motor features,predicts cognitive decline,and predicts loss of dopamine terminals.Methods 376 de novo PD patients from the PPMI database were recruited in this study.We analyzed the effect of baseline serum NFL levels on progression over eight years of motor impairment measured with the UPDRS,cognitive function measured with the Mo CA,and putamen dopamine transporter(DAT)binding ratio measured with Da Tscan.Results In longitudinal mixed effects models that controlled for age,gender,disease duration,and levodopa equivalent drug dose,higher levels of serum NFL at baseline were associated with greater increases of UPDRS-III and total UPDRS scores,with greater worsening of postural instability and gait disorder(PIGD)scores but not tremor scores over time.In contrast,baseline serum NFL was not associated with significant progression of Mo CA scores in this de novo PD cohort.Higher baseline serum NFL was associated with greater reduction of putamen DAT binding ratio over time.Conclusion These findings show that baseline serum NFL levels predict the rate of motor decline,the accumulation of PIGD clinical features,and the progression of dopamine transporter loss in the early stage of PD.