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Topography of cortical thinning in the Lewy body diseases.

ABSTRACT: OBJECTIVE: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, PiB 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 PiB 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. CONCLUSIONS: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.

SUBMITTER: Ye R

PROVIDER: S-EPMC7016450 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Topography of cortical thinning in the Lewy body diseases.

Ye Rong R Touroutoglou Alexandra A Brickhouse Michael M Katz Samantha S Growdon John H JH Johnson Keith A KA Dickerson Bradford C BC Gomperts Stephen N SN

NeuroImage. Clinical 20200131

<h4>Objective</h4>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 s ...[more]

PMID: 32059167

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Project description:BackgroundRetinal optical coherence tomography findings in Lewy body diseases and their implications for visual outcomes remain controversial. We investigated whether region-specific thickness analysis of retinal layers could improve the detection of macular atrophy and unravel its association with visual disability in Parkinson's disease.MethodsPatients with idiopathic Parkinson's disease (n = 63), dementia with Lewy bodies (n = 8), and E46K mutation carriers in the α-synuclein gene (E46K-SNCA) (n = 4) and 34 controls underwent Spectralis optical coherence tomography macular scans and a comprehensive battery of visual function and cognition tests. We computed mean retinal layer thicknesses of both eyes within 1-, 2-, 3-, and 6-mm diameter macular discs and in concentric parafoveal (1- to 2-mm, 2- to 3-mm, 1- to 3-mm) and perifoveal (3- to 6-mm) rings. Group differences in imaging parameters and their relationship with visual outcomes were analyzed. A multivariate logistic model was developed to predict visual impairment from optical coherence tomography measurements in Parkinson's disease, and cutoff values were determined with receiver operating characteristic analysis.ResultsWhen compared with controls, patients with dementia with Lewy bodies had significant thinning of the ganglion cell-inner plexiform layer complex within the central 3-mm disc mainly because of differences in 1- to 3-mm parafoveal thickness. This parameter was strongly correlated in patients, but not in controls, with low contrast visual acuity and visual cognition outcomes (P < .05, False Discovery Rate), achieving 88% of accuracy in predicting visual impairment in Parkinson's disease.ConclusionOur findings support that parafoveal thinning of ganglion cell-inner plexiform complex is a sensitive and clinically relevant imaging biomarker for Lewy body diseases, specifically for Parkinson's disease. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Project description:Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.

Project description:ImportanceThe causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown.ObjectiveTo contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function.Design, setting, and participantsThis cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET).ExposuresImaging with fluorine 18-labeled AV-1451 ([18F]AV-1451) (formerly known as [18F]T807), [11C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale.Main outcomes and measuresMain outcomes were differentiation of diagnostic groups on the basis of [18F]AV-1451 binding, the association of [18F]AV-1451 binding with [11C]PiB binding, and the association of [18F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function.ResultsIn patients with DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [18F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [18F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [11C]PiB retention. For DLB and PD-impaired patients, greater [18F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score.Conclusions and relevancePatients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.

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Topography of cortical thinning in the Lewy body diseases.

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Topography of cortical thinning in the Lewy body diseases.

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