Correlation of microglial activation with white matter changes in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer's pathology. Neuroinflammation is also increasingly recognized as a significant contributor to degeneration. We aimed to examine the relationship between microglial activation as measured with [11C]-PK11195 brain PET, MR diffusion tensor imaging (DTI) and grey matter atrophy in DLB. Nineteen clinically probable DLB and 20 similarly aged controls underwent 3T structural MRI (T1-weighted) and diffusion-weighted imaging. Eighteen DLB subjects also underwent [11C]-PK11195 PET imaging and 15 had [11C]-Pittsburgh compound B amyloid PET, resulting in 9/15 being amyloid-positive. We used Computational Anatomy Toolbox (CAT12) for volume-based morphometry (VBM) and Tract-Based Spatial Statistics (TBSS) for DTI to assess group comparisons between DLB and controls and to identify associations of [11C]-PK11195 binding with grey/white matter changes and cognitive score in DLB patients. VBM analyses showed that DLB had extensive reduction of grey matter volume in superior frontal, temporal, parietal and occipital cortices (family-wise error (FWE)-corrected p < 0.05). TBSS showed widespread changes in DLB for all DTI parameters (reduced fractional anisotropy, increased diffusivity), involving the corpus callosum, corona radiata and superior longitudinal fasciculus (FWE-corrected p < 0.05). Higher [11C]-PK11195 binding in parietal cortices correlated with widespread lower mean and radial diffusivity in DLB patients (FWE-corrected p < 0.05). Furthermore, preserved cognition in DLB (higher Addenbrookes Cognitive Evaluation revised score) also correlated with higher [11C]-PK11195 binding in frontal, temporal, and occipital lobes. However, microglial activation was not significantly associated with grey matter changes. Our study suggests that increased microglial activation is associated with a relative preservation of white matter and cognition in DLB, positioning neuroinflammation as a potential early marker of DLB etio-pathogenesis.

Nicastro N ，Mak E ，Williams GB ，Surendranathan A ，Bevan-Jones WR ，Passamonti L ，Vàzquez Rodrìguez P ，Su L ，Arnold R ，Fryer TD ，Hong YT ，Aigbirhio FI ，Rowe JB ，O'Brien JT ... -  《NeuroImage-Clinical》

Diffusion imaging in dementia with Lewy bodies: Associations with amyloid burden, atrophy, vascular factors and clinical features.

White matter disruption in dementia has been linked to a variety of factors including vascular disease and cortical pathology. We aimed to examine the relationship between white matter changes on diffusion tensor imaging (DTI) in DLB and factors including vascular disease, structural atrophy and amyloid burden. Participants with DLB (n = 29), Alzheimer's disease (AD, n = 17) and healthy controls (n = 20) had clinical and neuropsychological assessments followed by structural and diffusion tensor 3T MRI and 18F-Florbetapir PET-CT imaging. Voxelwise statistical analysis of white matter fractional anisotropy (FA) and mean diffusivity (MD) was carried out using Tract-Based Spatial Statistics with family-wise error correction (p < 0.05). DLB and AD groups demonstrated widespread increased MD and decreased FA when compared with controls. There were no differences between the DLB and AD groups. In DLB, increased MD and decreased FA correlated with decreased grey matter and hippocampal volumes as well as vascular disease. There was no correlation with cortical florbetapir SUVR. The relationship between DTI changes and grey matter/hippocampal volumes remained after including Cumulative Illness Rating Scale-Geriatric vascular score as a covariate. Widespread disruption of white matter tracts is present in DLB and is associated with vascular disease, reduced hippocampal volume and reduced grey matter volume, but not with cortical amyloid deposition. The mechanism behind the correlation observed between hippocampal volume and white matter tract disruption should be investigated in future cohorts using tau imaging, as hippocampal atrophy has been shown to correlate with tau deposition in DLB.

Donaghy PC ，Firbank M ，Petrides G ，Lloyd J ，Barnett N ，Olsen K ，Thomas AJ ，O'Brien JT ... -  《-》

White matter integrity in dementia with Lewy bodies: a voxel-based analysis of diffusion tensor imaging.

Many patients with dementia with Lewy bodies (DLB) have overlapping Alzheimer's disease (AD)-related pathology, which may contribute to white matter (WM) diffusivity alterations on diffusion tensor imaging (DTI). Consecutive patients with DLB (n = 30), age- and sex-matched AD patients (n = 30), and cognitively normal controls (n = 60) were recruited. All subjects underwent DTI, 18F 2-fluoro-deoxy-d-glucose, and (11)C Pittsburgh compound B positron emission tomography scans. DLB patients had reduced fractional anisotropy (FA) in the parietooccipital WM but not elsewhere compared with cognitively normal controls, and elevated FA in parahippocampal WM compared with AD patients, which persisted after controlling for β-amyloid load in DLB. The pattern of WM FA alterations on DTI was consistent with the more diffuse posterior parietal and occipital glucose hypometabolism of 2-fluoro-deoxy-d-glucose positron emission tomography in the cortex. DLB is characterized by a loss of parietooccipital WM integrity, independent of concomitant AD-related β-amyloid load. Cortical glucose hypometabolism accompanies WM FA alterations with a concordant pattern of gray and WM involvement in the parietooccipital lobes in DLB.

Nedelska Z ，Schwarz CG ，Boeve BF ，Lowe VJ ，Reid RI ，Przybelski SA ，Lesnick TG ，Gunter JL ，Senjem ML ，Ferman TJ ，Smith GE ，Geda YE ，Knopman DS ，Petersen RC ，Jack CR Jr ，Kantarci K ... -  《-》

Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies.

Alzheimer's disease pathology frequently coexists with Lewy body disease at autopsy in patients with probable dementia with Lewy bodies. More than half of patients with probable dementia with Lewy bodies have high amyloid-β deposition as measured with 11C-Pittsburgh compound B binding on positron emission tomography. Biomarkers of amyloid-β deposition precede neurodegeneration on magnetic resonance imaging during the progression of Alzheimer's disease, but little is known about how amyloid-β deposition relates to longitudinal progression of atrophy in patients with probable dementia with Lewy bodies. We investigated the associations between baseline 11C-Pittsburgh compound B binding on positron emission tomography and the longitudinal rates of grey matter atrophy in a cohort of clinically diagnosed patients with dementia with Lewy bodies (n = 20), who were consecutively recruited to the Mayo Clinic Alzheimer's Disease Research Centre. All patients underwent 11C-Pittsburgh compound B positron emission tomography and magnetic resonance imaging examinations at baseline. Follow-up magnetic resonance imaging was performed after a mean (standard deviation) interval of 2.5 (1.1) years. Regional grey matter loss was determined on three-dimensional T1-weighted magnetic resonance imaging with the tensor-based morphometry-symmetric normalization technique. Linear regression was performed between baseline 11C-Pittsburgh compound B standard unit value ratio and longitudinal change in regional grey matter volumes from an in-house modified atlas. We identified significant associations between greater baseline 11C-Pittsburgh compound B standard unit value ratio and greater grey matter loss over time in the posterior cingulate gyrus, lateral and medial temporal lobe, and occipital lobe as well as caudate and putamen nuclei, after adjusting for age (P < 0.05). Greater baseline 11C-Pittsburgh compound B standard unit value ratio was also associated with greater ventricular expansion rates (P < 0.01) and greater worsening over time in Clinical Dementia Rating Scale, sum of boxes (P = 0.02). In conclusion, in patients with probable dementia with Lewy bodies, higher amyloid-β deposition at baseline is predictive of faster neurodegeneration in the cortex and also in the striatum. This distribution is suggestive of possible interactions among amyloid-β, tau and α-synuclein aggregates, which needs further investigation. Furthermore, higher amyloid-β deposition at baseline predicts a faster clinical decline over time in patients with probable dementia with Lewy bodies.

Sarro L ，Senjem ML ，Lundt ES ，Przybelski SA ，Lesnick TG ，Graff-Radford J ，Boeve BF ，Lowe VJ ，Ferman TJ ，Knopman DS ，Comi G ，Filippi M ，Petersen RC ，Jack CR Jr ，Kantarci K ... -  《-》

Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation.

Racine AM ，Adluru N ，Alexander AL ，Christian BT ，Okonkwo OC ，Oh J ，Cleary CA ，Birdsill A ，Hillmer AT ，Murali D ，Barnhart TE ，Gallagher CL ，Carlsson CM ，Rowley HA ，Dowling NM ，Asthana S ，Sager MA ，Bendlin BB ，Johnson SC ... -  《NeuroImage-Clinical》