Search

INTRODUCTIONThe aim of this study was to identify the histopathological correlates of MRI cortical atrophy in (a)typical Alzheimer’s disease (AD) donors.METHODS19 AD and 10 control donors underwent post-mortem in-situ 3T-3DT1-MRI, from which cortical thickness was calculated. Upon subsequent autopsy, 21 cortical brain regions were selected and immunostained for amyloid-beta, phosphorylated-tau, and reactive microglia. MRI-pathology associations were assessed using linear mixed models. Post-mortem MRI was compared to ante-mortem MRI when available.RESULTSHigher amyloid-beta load weakly correlated with a higher cortical thickness globally. Phosphorylated-tau strongly correlated with cortical atrophy in temporo-frontal regions. Reactive microglia load strongly correlated with cortical atrophy in the parietal region. Post-mortem scans showed high concordance with ante-mortem scans acquired DISCUSSIONDistinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegenerative process. This study contributes in understanding the pathological underpinnings of MRI atrophy patterns.

Alzheimer’s disease is characterized by cortical atrophy on MRI and abnormal depositions of amyloid-beta, phosphorylated-tau and inflammation pathologically. However, the relative contribution of these pathological hallmarks to cortical atrophy, a widely used MRI biomarker in Alzheimer’s disease, is yet to be defined. Therefore, the aim of this study was to identify the histopathological correlates of MRI cortical atrophy in Alzheimer’s disease donors, and its typical amnestic and atypical non-amnestic phenotypes. Nineteen Alzheimer’s disease (of which 10 typical and 9 atypical) and 10 non-neurological control brain donors underwent post-mortem in situ 3T 3D-T1, from which cortical thickness was calculated with Freesurfer. Upon subsequent autopsy, 12 cortical brain regions from the right hemisphere and 9 from the left hemisphere were dissected and immunostained for amyloid-beta, phosphorylated-tau and reactive microglia, and percentage area load was calculated for each marker using ImageJ. In addition, post-mortem MRI was compared to ante-mortem MRI of the same Alzheimer’s disease donors when available. MRI-pathology associations were assessed using linear mixed models. Higher amyloid-beta load weakly correlated with higher cortical thickness globally (r = 0.22, P = 0.022). Phosphorylated-tau strongly correlated with cortical atrophy in temporal and frontal regions (−0.76 < r < −1.00, all P < 0.05). Reactive microglia load strongly correlated with cortical atrophy in the parietal region (r = −0.94, P < 0.001). Moreover, post-mortem MRI scans showed high concordance with ante-mortem scans acquired, Frigerio et al. report that in Alzheimer’s disease, amyloid-beta, phosphorylated-tau and reactive microglia load measured with immunohistochemistry, are important correlates of MRI cortical atrophy, acquired both ante-mortem in vivo and post-mortem in situ. In summary, distinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegeneration process., Graphical Abstract Graphical Abstract

Well-characterized, high-quality brain tissue of non-neurological control subjects is a prerequisite to study the healthy aging brain, and can serve as a control for the study of neurological disorders. The Normal Aging Brain Collection Amsterdam (NABCA) provides a comprehensive collection of post-mortem (ultra-)high-field MRI (3Tesla and 7 Tesla) and neuropathological datasets of non-neurological controls. By providing MRI within the pipeline, NABCA uniquely stimulates translational neurosciences; from molecular and morphometric tissue studies to the clinical setting. We describe our pipeline, including a description of our on-call autopsy team, donor selection, in situ and ex vivo post-mortem MRI protocols, brain dissection and neuropathological diagnosis. A demographic, radiological and pathological overview of five selected cases on all these aspects is provided. Additionally, information is given on data management, data and tissue application procedures, including review by a scientific advisory board, and setting up a material transfer agreement before distribution of tissue. Finally, we focus on future prospects, which includes laying the foundation for a unique platform for neuroanatomical, histopathological and neuro-radiological education, of professionals, students and the general (lay) audience., Highlights • NABCA provides a collection of correlative post-mortem MRI and pathological datasets. • Non-neurological control brains for studies on aging and neurological disorders. • Stimulating micro- to macroscale structural exploration within same patient • Post-mortem MRI data and tissue available for integrated advanced data analytics

Introduction The disease course of dementia with Lewy bodies (DLB) can be rapidly progressive, clinically resembling Creutzfeldt-Jakob's disease (CJD). To better understand factors contributing to this rapidly progressive disease course, we describe load and distribution of neuropathology, and the presence of possible disease-associated genetic defects in a post-mortem series of DLB cases clinically suspected of CJD. Methods We included pathologically confirmed DLB cases with a disease duration of 3.5 years or less from the Dutch Surveillance Center for Prion Diseases, collected between 1998 and 2014. Lewy body disease (LBD) and Alzheimer's disease (AD)-related pathology were staged and semi-quantitatively scored in selected brain regions. Whole exome sequencing analysis of known disease-associated genes, copy number analysis, APOE e genotyping and C9orf72 repeat expansion analysis were performed to identify defects in genes with a well-established involvement in Parkinson's disease or AD. Results Diffuse LBD was present in nine cases, transitional LBD in six cases and brainstem-predominant LBD in one case. Neocortical alpha-synuclein load was significantly higher in cases with intermediate-to-high than in cases with low-to-none AD-related pathology (p = 0.007). We found two GBA variants (p.D140H and p.E326K) in one patient and two heterozygous rare variants of unknown significance in SORL1 in two patients. Conclusion A high load of neocortical alpha-synuclein pathology was present in most, but not all DLB cases. Additional burden from presence of concomitant pathologies, synergistic effects and specific genetic defects in the known disease-associated genes may have contributed to the rapid disease progression.