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Cognitive deficits in Alzheimer’s disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The cholinergic nucleus within the basal forebrain, the nucleus basalis of Meynert, exhibits local atrophy and reduced cortical tract integrity on MRI, and reveals amyloid-β and phosphorylated-tau pathology at autopsy. To better understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimer’s disease, we utilized a combined post-mortem in-situ MRI and histopathology approach. A total of 19 Alzheimer’s disease (10 amnestic and 9 non-amnestic) and 9 non-neurological control donors underwent 3T T1-weighted MRI for anatomical delineation and volume assessment of the nucleus basalis of Meynert, and diffusion-weighted imaging for microstructural assessment of the nucleus and its projections. At subsequent brain autopsy, tissue dissection and immunohistochemistry were performed for amyloid-β, phosphorylated-tau and choline acetyltransferase. Compared to controls, we observed an MRI-derived volume reduction and altered microstructural integrity of the nucleus basalis of Meynert in Alzheimer’s disease donors. Furthermore, decreased cholinergic cell density was associated with reduced integrity of the nucleus and its tracts to the temporal lobe, specifically to the temporal pole of the superior temporal gyrus, and the parahippocampal gyrus. The association between cholinergic cell density and alteration to cortical tracts was specific for amnestic, compared to non-amnestic Alzheimer’s disease donors. Our study illustrates that the nucleus basalis of Meynert is severely affected in amnestic Alzheimer’s disease, both in terms of pathology within the nucleus, but also in terms of damage to its cortical projections, specifically to the temporal lobe, which may contribute to the observed cognitive deterioration.

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.

Melodic intonation therapy (MIT) has been widely reported as an effective approach for improving speech production in people with non-fluent aphasia. Originally developed for native English speakers with aphasia, few has investigated its cross-linguistic effect in a tonal language, such as Chinese. In addition, despite that some studies have provided accounts for the underlying mechanism of MIT-specific behavioral change, literature on the potential white-matter plasticity elicited by the therapy is limited. Aphasia recovery has been reported to employ the perilesional areas in the left hemisphere and/or the homologous language regions in the right hemisphere. Yet, potential white-matter microstructural alteration in language-related regions in the right hemisphere after MIT received surprisingly little attention. This study demonstrated greater facilitation in recovery of speech production after MIT than conventional speech and language therapy among native Chinese speakers with non-fluent aphasia. Further, using diffusion tensor imaging technique, we revealed therapy induced changes in white-matter volumes in the well-established dorsal and ventral language stream tracts in the right hemisphere. The current study offers two accounts for the finding reported: Right hemisphere advantage for tonal language speakers and the role of formulaic language in recovery from non-fluent aphasia are discussed.

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

Alzheimer's disease (AD), an irreversible neurodegenerative disease, is the most common type of dementia in elderly people. This present study incorporated multiple structural and functional connectivity metrics into a graph theoretical analysis framework and investigated alterations in brain network topology in patients with mild cognitive impairment (MCI) and AD. By using this multiparametric analysis, we expected different connectivity metrics may reflect additional or complementary information regarding the topological changes in brain networks in MCI or AD. In our study, a total of 73 subjects participated in this study and underwent the magnetic resonance imaging scans. For the structural network, we compared commonly used connectivity metrics, including fractional anisotropy and normalized streamline count, with multiple diffusivity-based metrics. We compared Pearson correlation and covariance by investigating their sensitivities to functional network topology. Significant disruption of structural network topology in MCI and AD was found predominantly in regions within the limbic system, prefrontal and occipital regions, in addition to widespread alterations of local efficiency. At a global scale, our results showed that the disruption of the structural network was consistent across different edge definitions and global network metrics from the MCI to AD stages. Significant changes in connectivity and tract-specific diffusivity were also found in several limbic connections. Our findings suggest that tract-specific metrics (e.g., fractional anisotropy and diffusivity) provide more sensitive and interpretable measurements than does metrics based on streamline count. Besides, the use of inversed radial diffusivity provided additional information for understanding alterations in network topology caused by AD progression and its possible origins. Use of this proposed multiparametric network analysis framework may facilitate early MCI diagnosis and AD prevention., Highlights • Alzheimer's disease alters structural network mainly in limbic and superior frontal regions. • Altered global network topology may occur in earlier stage during mild cognitive impairment. • The capability of proposed multiparametric network analysis has been demonstrated. • The potential of inversed radial diffusivity on network analysis has been shown.