The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer’s disease (AD). We have reviewed the spatiotemporal patterns of amyloid-β and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-β plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-β and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-β pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events.

Introduction:A fixed hemodynamic response function (HRF) is commonly used for functional magnetic resonance imaging (fMRI) analysis. However, HRF may vary from region to region and subject to subject. We investigated the effect of locally estimated HRF (in functionally homogenous parcels) on activation detection sensitivity in a heroin cue reactivity study.Methods:We proposed a novel exploratory method for brain parcellation based on a probabilistic model to segregate the brain into spatially connected and functionally homogeneous components. Then, we estimated HRF and detected activated regions in response to an experimental task in each parcel using a joint detection estimation (JDE) method. We compared the proposed JDE method with the general linear model (GLM) that uses a fixed HRF and is implemented in FEAT (as a part of FMRIB Software Library, version 4.1).Results:1) Regions detected by JDE are larger than those detected by fixed HRF, 2) In group analysis, JDE found areas of activation not detected by fixed HRF. It detected drug craving a priori “regions-of-interest” in the limbic lobe (anterior cingulate cortex [ACC], posterior cingulate cortex [PCC] and cingulate gyrus), basal ganglia, especially striatum (putamen and head of caudate), and cerebellum in addition to the areas detected by the fixed HRF method, 3) JDE obtained higher Z-values of local maxima compared to those obtained by fixed HRF.Conclusion:In our study of heroin cue reactivity, our proposed method (that estimates HRF locally) outperformed the conventional GLM that uses a fixed HRF.

199/200)Alzheimer's disease (AD) and mild cognitive impairment (MCI) are characterized by aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). It is, however, poorly understood how changes in regional neural activity and inter-regional FC interact in AD and MCI. Here, we investigated the link between regional neural activity and nodal topological measures of FC through simultaneous PET/MR measurement in 20 patients with MCI, 33 patients with AD, and 26 healthy individuals. First, we assessed regional glucose metabolism identified through FDG-PET (rFDG) (as a proxy of regional neural activity), and regional FC topology through clustering coefficient (CC) and degree centrality (DC) (as surrogates of local segregation and global connectivity, respectively). Next, we examined the potential moderating effect of disease status (AD or MCI) on the link between rFDG and FC topology using hierarchical moderated multiple regression analysis. Alterations in rFDG, CC, and DC were widespread in patients, and AD alters physiological coupling between regional metabolism and functional connectivity particularly in the inferior temporal gyus and supplementary motor areas. While rFDG correlated with CC in healthy subjects, this correlation was lost in AD patients. We suggest that AD pathology decouples the normal association between regional neural activity and functional segregation.

Although the cognitive deficits due to age-related brain differences have been largely analyzed, the altered connectivity of task related functional networks in aging requires more studies. As the brain of old adults experience some alterations in task performance during cognitive challenges, the related effects on connectivity of functional networks are here evaluated using event-related functional Magnetic Resonance Imaging (fMRI). The fMRI data have been acquired for simple visual and motor tasks from 18 subjects (8 young and 10 elderly). For each subject, several Functional Connectivity (FC) networks including, motor, visual and the default mode networks are firstly calculated using a conventional voxel-wise correlation analysis with predefined region of interest. Then, the strength of functional connectivity is assessed and compared for different age groups. The current study has evaluated three hypotheses on FC of aging brain: the frontal regions involved with motor network try to compensate for declines in the posterior regions, default-mode network are less suppressed and, the posterior regions involved with visual network exhibit less connectivity. The first two hypotheses are accepted by analysis results but visual network behaves differently. Also, results show that the task related functional connectivity is considerably altered in old adults compared to young adults. Old adults demonstrate higher connectivity strength on average with a slightly smaller variance than young adults.