Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

OBJECTIVE-Alzheimer's disease (AD) is found at autopsy in up to one-third of patients with primary progressive aphasia (PPA), but clinical features that predict AD pathology in PPA are not well defined. We studied the relationships between language presentation, Aβ amyloidosis and glucose metabolism in three variants of PPA using [ 11 C]PIB and [ 18 F]FDG-PET. METHODS-Patientsmeeting PPA criteria (N=15) were classified as logopenic aphasia (LPA), progressive non-fluent aphasia (PNFA) or semantic dementia (SD) based on language testing. [ 11 C] PIB distribution volume ratios were calculated using Logan graphical analysis (cerebellar reference).[ 18 F]FDG images were normalized to pons. Partial volume correction was applied.RESULTS-Elevated cortical PIB (by visual inspection) was more common in LPA (4/4 patients) than in PNFA (1/6) and SD (1/5) (p<0.02). In all PIB-positive cases, PIB uptake was diffuse and indistinguishable from the pattern in matched AD patients (N=10). FDG patterns were focal and varied by PPA subtype, with left temporoparietal hypometabolism in LPA, left frontal hypometabolism in PNFA, and left anterior temporal hypometabolism in SD. FDG patterns in PIBpositive PNFA and SD were similar to PIB-negative cases. Language regions showed asymmetric left hypometabolism in PPA (p<0.005) but not in AD.INTERPRETATION-LPA is associated with Aβ amyloidosis, suggesting that sub-classification of PPA based on language features can help predict the likelihood of underlying AD pathology. Language phenotype in PPA is closely related to metabolic changes that are focal and anatomically distinct between subtypes, but not to amyloid deposition patterns that are diffuse and similar to AD.

A dual-task methodology was used to investigate the roles played by executive and phonological aspects of working memory in mental arithmetic. Experiment 1 showed that suppression of articulation impaired the ability to add a pair of briefly presented three-digit numbers. Suppression had no effect when the need to store temporarily was minimized by making the numbers visible throughout calculation. Experiment 2 showed that disrupting executive processes by requiring concurrent performance of a Trails task impaired the ability to add numbers that remained permanently visible. Performance on the Trails task deteriorated as the number of carry operations in the addition increased. Experiment 3 showed that this decline in Trails performance was not simply due to the extra time taken by carrying. These and other features of the results suggest that the carrying component of mental arithmetic places substantial demands on executive processes, whereas the need to retain problem information is met by the phonological loop. The results are consistent with an interpretation of executive processes according to which there is a limit on the capacity to inhibit strongly primed routine operations.In a recent review, Ashcraft (1995) emphasized the dependence of mental calculation on working memory, the limited-capacity system for keeping track of temporary information during ongoing processing (see, e.g.,

We use a novel balanced experimental design to specifically investigate brain mechanisms underlying the modulating effect of expected pain intensity on afferent nociceptive processing and pain perception. We used two visual cues, each conditioned to one of two noxious thermal stimuli [ϳ48°C (high) or 47°C (low)]. The visual cues were presented just before and during application of the noxious thermal stimulus. Subjects reported significantly higher pain when the noxious stimulus was preceded by the high-intensity visual cue. To control for expectancy effects, for one-half of the runs, the noxious thermal stimuli were accompanied by the cue conditioned to the other stimulus. Comparing functional magnetic resonance imaging blood oxygenation level-dependent activations produced by the high and low thermal stimulus intensities presented with the high-intensity visual cue showed significant activations in nociceptive regions of the thalamus, second somatosensory cortex, and insular cortex. To isolate the effect of expectancy, we compared activations produced by the two visual cues presented with the high-intensity noxious thermal stimulus; this showed significant differences in the ipsilateral caudal anterior cingulate cortex, the head of the caudate, cerebellum, and the contralateral nucleus cuneiformis (nCF). We propose that pain intensity expectancy modulates activations produced by noxious stimuli through a distinct modulatory network that converges with afferent nociceptive input in the nCF.