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.

Objective:To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods:Patients meeting clinical criteria for AD (n ϭ 62) and FTLD (n ϭ 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n ϭ 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls.Results: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB ( ϭ 0.96) than FDG ( ϭ 0.72), as was agreement between visual and quantitative classification (PiB ϭ 0.88-0.92; FDG ϭ 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n ϭ 12 patients) and 87% for FDG (n ϭ 10). Conclusions:PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology. Neurology Differentiating Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) has implications for prognosis and symptomatic treatment, 1,2 and is critical for the efforts to develop disease-specific therapies. Making an accurate diagnosis during life can be challenging given overlapping clinical features.3,4 MRI or fluorodeoxyglucose PET (FDG-PET) can improve diagnostic accuracy by demonstrating distinct topographic patterns of atrophy or hypometabolism (temporoparietal predominant in AD; frontal and anterior temporal involvement in FTLD), 5,6 but anatomic overlap between the diseases is increasingly apparent. 5,7 Consequently, many patients with pathologically confirmed FTLD are diagnosed with AD during

PET imaging with (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) helps discriminate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). Pathologic correlation is needed to determine whether patients with PIB-positive FTLD represent false positives, comorbid FTLD/AD pathology, or AD pathology mimicking an FTLD clinical syndrome.

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

Patients with early age-of-onset Alzheimer's disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer's disease are associated with differences in the distribution and burden of fibrillar amyloid-beta. Patients meeting criteria for probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 +/- 5.9 years) and late-onset (n = 18, 72.0 +/- 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-beta-ligand [(11)C]-labelled Pittsburgh compound-B and the glucose analogue [(18)F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 +/- 6.4) was studied for comparison. [(11)C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [(18)F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer's disease patient groups showed increased [(11)C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [(11)C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo-parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [(11)C]-labelled Pittsburgh compound-B and [(18)F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [(11)C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-beta was associated with greater posterior cortical hypometabolism in early-onset Alzheimer's disease. Our d...