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

Objectives:In Alzheimer disease (AD), mounting evidence points to a greater role for synaptic loss than neuronal loss. Supporting this notion, multiple postmortem studies have demonstrated that the hippocampal CA1 apical neuropil is one of the earliest sites of pathology, exhibiting tau aggregates and then atrophy before there is substantial loss of the CA1 pyramidal neurons themselves. In this cross-sectional study, we tested whether tissue loss in the CA1 apical neuropil layer can be observed in vivo in patients with mild AD. Methods:We performed ultra-high-field 7-T MRI on subjects with mild AD (n ϭ 14) and agematched normal controls (n ϭ 16). With a 2-dimensional T2*-weighted gradient-recalled echo sequence that was easily tolerated by subjects, we obtained cross-sectional slices of the hippocampus at an in-plane resolution of 195 m. Results:On images revealing the anatomic landmarks of hippocampal subfields and strata, we observed thinning of the CA1 apical neuropil in subjects with mild AD compared to controls. By contrast, the 2 groups exhibited no difference in the thickness of the CA1 cell body layer or of the entire CA1 subfield. Hippocampal volume, measured on a conventional T1-weighted sequence obtained at 3T, also did not differentiate these patients with mild AD from controls.Conclusions: CA1 apical neuropil atrophy is apparent in patients with mild AD. With its superior spatial resolution, 7-T MRI permits in vivo analysis of a very focal, early site of AD pathology. GLOSSARYAD ϭ Alzheimer disease; CDR ϭ Clinical Dementia Rating; DG ϭ dentate gyrus; GRE ϭ gradient-recalled echo; NC ϭ normal control; PiB ϭ Pittsburgh Compound B; SP ϭ stratum pyramidale; SRLM ϭ stratum radiatum and stratum lacunosummoleculare; TIV ϭ total intracranial volume.Neuronal death is a late manifestation of Alzheimer disease (AD), with synaptic dysfunction and loss occurring much earlier. 1 Within the hippocampal CA1 subfield, one of the earliest sites of pathologic change in AD, 2 numerous lines of evidence point to disproportionate synaptic loss in the apical neuropil layer, where CA1 pyramidal neurons receive synapses both from the Schaffer collateral axons originating from hippocampal CA3 neurons, and from the perforant pathway axons projecting from the entorhinal cortex. In a rodent model of AD, electrophysiologic evidence of synaptic loss within the CA1 apical neuropil preceded both neuronal death and the appearance of histopathologic changes.3 In humans, hyperphosphorylated tau aggregates appeared inside the distal apical dendritic branches of hippocampal CA1 pyramidal neurons at Braak stage II (clinically silent), prior to any loss of the neurons themselves.4-6 These dendritic segments became dilated and dystrophic, then disappeared by Braak stages IV-V (as clinical signs of AD become fully developed), apparently by amputation and resorption.4 In

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The common and specific involvement of brain networks in clinical variants of Alzheimer’s disease (AD) is not well understood. We performed task-free (“resting-state”) functional imaging in 60 non-familial AD patients, including 20 early-onset AD (EOAD, age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (lvPPA, language deficits) and 16 posterior cortical atrophy patients (PCA, visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior and ventral) and four additional non-DMN networks: left and right executive-control, language and higher visual networks. Significant decreases in connectivity were found across AD variants compared with controls in the non-DMN networks. Within the DMN components, patients showed higher connectivity in the anterior DMN, in particular in lvPPA. No significant differences were found for the posterior and ventral DMN. Our findings suggest that loss of functional connectivity is greatest in networks outside the DMN in early-onset and non-amnestic AD variants, and may thus be a better biomarker in these patients.