In memoriam Mario Savoiardo, M.D.

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Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer's Disease and Frontotemporal Dementia: An Extended Case Series

Background: Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. Objectives: The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. Method: PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen’s kappa. Results: Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0–0.25 for PCA to 0.29–0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. Conclusion: The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practic

Diagnostic differentiation of mild cognitive impairment due to Alzheimer's disease using a hippocampus-dependent test of spatial memory.

The hippocampus is one of the earliest brain regions affected in Alzheimer's disease (AD) and tests of hippocampal function have the potential to detect AD in its earliest stages. Given that the hippocampus is critically involved in allocentric spatial memory, this study applied a short test of spatial memory, the 4 Mountains Test (4MT), to determine whether test performance can differentiate mild cognitive impairment (MCI) patients with and without CSF biomarker evidence of underlying AD and whether the test can distinguish patients with MCI and mild AD dementia when applied in different cultural settings. Healthy controls (HC), patients with MCI, and mild AD dementia were recruited from study sites in UK and Italy. Study numbers were: HC (UK 20, Italy 10), MCI (UK 21, Italy 14), and AD (UK 11, Italy 9). Nineteen UK MCI patients were grouped into CSF biomarker-positive (MCI+, n = 10) and biomarker-negative (MCI-, n = 9) subgroups. Behavioral data were correlated with hippocampal volume and cortical thickness of the precuneus and posterior cingulate gyrus. Spatial memory was impaired in both UK and Italy MCI and AD patients. Test performance additionally differentiated between MCI+ and MCI- subgroups (P = 0.001). A 4MT score of ≤8/15 was associated with 100% sensitivity and 90% specificity for detection of early AD (MCI+ and mild AD dementia) in the UK population, and with 100% sensitivity and 50% specificity for detection of MCI and AD in the Italy sample. 4MT performance correlated with hippocampal volume in the UK population and cortical thickness of the precuneus in both study populations. In conclusion, performance on a hippocampus-sensitive test of spatial memory differentiates MCI due to AD with high diagnostic sensitivity and specificity. The observation that similar diagnostic sensitivity was obtained in two separate study populations, allied to the scalability and usability of the test in community memory clinics, supports future application of the 4MT in the diagnosis of pre-dementia due to AD.Alzheimer's Research UK (D.C.) and Italian Ministry of Health (F.T.

From brain topography to brain topology: relevance of graph theory to functional neuroscience

Although several brain regions show significant specialization, higher functions such as cross-modal information integration, abstract reasoning and conscious awareness are viewed as emerging from interactions across distributed functional networks. Analytical approaches capable of capturing the properties of such networks can therefore enhance our ability to make inferences from functional MRI, electroencephalography and magnetoencephalography data. Graph theory is a branch of mathematics that focuses on the formal modelling of networks and offers a wide range of theoretical tools to quantify specific features of network architecture (topology) that can provide information complementing the anatomical localization of areas responding to given stimuli or tasks (topography). Explicit modelling of the architecture of axonal connections and interactions among areas can furthermore reveal peculiar topological properties that are conserved across diverse biological networks, and highly sensitive to disease states. The field is evolving rapidly, partly fuelled by computational developments that enable the study of connectivity at fine anatomical detail and the simultaneous interactions among multiple regions. Recent publications in this area have shown that graph-based modelling can enhance our ability to draw causal inferences from functional MRI experiments, and support the early detection of disconnection and the modelling of pathology spread in neurodegenerative disease, particularly Alzheimer's disease. Furthermore, neurophysiological studies have shown that network topology has a profound link to epileptogenesis and that connectivity indices derived from graph models aid in modelling the onset and spread of seizures. Graph-based analyses may therefore significantly help understand the bases of a range of neurological conditions. This review is designed to provide an overview of graph-based analyses of brain connectivity and their relevance to disease aimed principally at general neuroscientists and clinicians

FMRI/ERP of musical syntax: comparison of melodies and unstructured note sequences

To date, the neural correlates of musical syntax processing have been investigated mainly by means of paradigms in which isolated chords are made incongruent with the harmonic context. Here, we present results obtained contrasting unfamiliar one-part piano melodies with unstructured note sequences, comparable in pitch and rhythm but devoid of any syntactic structure. This paradigm indexes a superset of the cognitive functions involved in processing of harmonic rules. Using functional magnetic resonance imaging, differential activation of a bilateral cortical network comprising the inferior frontal gyrus, superior temporal gyrus and premotor cortex was found. Using event-related potentials, the N2 evoked by each note in melodies was found to have longer latency and a more frontal distribution than that evoked in unstructured sequences