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Additional file 1: Supplementary materials. Table S1. Correction grids for age, education and sex and Equivalent Scores for each test (when available). To correct the raw score, the examiner has to add/subtract the values indicated on the bases of the subject age and/or education and/or sex to the raw score. Corrected score is then assigned an Equivalent Score (when available) according to the corresponding grid of values.

Background Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer’s disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue. Methods Following the initiative of the University of Washington’s National Alzheimer’s Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms. Results Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward. Conclusions The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings.

Biomarkers of brain amyloidosis and neurodegeneration/synaptic dysfunction are featured in recent diagnostic criteria for Alzheimer's disease. Several gaps in our knowledge, however, need to be filled before they can be adopted clinically. The aim of this article is to describe a roadmap, developed by a multidisciplinary task force, to rationally implement biomarkers for Italian Memory Clinics. This roadmap is based on a framework comprising 5 sequential phases: identification of leads for potentially useful biomarkers; development of clinical assays for clinical disease; evaluation of detection of early stages; definition of operating characteristics in relevant populations; and estimation of reducing disease-associated mortality, morbidity, and disability. The roadmap was devised by identifying current evidence of validity, still missing evidence, and action needed to collect this missing evidence. With appropriate adaptation to local, country-specific circumstances, the roadmap can be translated to other countries.

Background and Objective: Primary progressive aphasia (PPA) is a clinical syndrome due to different neurodegenerative conditions in which an accurate early diagnosis needs to be supported by a reliable diagnostic tool at the individual level. In this study, we investigated in PPA the FDG-PET brain metabolic patterns at the single-subject level, in order to assess the case-to-case variability and its relationship with clinical-neuropsychological findings. Material and Methods: 55 patients (i.e., 11 semantic variant/sv-PPA, 19 non fluent variant/nfv-PPA, 17 logopenic variant/lv-PPA, 3 slowly progressive anarthria/SPA, and 5 mixed PPA/m-PPA) were included. Clinical-neuropsychological information and FDG-PET data were acquired at baseline. A follow-up of 27.4±12.55 months evaluated the clinical progression. Brain metabolism was analyzed using an optimized and validated voxel-based SPM method at the single-subject level. Results: FDG-PET voxel-wise metabolic assessment revealed specific metabolic signatures characterizing each PPA variant at the individual level, reflecting the underlying neurodegeneration in language networks. Notably, additional dysfunctional patterns predicted clinical progression to specific dementia conditions. In the case of nfv-PPA, a metabolic pattern characterized by involvement of parietal, subcortical and brainstem structures predicted progression to a corticobasal degeneration syndrome or to progressive supranuclear palsy. lv-PPA and sv-PPA cases who progressed to Alzheimer’s disease and frontotemporal dementia at the follow-up presented with extended bilateral patterns at baseline. Discussion: Our results indicate that FDG-PET voxel-wise imaging is a valid biomarker for the early differential diagnosis of PPAs and for the prediction of progression to specific dementia condition. This study supports the use of FDG-PET imaging quantitative assessment in clinical settings for a better characterization of PPA individuals and prognostic definition of possible endo-phenotypes.

BACKGROUND: The diagnosis of probable behavioral variant of fronto-temporal dementia (bvFTD) according to current criteria requires the imaging evidence of frontal and/or anterior temporal atrophy or hypoperfusion/hypometabolism. Different variants of this pattern of brain involvement may, however, be found in individual cases, supporting the presence of heterogeneous phenotypes. OBJECTIVE: We examined in a case-by-case approach the FDG-PET metabolic patterns of patients fulfilling clinical criteria for probable bvFTD, assessing the presence and frequency of specific FDG-PET features. MATERIALS AND METHODS: Fifty two FDG-PET scans of probable bvFTD patients were retrospectively analyzed together with clinical and neuropsychological data. Neuroimaging experts rated the FDG-PET hypometabolism maps obtained at the single-subject level with optimized voxel-based Statistical Parametric Mapping (SPM). The functional metabolic heterogeneity was further tested by hierarchical cluster analysis and principal component analysis (PCA). RESULTS: Both the SPM maps and cluster analysis identified two major variants of cerebral hypometabolism, namely the "frontal" and the "temporo-limbic", which were correlated with different cognitive profiles. Executive and language deficits were the cognitive hallmark in the "frontal" subgroup, while poor encoding and recall on long-term memory tasks was typical of the "temporo-limbic" subgroup. DISCUSSION: SPM single-subject analysis indicates distinct patterns of brain dysfunction in bvFTD, coupled with specific clinical features, suggesting different profiles of neurodegenerative vulnerability. These findings have important implications for the early diagnosis of bvFTD and for the application of the recent international consensus criteria.

Theory of Mind (ToM), the process by which an individual imputes mental states to himself and others, is presently considered as a multidimensional cognitive domain, with two main facets (i.e., cognitive and affective ToM) accounting, respectively, for the ability to under- stand others' intention (intention attribution-IA) and emotions (emotion attribution-EA). Despite the large amount of literature investigating the behavioural and neural bases of mentalizing abilities in neurological con- ditions, there is still a lack of validated neuropsycholog- ical tools specifically designed to assess such skills. Here, we report the normative data of the Story-Based Empathy Task (SET), a non-verbal test developed for the assess- ment of intention and emotion attribution in the neu- rodegenerative conditions characterized by the impairment of social-emotional abilities. It is an easy-to- administer task including 18 stimuli, sub-grouped into two experimental conditions assessing, respectively, the ability to infer others' intentions (SET-IA) and emotions (SET- EA), compared to a control condition of causal inference (SET-CI). Normative data were collected in 136 Italian subjects pooled across subgroups homogenous for age (range 20-79 years), sex, and education (at least 5 years). The results show a detrimental effect of age and a ben- eficial effect of education on both the global score and each subscale, for which we provide correction grids. This new task could be a useful tool to investigate both affective and cognitive aspects of ToM in the course of disorders of socio-emotional behaviour, such as the fronto-temporal dementia spectrum.

[18F]FDG-PET imaging has been recognized as a crucial diagnostic marker in Mild Cognitive Impairment (MCI), supporting the presence or the exclusion of Alzheimer's Disease (AD) pathology. A clinical heterogeneity, however, underlies MCI definition. In this study, we aimed to evaluate the predictive role of single-subject voxel-based maps of [18F]FDG distribution generated through statistical parametric mapping (SPM) in the progression to different dementia subtypes in a sample of 45 MCI. Their scans were compared to a large normal reference dataset developed and validated for comparison at single-subject level. Additionally, Aβ42 and Tau CSF values were available in 34 MCI subjects. Clinical follow-up (mean 28.5 ± 7.8 months) assessed subsequent progression to AD or non-AD dementias. The SPM analysis showed: 1) normal brain metabolism in 14 MCI cases, none of them progressing to dementia; 2) the typical temporo-parietal pattern suggestive for prodromal AD in 15 cases, 11 of them progressing to AD; 3) brain hypometabolism suggestive of frontotemporal lobar degeneration (FTLD) subtypes in 7 and dementia with Lewy bodies (DLB) in 2 subjects (all fulfilled FTLD or DLB clinical criteria at follow-up); and 4) 7 MCI cases showed a selective unilateral or bilateral temporo-medial hypometabolism without the typical AD pattern, and they all remained stable. In our sample, objective voxel-based analysis of [18F]FDG-PET scans showed high predictive prognostic value, by identifying either normal brain metabolism or hypometabolic patterns suggestive of different underlying pathologies, as confirmed by progression at follow-up. These data support the potential usefulness of this SPM [18F]FDG PET analysis in the early dementia diagnosis and for improving subject selection in clinical trials based on MCI definition., Highlights • We used an optimized voxel-based single-subject [18F]FDG-PET analysis • We showed different hypometabolic patterns (AD and non-AD) underlying MCI condition • Heterogeneous PET profiles predicted progression into specific dementia subtypes. • Statistical analyses showed high positive and negative post-test probability values. • CSF findings agreed with [18F]FDG-PET imaging in single cases.

Neuroimaging techniques, such as positron emission tomography and functional magnetic resonance imaging are essential tools for the analysis of organized neural systems in working and resting states, both in physiological and pathological conditions. They provide evidence of coupled metabolic and cerebral local blood flow changes that strictly depend upon cellular activity. In 1890, Charles Smart Roy and Charles Scott Sherrington suggested a link between brain circulation and metabolism. In the same year William James, in his introduction of the concept of brain blood flow variations during mental activities, briefly reported the studies of the Italian physiologist Angelo Mosso, a multifaceted researcher interested in the human circulatory system. James focused on Mosso's recordings of brain pulsations in patients with skull breaches, and in the process only briefly referred to another invention of Mosso's, the 'human circulation balance', which could non-invasively measure the redistribution of blood during emotional and intellectual activity. However, the details and precise workings of this instrument and the experiments Mosso performed with it have remained largely unknown. Having found Mosso's original manuscripts in the archives, we remind the scientific community of his experiments with the 'human circulation balance' and of his establishment of the conceptual basis of non-invasive functional neuroimaging techniques. Mosso unearthed and investigated several critical variables that are still relevant in modern neuroimaging such as the 'signal-to-noise ratio', the appropriate choice of the experimental paradigm and the need for the simultaneous recording of differing physiological parameters.

Decision-making is strongly influenced by the counterfactual anticipation of personal regret and relief, through a learning process involving the ventromedial-prefrontal cortex. We previously reported that observing the regretful outcomes of another's choices reactivates the regret-network. Here we extend those findings by investigating whether this resonant mechanism also underpins interactive-learning from others' previous outcomes. In this functional-Magnetic-Resonance-Imaging study 24 subjects either played a gambling task or observed another player's risky/non-risky choices and resulting outcomes, thus experiencing personal or shared regret/relief for risky/non-risky decisions. Subjects' risk-aptitude in subsequent choices was significantly influenced by both their and the other's previous outcomes. This influence reflected in cerebral regions specifically coding the effect of previously experienced regret/relief, as indexed by the difference between factual and counterfactual outcomes in the last trial, when making a new choice. The subgenual cortex and caudate nucleus tracked the outcomes that increased risk-seeking (relief for a risky choice, and regret for a non-risky choice), while activity in the ventromedial-prefrontal cortex, amygdala and periaqueductal gray-matter reflected those reducing risk-seeking (relief for a non-risky choice, and regret for a risky choice). Crucially, a subset of the involved regions was also activated when subjects chose after observing the other player's outcomes, leading to the same behavioural change as in a first person experience. This resonant neural mechanism at choice may subserve interactive-learning in decision-making.

We report a new, pathologically verified Italian case of fatal familial insomnia, whose clinical presentation was characterised by complex behavioural disturbances, suggesting wakefulness/NREM/REM combinations.

Background: Previous reports have shown that higher education is associated with more severe brain pathology in patients with Alzheimer disease (AD), suggesting that these individuals have a functional reserve provided by education, which masks the clinical expression of a higher degree of neurodegeneration. It is unknown if a similar reserve mechanism exists in patients with amnestic mild cognitive impairment (aMCI). The aim of this study was to assess the impact of education and occupation on brain glucose metabolism (rCMRglc) measured with FDG-PET in aMCI and in a very large sample of subjects with probable AD (pAD). Methods: A total of 242 patients with pAD, 72 with aMCI, and 144 healthy controls participated in the study. At follow-up, 21 subjects with aMCI progressed to AD. A regression analysis was conducted (SPM2), with education and occupation as independent variables, and rCMRglc as dependent variable, adjusting for demographic data, global cognitive status, and neuropsychological scores. Results: The analysis showed a significant association between higher education/occupation and lower rCMRglc in posterior temporoparietal cortex and precuneus in pAD and aMCI converters, and no correlation in aMCI nonconverters and healthy controls. This means that, when submitted to FDG-PET for diagnostic evaluation, pAD and aMCI converters with higher education/occupation had, for comparable cognitive impairment, a more severe rCMRglc reduction than the ones with lower education/occupation. Conclusions: This study suggests that education and occupation may be proxies for brain functional reserve, reducing the severity and delaying the clinical expression of Alzheimer disease (AD) pathology. The results in aMCI converters suggest that functional reserve is already at play in the predementia phase of AD.

Objective: Primary progressive aphasia (PPA) is characterized by isolated decline in language functions. Semantic dementia and progressive nonfluent aphasia are accepted PPA variants. A “logopenic” variant (LPA) has also been proposed, but its cognitive and anatomic profile is less defined. The aim of this study was to establish the cognitive and anatomic features of LPA. Methods: Six previously unreported LPA cases underwent extensive neuropsychological evaluation and an experimental study of phonological loop functions, including auditory and visual span tasks with digits, letters, and words. For each patient, a voxel-wise, automated analysis of MRI or SPECT data were conducted using SPM2. Results: In LPA, speech rate was slow, with long word-finding pauses. Grammar and articulation were preserved, although phonological paraphasias could be present. Repetition and comprehension were impaired for sentences but preserved for single words, and naming was moderately affected. Investigation of phonological loop functions showed that patients were severely impaired in digit, letter, and word span tasks. Performance did not improve with pointing, was influenced by word length, and did not show the normal phonological similarity effect. Atrophy or decreased blood flow was consistently found in the posterior portion of the left superior and middle temporal gyri and inferior parietal lobule. Conclusions: Logopenic progressive aphasia (LPA) is a distinctive variant of primary progressive aphasia. Cognitive and neuroimaging data indicate that a deficit in phonological loop functions may be the core mechanism underlying the LPA clinical syndrome. Recent studies suggest that Alzheimer disease may be the most common pathology underlying the LPA clinical syndrome. GLOSSARY: AD = Alzheimer disease; BA = Brodmann area; CDR = Clinical Dementia Rating; CVLT-MS = California Verbal Learning Test–Mental Status Edition; ECD = ethyl cysteinate dimer; FWHM = full-width at half-maximum; GM = gray matter; LPA = logopenic progressive aphasia; MMSE = Mini-Mental State Examination; PNFA = progressive nonfluent aphasia; PPA = primary progressive aphasia; Rey-O = Rey–Osterrieth; SemD = semantic dementia; VBM = voxel-based morphometry; WAB = Western Aphasia Battery; WAIS-III = Wechsler Adult Intelligence Scale, Third Edition.

Dementia with Lewy bodies is characterized by α-synuclein accumulation and degeneration of dopaminergic and cholinergic pathways. To gain an overview of brain systems affected by neurodegeneration, we characterized the [18F]FDG-PET metabolic connectivity in 42 dementia with Lewy bodies patients, as compared to 42 healthy controls, using sparse inverse covariance estimation method and graph theory. We performed whole-brain and anatomically driven analyses, targeting cholinergic and dopaminergic pathways, and the α-synuclein spreading. The first revealed substantial alterations in connectivity indexes, brain modularity, and hubs configuration. Namely, decreases in local metabolic connectivity within occipital cortex, thalamus, and cerebellum, and increases within frontal, temporal, parietal, and basal ganglia regions. There were also long-range disconnections among these brain regions, all supporting a disruption of the functional hierarchy characterizing the normal brain. The anatomically driven analysis revealed alterations within brain structures early affected by α-synuclein pathology, supporting Braak's early pathological staging in dementia with Lewy bodies. The dopaminergic striato-cortical pathway was severely affected, as well as the cholinergic networks, with an extensive decrease in connectivity in Ch1-Ch2, Ch5-Ch6 networks, and the lateral Ch4 capsular network significantly towards the occipital cortex. These altered patterns of metabolic connectivity unveil a new invivo scenario for dementia with Lewy bodies underlying pathology in terms of changes in whole-brain metabolic connectivity, spreading of α-synuclein, and neurotransmission impairment.

With event‐related functional MRI (fMRI) and with behavioral measures we studied the brain processes underlying the acquisition of native language literacy. Adult dialect speakers were scanned while reading words belonging to three different conditions: dialect words, i.e., the native language in which subjects are illiterate (dialect), German words, i.e., the second language in which subjects are literate, and pseudowords. Investigating literacy acquisition of a dialect may reveal how novel readers of a language build an orthographic lexicon, i.e., establish a link between already available semantic and phonological representations and new orthographic word forms. The main results of the study indicate that a set of regions, including the left anterior hippocampal formation and subcortical nuclei, is involved in the buildup of orthographic representations. The repeated exposure to written dialect words resulted in a convergence of the neural substrate to that of the language in which these subjects were already proficient readers. The latter result is compatible with a “fast” brain plasticity process that may be related to a shift of reading strategies. Hum Brain Mapp, 2007. © 2006 Wiley‐Liss, Inc.