Showing papers by "Daniela Perani published in 2017"

The impact of bilingualism on brain reserve and metabolic connectivity in Alzheimer's dementia.

Abstract: Cognitive reserve (CR) prevents cognitive decline and delays neurodegeneration. Recent epidemiological evidence suggests that lifelong bilingualism may act as CR delaying the onset of dementia by ∼4.5 y. Much controversy surrounds the issue of bilingualism and its putative neuroprotective effects. We studied brain metabolism, a direct index of synaptic function and density, and neural connectivity to shed light on the effects of bilingualism in vivo in Alzheimer's dementia (AD). Eighty-five patients with probable AD and matched for disease duration (45 German-Italian bilingual speakers and 40 monolingual speakers) were included. Notably, bilingual individuals were on average 5 y older than their monolingual peers. In agreement with our predictions and with models of CR, cerebral hypometabolism was more severe in the group of bilingual individuals with AD. The metabolic connectivity analyses crucially supported the neuroprotective effect of bilingualism by showing an increased connectivity in the executive control and the default mode networks in the bilingual, compared with the monolingual, AD patients. Furthermore, the degree of lifelong bilingualism (i.e., high, moderate, or low use) was significantly correlated to functional modulations in crucial neural networks, suggesting both neural reserve and compensatory mechanisms. These findings indicate that lifelong bilingualism acts as a powerful CR proxy in dementia and exerts neuroprotective effects against neurodegeneration. Delaying the onset of dementia is a top priority of modern societies, and the present in vivo neurobiological evidence should stimulate social programs and interventions to support bilingual or multilingual education and the maintenance of the second language among senior citizens.

Gender differences in healthy aging and Alzheimer's Dementia: A 18F‐FDG‐PET study of brain and cognitive reserve

Abstract: Cognitive reserve (CR) and brain reserve (BR) are protective factors against age-associated cognitive decline and neurodegenerative disorders Very limited evidence exists about gender effects on brain aging and on the effect of CR on brain modulation in healthy aging and Alzheimer's Dementia (AD) We investigated gender differences in brain metabolic activity and resting-state network connectivity, as measured by 18F-FDG-PET, in healthy aging and AD, also considering the effects of education and occupation The clinical and imaging data were retrieved from large datasets of healthy elderly subjects (HE) (225) and AD patients (282) In HE, males showed more extended age-related reduction of brain metabolism than females in frontal medial cortex We also found differences in brain modulation as metabolic increases induced by education and occupation, namely in posterior associative cortices in HE males and in the anterior limbic-affective and executive networks in HE females In AD patients, the correlations between education and occupation levels and brain hypometabolism showed gender differences, namely a posterior temporo-parietal association in males and a frontal and limbic association in females, indicating the involvement of different networks Finally, the metabolic connectivity in both HE and AD aligned with these results, suggesting greater efficiency in the posterior default mode network for males, and in the anterior frontal executive network for females The basis of these brain gender differences in both aging and AD, obtained exploring cerebral metabolism, metabolic connectivity and the effects of education and occupation, is likely at the intersection between biological and sociodemographic factors Hum Brain Mapp, 2017 © 2017 Wiley Periodicals, Inc

Molecular Imaging of Neuroinflammation in Neurodegenerative Dementias: The Role of In Vivo PET Imaging

Abstract: Neurodegeneration elicits neuroinflammatory responses to kill pathogens, clear debris and support tissue repair. Neuroinflammation is a dynamic biological response characterized by the recruitment of innate and adaptive immune system cells in the site of tissue damage. Resident microglia and infiltrating immune cells partake in the restoration of central nervous system homeostasis. Nevertheless, their activation may shift to chronic and aggressive responses, which jeopardize neuron survival and may contribute to the disease process itself. Positron Emission Tomography (PET) molecular imaging represents a unique tool contributing to in vivo investigating of neuroinflammatory processes in patients. In the present review, we first provide an overview on the molecular basis of neuroinflammation in neurodegenerative diseases with emphasis on microglia activation, astrocytosis and the molecular targets for PET imaging. Then, we review the state-of-the-art of in vivo PET imaging for neuroinflammation in dementia conditions associated with different proteinopathies, such as Alzheimer's disease, frontotemporal lobar degeneration and Parkinsonian spectrum.

Altered brain metabolic connectivity at multiscale level in early Parkinson's disease

Abstract: To explore the effects of PD pathology on brain connectivity, we characterized with an emergent computational approach the brain metabolic connectome using [18F]FDG-PET in early idiopathic PD patients. We applied whole-brain and pathology-based connectivity analyses, using sparse-inverse covariance estimation in thirty-four cognitively normal PD cases and thirty-four age-matched healthy subjects for comparisons. Further, we assessed high-order resting state networks by interregional correlation analysis. Whole-brain analysis revealed altered metabolic connectivity in PD, with local decreases in frontolateral cortex and cerebellum and increases in the basal ganglia. Widespread long-distance decreases were present within the frontolateral cortex as opposed to connectivity increases in posterior cortical regions, all suggestive of a global-scale connectivity reconfiguration. The pathology-based analyses revealed significant connectivity impairment in the nigrostriatal dopaminergic pathway and in the regions early affected by α-synuclein pathology. Notably, significant connectivity changes were present in several resting state networks especially in frontal regions. These findings expand previous imaging evidence of altered connectivity in cognitively stable PD patients by showing pathology-based connectivity changes and disease-specific metabolic architecture reconfiguration at multiple scale levels, from the earliest PD phases. These alterations go well beyond the known striato-cortical connectivity derangement supporting in vivo an extended neural vulnerability in the PD synucleinopathy.

Metabolic connectomics targeting brain pathology in dementia with Lewy bodies

Abstract: 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 r...

A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting.

Abstract: Assessments of brain glucose metabolism (18F-FDG-PET) and cerebral amyloid burden (11C-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of 18F-FDG-PET and 11C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18F-FDG-PET and of standardized uptake value ratio semiquantification for 11C-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57±7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both 18F-FDG-PET and 11C-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

The emerging role of PET imaging in dementia.

Abstract: A compelling need in the field of neurodegenerative diseases is the development and validation of biomarkers for early identification and differential diagnosis. The availability of positron emission tomography (PET) neuroimaging tools for the assessment of molecular biology and neuropathology has opened new venues in the diagnostic design and the conduction of new clinical trials. PET techniques, allowing the in vivo assessment of brain function and pathology changes, are increasingly showing great potential in supporting clinical diagnosis also in the early and even preclinical phases of dementia. This review will summarize the most recent evidence on fluorine-18 fluorodeoxyglucose-, amyloid -, tau -, and neuroinflammation - PET tools, highlighting strengths and limitations and possible new perspectives in research and clinical applications. Appropriate use of PET tools is crucial for a prompt diagnosis and target evaluation of new developed drugs aimed at slowing or preventing dementia.

Evaluation of an optimized [18F]fluoro‐deoxy‐glucose positron emission tomography voxel‐wise method to early support differential diagnosis in atypical Parkinsonian disorders

Abstract: BACKGROUND AND PURPOSE Atypical Parkinsonian disorders (APD) frequently overlap in clinical presentations, making the differential diagnosis challenging in the early stages. The present study aimed to evaluate the accuracy of the [18 F]fluoro-deoxy-glucose positron emission tomography Statistical Parametric Mapping (SPM) optimized procedure in supporting the early and differential diagnosis of APD. METHODS Seventy patients with possible APD were retrospectively included from a large clinical cohort. The included patients underwent [18 F]fluoro-deoxy-glucose positron emission tomography within 3 months of the first clinical assessment and a diagnostic follow-up. An optimized SPM voxel-wise procedure was used to produce t-maps of brain hypometabolism in single subjects, which were classified by experts blinded to any clinical information. We compared the accuracy of both the first clinical diagnosis and the SPM t-map classifications with the diagnosis at follow-up as the reference standard. RESULTS At first diagnosis, 60% of patients were classified as possible APD (progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy) and about 40% as APD with uncertain diagnosis, providing 52% sensitivity, 97% specificity and 86% accuracy with respect to the reference standard. SPM t-map classification showed 98% sensitivity, 99% specificity and 99% accuracy, and a significant agreement with the diagnosis at follow-up (P < 0.001). CONCLUSIONS The SPM t-map classification at entry predicted the second diagnosis at follow-up. This indicates its significantly superior role for an early identification of APD subtypes, particularly in cases of uncertain diagnosis. The use of a metabolic biomarker at entry in the instrumental work-up of APD may shorten the diagnostic time, producing benefits for treatment options and support to the patients.

Validation of 18F-FDG-PET Single-Subject Optimized SPM Procedure with Different PET Scanners.

Abstract: 18F–fluoro-deoxy-glucose Positron Emission Tomography (FDG-PET) allows early identification of neurodegeneration in dementia. The use of an optimized method based on the SPM software package highly improves diagnostic accuracy. However, the impact of different scanners for data acquisition on the SPM results and the effects of different pools of healthy subjects on the statistical comparison have not been investigated yet. Images from 144 AD patients acquired using six different PET scanners were analysed with an optimized single-subject SPM procedure to identify the typical AD hypometabolism pattern at single subject level. We compared between-scanners differences on the SPM outcomes in a factorial design. Single-subject SPM comparison analyses were also performed against a different group of healthy controls from the ADNI initiative. The concordance between the two analyses (112 vs. 157 control subjects) was tested using Dice scores. In addition, we applied the optimized single-subject SPM procedure to the FDG-PET data acquired with 3 different scanners in 57 MCI subjects, in order to assess for tomograph influence in early disease phase. All the patients showed comparable AD-like hypometabolic patterns, also in the prodromal phase, in spite of being acquired with different PET scanners. SPM statistical comparisons performed with the two different healthy control databases showed a high degree of concordance (76% average pattern volume overlap and 90% voxel-wise agreement in AD-related brain structures). The validated optimized SPM-based single-subject procedure is influenced neither by the scanners used for image acquisition, nor by differences in healthy control groups, thus implying a great reliability of this method for longitudinal and multicentre studies.

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Abstract: Objective Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients. Methods We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis. Results After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded. Interpretation DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.

Executive dysfunction affects word list recall performance: Evidence from amyotrophic lateral sclerosis and other neurodegenerative diseases.

Abstract: The Rey Auditory Verbal Learning Test (RAVLT) is widely used in clinical practice to evaluate verbal episodic memory. While there is evidence that RAVLT performance can be influenced by executive dysfunction, the way executive disorders affect the serial position curve (SPC) has not been yet explored. To this aim, we analysed immediate and delayed recall performances of 13 non-demented amyotrophic lateral sclerosis (ALS) patients with a specific mild executive dysfunction (ALSci) and compared their performances to those of 48 healthy controls (HC) and 13 cognitively normal patients with ALS. Moreover, to control for the impact of a severe dysexecutive syndrome and a genuine episodic memory deficit on the SPC, we enrolled 15 patients with a diagnosis of behavioural variant of frontotemporal dementia (bvFTD) and 18 patients with probable Alzheimer's disease (AD). Results documented that, compared to cognitively normal subjects, ALSci patients had a selective mid-list impairment for immediate recall scores. The bvFTD group obtained low performances with a selectively increased forgetting rate for terminal items, whereas the AD group showed a disproportionately large memory loss on the primary and middle part of the SPC for immediate recall scores and were severely impaired in the delayed recall trial. These results suggested that subtle executive dysfunctions might influence the recall of mid-list items, possibly reflecting deficiency in control strategies at retrieval of word lists, whereas severer dysexecutive syndrome might also affect the recall of terminal items possibly due to attention deficit or retroactive interference.

The impact of different 18FDG PET healthy subject scans for comparison with single patient in SPM analysis.

Abstract: BACKGROUND Statistical Parametric Mapping (SPM) has been applied for single-subject evaluation of [18F]FDG uptake in Alzheimer Disease (AD). In a single-subject framework, the patient is compared to a dataset of [18F]FDG PET images from healthy subjects (HS) evaluating brain metabolic abnormalities. No studies exist that assess the effects on SPM analysis of HS [18F]FDG PET datasets acquired from different subjects and using different PET scanners including the same or different PET scanners than those used for patients. This work aims to elucidate this issue from a methodological perspective. METHODS We considered six different [18F]FDG PET datasets, from different HS populations, acquired by different PET scanners. We applied SPM5 procedures for single-subject comparison with each of the six HS datasets in 10 probable AD patients showing the typical [18F]FDG pattern. We also implemented the same comparison in 3 probable AD patients and in 7 patients with a clinical diagnosis of Mild Cognitive Impariment (MCI), showing subtle changes on visual inspection of [18F]FDG distribution. RESULTS Considering the 10 patients with the typical [18F]FDG pattern, the results were comparable for all the SPM maps. In the 3 probable AD patients with subtle changes in [18F]FDG distribution, no significant AD pattern emerged when a small number ( 50) HS image set was used. In the 7 considered MCI patients the use of a large (>50) HS image set allowed to assess significant hypometabolic patterns related to a probable neurodegenerative pathology. CONCLUSIONS The use of large HS datasets of PET scans (>50) is recommended for single-subject SPM analysis. On condition that appropriate preprocessing steps are provided, large HS datasets can include HS images acquired with different PET systems, not including images from the same scanner of that used for patients.

Unaware Processing of Tools in the Neural System for Object-Directed Action Representation.

Abstract: The hypothesis that the brain constitutively encodes observed manipulable objects for the actions they afford is still debated. Yet, crucial evidence demonstrating that, even in the absence of perceptual awareness, the mere visual appearance of a manipulable object triggers a visuomotor coding in the action representation system including the premotor cortex, has hitherto not been provided. In this fMRI study, we instantiated reliable unaware visual perception conditions by means of continuous flash suppression, and we tested in 24 healthy human participants (13 females) whether the visuomotor object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices is activated even under subliminal perceptual conditions. We found consistent activation in the target visuomotor cortices, both with and without perceptual awareness, specifically for pictures of manipulable versus non-manipulable objects. By means of a multivariate searchlight analysis, we also found that the brain activation patterns in this visuomotor network enabled the decoding of manipulable versus non-manipulable object picture processing, both with and without awareness. These findings demonstrate the intimate neural coupling between visual perception and motor representation that underlies manipulable object processing: manipulable object stimuli specifically engage the visuomotor object-directed action representation system, in a constitutive manner that is independent from perceptual awareness. This perceptuo-motor coupling endows the brain with an efficient mechanism for monitoring and planning reactions to external stimuli in the absence of awareness.SIGNIFICANCE STATEMENT Our brain constantly encodes the visual information that hits the retina, leading to a stimulus-specific activation of sensory and semantic representations, even for objects that we do not consciously perceive. Do these unconscious representations encompass the motor programming of actions that could be accomplished congruently with the objects' functions? In this fMRI study, we instantiated unaware visual perception conditions, by dynamically suppressing the visibility of manipulable object pictures with mondrian masks. Despite escaping conscious perception, manipulable objects activated an object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices. This demonstrates that visuomotor encoding occurs independently of conscious object perception.

FDG PET/MR Imaging in Major Neurocognitive Disorders.

Abstract: PET/MRI tomographs represent the latest development in hybrid molecular imaging, opening new perspectives for clinical and research applications and attracting a large interest among the medical community. This new hybrid modality is expected to play a pivotal role in a number of clinical applications and among these the assessment of neurodegenerative disorders. PET and MRI, acquired separately, are already the imaging biomarkers of choice for a comprehensive assessment of the changes occurring in dementias (major cognitive disorders) as well as in their prodromal phase. In this paper we review the current evidence on the use of integrated PET/MRI scanners to investigate patients with neurodegenerative conditions, and in particular major neurocognitive disorders. The number of studies performed is still limited and shows that the use of PET/MRI gives results overall comparable to PET/CT and MRI acquired independently. We also address the challenges for quantitative aspects in PET/MRI, namely attenuation, partial volume and motion correction and the use of semi-quantitative approaches for FDG PET image analysis in this framework. The recent development of PET tracers for the in vivo differential diagnosis of dementias, able to visualize amyloid and tau deposits, suggests that in the future PET/MRI might represent the investigation of choice for a single session evaluation of morphological, functional and molecular markers.

The Italian dementia with Lewy bodies study group (DLB-SINdem): toward a standardization of clinical procedures and multicenter cohort studies design

Abstract: Dementia with Lewy bodies (DLB) causes elevated outlays for the National Health Systems due to high institutionalization rate and patients’ reduced quality of life and high mortality. Furthermore, DLB is often misdiagnosed as Alzheimer’s disease. These data motivate harmonized multicenter longitudinal cohort studies to improve clinical management and therapy monitoring. The Italian DLB study group of the Italian Neurological Society for dementia (SINdem) developed and emailed a semi-structured questionnaire to 572 national dementia centers (from primary to tertiary) to prepare an Italian large longitudinal cohort. The questionnaire surveyed: (1) prevalence and incidence of DLB; (2) clinical assessment; (3) relevance and availability of diagnostic tools; (4) pharmacological management of cognitive, motor, and behavioural disturbances; (5) causes of hospitalization, with specific focus on delirium and its treatment. Overall, 135 centers (23.6 %) contributed to the survey. Overall, 5624 patients with DLB are currently followed by the 135 centers in a year (2042 of them are new patients). The percentage of DLB patients was lower (27 ± 8 %) than that of Alzheimer’s disease and frontotemporal dementia (56 ± 27 %) patients. The majority of the centers (91 %) considered the clinical and neuropsychological assessments as the most relevant procedure for a DLB diagnosis. Nonetheless, most of the centers has availability of magnetic resonance imaging (MRI; 95 %), electroencephalography (EEG; 93 %), and FP-CIT single photon emission-computerized tomography (SPECT; 75 %) scan for clinical applications. It will be, therefore, possible to recruit a large harmonized Italian cohort of DLB patients for future cross-sectional and longitudinal multicenter studies.

Unaware processing of tools in the neural system for object-directed action representation

Abstract: The hypothesis that the brain constitutively encodes observed manipulable objects for the actions they afford is still debated. Yet, crucial supporting evidence demonstrating that such visuo-motor embodiment occurs even without awareness has hitherto not been provided. In this fMRI study, we reliably instantiated unaware visual perception conditions by means of Continuous Flash Suppression, and found consistent activation in the target visuo-motor, action representation system, specifically for manipulable versus non-manipulable objects.