Papers by Carlo Caltagirone
Alzheimer's research & therapy, Jan 17, 2017
Cognitive, behavioural, and functional assessment is crucial in longitudinal studies of neurodege... more Cognitive, behavioural, and functional assessment is crucial in longitudinal studies of neurodegenerative dementias (NDD). Central issues, such as the definition of the study population (asymptomatic, at risk, or individuals with dementia), the detection of change/decline, and the assessment of relevant outcomes depend on quantitative measures of cognitive, behavioural, and functional status.Currently, we are far from having available reliable protocols and tools for the assessment of dementias in Europe. The main problems are the heterogeneity of the tools used across different European countries, the lack of standardisation of administration and scoring methods across centres, and the limited information available about the psychometric properties of many tests currently in widespread use. This situation makes it hard to compare results across studies carried out in different centres, thus hampering research progress, in particular towards the contribution to a "big data"...
PLOS ONE, 2016
Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessi... more Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients' cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms.
Journal of neuroengineering and rehabilitation, Jan 26, 2016
Patients affected by mild stroke benefit more from physiological overground walking training than... more Patients affected by mild stroke benefit more from physiological overground walking training than walking-like training performed in place using specific devices. The aim of the study was to evaluate the effects of overground robotic walking training performed with the servo-assistive robotic rollator (i-Walker) on walking, balance, gait stability and falls in a community setting in patients with mild subacute stroke. Forty-four patients were randomly assigned to two different groups that received the same therapy in two daily 40-min sessions 5 days a week for 4 weeks. Twenty sessions of standard therapy were performed by both groups. In the other 20 sessions the subjects enrolled in the i-Walker-Group (iWG) performed with the i-Walker and the Control-Group patients (CG) performed the same amount of conventional walking oriented therapy. Clinical and instrumented gait assessments were made pre- and post-treatment. The follow-up observation consisted of recording the number of faller...
Journal of neuroinflammation, Jan 25, 2016
Dendritic cells (DCs) are major orchestrators of immune responses and inflammation. They are migr... more Dendritic cells (DCs) are major orchestrators of immune responses and inflammation. They are migratory cells, which may play a role in Alzheimer's disease (AD), as suggested by prior in vitro studies. With the intent to investigate the clinical relevance of DC modifications in vivo, the present study was aimed to evaluate the levels of blood DCs in AD patients, in relation to the progression of the disease, the severity of its symptoms, and the treatment with acetylcholinesterase inhibitors (AChEIs), a class of drugs used to improve cognitive functioning in people with dementia. The two main subpopulations of immature blood DCs, namely myeloid (mDCs) and plasmacytoid (pDCs) cells, were evaluated by flow cytometry analysis in 106 AD patients, in comparison with the same cells from 65 individuals with mild cognitive impairment (MCI) and 73 healthy control subjects (HC). The relationship between blood DC levels and symptom severity was also assessed in AD patients, and their blood ...
Canadian journal of physiology and pharmacology, Jan 10, 2016
Increasing evidence suggests that motor rehabilitation may delay Parkinson's disease (PD) pro... more Increasing evidence suggests that motor rehabilitation may delay Parkinson's disease (PD) progression. Moreover, parallel treatments in animals up-regulate brain-derived neurotrophic factor (BDNF). Thus, we investigated the effect of a motor rehabilitation protocol on PD symptoms and BDNF serum levels. Motor rehabilitation training consisted of a cycle of 20 days/month of physiotherapy divided in 3 daily sessions. Clinical data were collected at the beginning, at the end, and at 90 days follow-up. BDNF serum levels were detected by ELISA at 0, 7, 14, 21, 30, and 90 days. The follow-up period had a duration of 60 days (T30-T90). The results showed that at the end of the treatment (day 30), an improvement in extrapyramidal signs (UPDRS III; UPDRS III - Gait and Balance items), motor (6 Minute Walking Test), and daily living activities (UPDRS II; PDQ-39) was observed. BDNF levels were increased at day 7 as compared with baseline. After that, no changes in BDNF were observed during ...
Human brain mapping, Jan 24, 2015
We investigated the role of the dopamine system [i.e., subcortical-medial prefrontal cortex (mPFC... more We investigated the role of the dopamine system [i.e., subcortical-medial prefrontal cortex (mPFC) network] in dreaming, by studying patients with Parkinson's Disease (PD) as a model of altered dopaminergic transmission. Subcortical volumes and cortical thickness were extracted by 3T-MR images of 27 PD patients and 27 age-matched controls, who were asked to fill out a dream diary upon morning awakening for one week. PD patients do not substantially differ from healthy controls with respect to the sleep, dream, and neuroanatomical measures. Multivariate correlational analyses in PD patients show that dopamine agonist dosage is associated to qualitatively impoverished dreams, as expressed by lower bizarreness and lower emotional load values. Visual vividness (VV) of their dream reports positively correlates with volumes of both the amygdalae and with thickness of the left mPFC. Emotional load also positively correlates with hippocampal volume. Beside the replication of our previou...
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2015
Background: There is no consensus about which hippocampal subfields become atrophic earliest in t... more Background: There is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD). Methods: Thirty AD patients, 41 mild cognitive impairment (MCI) patients, and 38 healthy controls (HCs) underwent cerebral magnetic resonance imaging (with an automated segmentation protocol for the volumetric analysis of hippocampal subfields) and a test of immediate and delayed recall of a 15word list. Results: The volumes of the presubiculum and subiculum presented the most remarkable reduction in the patient's groups. In the MCI group, only the volumes of presubiculum and subiculum predicted performance on the memory tests. In AD patients, the volumes of all hippocampal subfields (with the notable exception of the CA1) predicted memory scores. Conclusions: Our data point to a prevalent atrophy of the presubicular-subicular complex from the early phases of AD. This finding is consistent with neuropathological observations in AD patients and probably reflects the severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field in its course from the entorhinal cortex to the dentate gyrus.
Frontiers in systems neuroscience, 2015
Approach and avoidance are two basic behavioral aptitudes of humans whose correct balance is crit... more Approach and avoidance are two basic behavioral aptitudes of humans whose correct balance is critical for successful adaptation to the environment. As the expression of approach and avoidance tendencies may differ significantly between healthy individuals, different psychobiological factors have been posited to account for such variability. In this regard, two main issues are still open that refers to (i) the role played by dopamine neurotransmission; and (ii) the possible influence of cognitive characteristics, particularly executive functioning. The aim of the present paper was to highlight the contribution of research on Parkinson's disease (PD) to our understanding of the above issues. In particular, we here reviewed PD literature to clarify whether neurobiological and neuropsychological modifications due to PD are associated to changes in approach-avoidance related personality features. Available data indicate that PD patients may show and approach-avoidance imbalance as do...
Current biology : CB, Jan 15, 2014
A fully adapted behavior requires maximum efficiency to inhibit processes in the motor domain. Al... more A fully adapted behavior requires maximum efficiency to inhibit processes in the motor domain. Although a number of cortical and subcortical brain regions have been implicated, converging evidence suggests that activation of right inferior frontal gyrus (r-IFG) and right presupplementary motor area (r-preSMA) is crucial for successful response inhibition. However, it is still unknown how these prefrontal areas convey the necessary signal to the primary motor cortex (M1), the cortical site where the final motor plan eventually has to be inhibited or executed. On the basis of the widely accepted view that brain oscillations are fundamental for communication between neuronal network elements, one would predict that the transmission of these inhibitory signals within the prefrontal-central networks (i.e., r-IFG/M1 and/or r-preSMA/M1) is realized in rapid, periodic bursts coinciding with oscillatory brain activity at a distinct frequency. However, the dynamics of corticocortical effectiv...
Advances in Alzheimer's Disease, 2013
Objective: As the literature on conventional criteria for discriminating early-onset (EO) from la... more Objective: As the literature on conventional criteria for discriminating early-onset (EO) from late-onset (LO) Alzheimer's disease (AD) is sparse and controversial, the aim of this study was to establish a precise age at onset (AAO) criterion, by using a specific statistical procedure, and to describe the clinical characteristics of the two subgroups. Methods: Admixture analysis was performed to establish the AAO cutoff in a multi-center study including 2000 AD patients consecutively recruited in eight Italian Memory Clinics. None of the patients were taking acetylcholinesterase inhibitors, antipsychotic or anti-depressant drugs. At the first diagnostic visit, they were administered the Mini Mental State Examination, the Basic and Instrumental Activities of Daily Living and the Neuropsychiatric Inventory to assess clinical phenomenology. Results: Using a specific statistical procedure, we established that AAO that discriminated EOfrom LOAD was 66. Compared with the LOAD group, the EO-AD group showed longer duration of illness and a higher educational level as well as less severe functional impairment and delusions. Conclusions: Differences in sociodemographic and clinical characteristics, such as duration of illness, education and delusion severity, suggested the involvement of different pathogenic processes. Additional studies are needed to further investigate the mechanisms underlying the disorder in the two subgroups of AD patients.
Neurobiology of Aging, 2015
This study investigates how cognitive reserve (CR) interacts with neurodegeneration (quantified b... more This study investigates how cognitive reserve (CR) interacts with neurodegeneration (quantified by medial temporal atrophy, MTA) and macroscopic white matter lesions (WMLs) in delaying the conversion from amnestic mild cognitive impairment to Alzheimer's disease (AD). Forty-two amnestic mild cognitive impairment patients were consecutively recruited. They underwent magnetic resonance imaging and a comprehensive questionnaire to classify them as individuals with low or high CR. Patients were then clinically followed-up for 2 years. The patients' risk for conversion to AD because of CR was estimated by controlling for cognitive efficiency, MTA, and WMLs at baseline. Global cognition was the best predictor of conversion to AD in low CR patients. Conversely, in high CR patients only, WMLs (but not MTA) highly contributed in increasing the risk for conversion to AD. In conclusion, CR interacts with both patients' cognitive features and WMLs in modulating the impact of AD pathology. This seems relevant for clinical prognosis and therapeutic strategies.
Cardiovascular Psychiatry and Neurology, 2013
Background. Endarterectomy (CEA) or stenting (CAS) of a stenotic carotid artery is currently unde... more Background. Endarterectomy (CEA) or stenting (CAS) of a stenotic carotid artery is currently undertaken to reduce stroke risk. In addition removal of the arterial narrowing has been hypothesized to improve cerebral hemodynamics and provide benefits in cognitive functions, by supposedly resolving a “hypoperfusion” condition. Methods. In this study we sought to test whether resolution of a carotid stenosis is followed by measurable changes in cognitive functions in 22 subjects with “asymptomatic” stenosis. Results. A main finding of the study was the statistically significant pre-post difference observed in the performance of phonological verbal fluency and Rey’s 15-word immediate recall. Remarkably, there was a significant interaction between phonological verbal fluency performance and side of the carotid intervention, as the improvement in the verbal performance, a typical “lateralized” skill, was associated with resolution of the left carotid stenosis. Conclusion. The results refle...
BioMed Research International, 2014
Neurobiology of Aging, 2012
Granulin (GRN) mutations have been identified as a major cause of frontotemporal lobar degenerati... more Granulin (GRN) mutations have been identified as a major cause of frontotemporal lobar degeneration (FTLD) by haploinsufficiency mechanism, although their effects on brain tissue dysfunction and damage still remain to be clarified. In this study, we investigated the pattern of neuroimaging abnormalities in FTLD patients, carriers and noncarriers of GRN Thr272fs mutation, and in presymptomatic carriers. We assessed regional gray matter (GM) atrophy, and resting (RS)-functional magnetic resonance imaging (fMRI). The functional connectivity maps of the salience (SN) and the default mode (DMN) networks were considered. Frontotemporal gray matter atrophy was found in all FTLD patients (more remarkably in those GRN Thr272fs carriers), but not in presymptomatic carriers. Functional connectivity within the SN was reduced in all FTLD patients (again more remarkably in those mutation carriers), while it was enhanced in the DMN. Conversely, presymptomatic carriers showed increased connectivity in the SN, with no changes in the DMN. Our findings suggest that compensatory mechanisms of brain plasticity are present in GRN-related FTLD, but with different patterns at a preclinical and symptomatic disease stage.
Brain and Behavior, 2014
Object: The aim of this study was to investigate macrostructural and microstructural brain change... more Object: The aim of this study was to investigate macrostructural and microstructural brain changes in patients with pure obsessive compulsive disorder (OCD) and to examine the relationship between brain structure and neuropsychological deficits. Method: 20 patients with OCD underwent a comprehensive neuropsychological battery. A combined voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis was used to capture gray matter (GM) and white matter changes in OCD patients as compared to pair-matched healthy volunteers. Multiple regression designs explored the relationship between cognition and neuroimaging parameters. Results: OCD patients had increased mean diffusivity (MD) in GM nodes of the orbitofronto-striatal loop (left dorsal anterior cingulate [Z = 3.67, P < 0.001] left insula [Z = 3.35 P < 0.001] left thalamus [Z = 3.59, P < 0.001] left parahippocampal gyrus [Z = 3.77 P < 0.001]) and in lateral frontal and posterior associative cortices (right frontal operculum [Z = 3.42 P < 0.001], right temporal lobe [Z = 3.79 P < 0.001] left parietal lobe [Z = 3.91 P < 0.001]). Decreased fractional anisotropy (FA) was detected in intrahemispheric (left superior longitudinal fasciculus [Z = 4.07 P < 0.001]) and interhemispheric (body of corpus callosum [CC, Z = 4.42 P < 0.001]) bundles. Concurrently, the semantic fluency score, a measure of executive control processes, significantly predicted OCD diagnosis (Odds Ratio = 1.37; 95% Confidence Intervals = 1.09-1.73; P = 0.0058), while variation in performance was correlated with increased MD in left temporal (Z = 4.25 P < 0.001) and bilateral parietal regions (left Z = 3.94, right Z = 4.19 P < 0.001), and decreased FA in the right posterior corona radiata (Z = 4.07 P < 0.001) and the left corticospinal tract (Z = 3.95 P < 0.001). Conclusions: The reported deficit in executive processes and the underlying microstructural alterations may qualify as behavioral and biological markers of OCD.
Hippocampus, 2005
Visuospatial short-term memory relies on a widely distributed neocortical network: some areas sup... more Visuospatial short-term memory relies on a widely distributed neocortical network: some areas support the encoding process of the visually acquired spatial information, whereas other ares are more involved in the active maintenance of the encoded information. Recently, in a pointing to remembered targets task, it has been shown in healthy subjects that, for memory delays of 5 s, spatial errors are affected also by cognitive allocentric information, i.e., covert spatial information derived from a pure mental representation. We tested the effect of a lesion of the hippocampus on the accuracy of pointing movements toward remembered targets, with memory delays falling in the 0.5-30 s range. The spatial distributions of the two target sets we used (line and left-right) allowed the exploitation of cognitive allocentric spatial information: both sets were in the frontal plane, the line one being composed by eleven points distributed uniformly along a virtual line tilted 458 away from the vertical, whereas the left-right set was composed by two workspaces symmetrically distributed at the extremes of a horizontal virtual line. We have found a significant difference between the performance of three hippocampal amnesic subjects and a group of normal controls for delays equal to or longer than 15 s, the difference being along the allocentric axis, i.e., the direction of the virtual line defined by the target set. On this basis we suggest that the hippocampal formation may enhance the spatial information processed within shortterm memory with cognitive allocentric information. The association that may be operated through the neocortical-hippocampal loop of the newly acquired spatial information with well established spatial cognitive items could affect the precision of the short-term memory storage for memory delays exceeding about 15 s and might be the result of a modulation of the span of the spatial memory buffer along context-specific directions. V
Social Cognitive and Affective Neuroscience, 2012
Insight has been mostly studied from a clinical perspective. Recently, attention moved to cogniti... more Insight has been mostly studied from a clinical perspective. Recently, attention moved to cognitive insight or the ability to monitor and correct one's erroneous convictions. Here, we investigated the neuroanatomical correlates of cognitive insight. We administered the Beck cognitive insight scale to 45 outpatients with a schizophrenia diagnosis and 45 age-and gender-matched healthy control subjects who underwent a MRI investigation, including high-resolution volumetric and diffusion tensor imaging sequences. Gray and white matter volume, mean diffusivity and fractional anisotropy were used as dependent variables and were analyzed on a voxel-by-voxel basis with reference to the cognitive insight indexes. Self-reflectiveness was positively related to gray matter volume of the right ventro-lateral prefrontal cortex (VLPFC). No statistically significant results emerged from the DTI analyses, and no significant relationships were found for self-certainty and global cognitive insight. Reduced self-reflectiveness is related to a reduced volume of the VLPFC, an area involved in generating and maintaining in working memory different hypotheses about the self. This line of research focusing on the metacognitive features of insight in schizophrenia can provide relevant information to identify patients who are most vulnerable to lack of insight and develop effective cognitive therapeutic strategies.
Psychiatry Research: Neuroimaging, 2010
Cortical and subcortical gray matter volumes were correlated with a set of linguistic scores in a... more Cortical and subcortical gray matter volumes were correlated with a set of linguistic scores in a group of schizophrenia patients. Lexical informativeness was positively associated with the volume of the left frontal cortical and accumbal areas, while left hippocampal atrophy and right ventricle enlargement predicted increased production of semantic paraphasias. Global coherence impairment was predicted by left accumbal volume reduction and left ventricle enlargement. These data confirm that the brain structure of specific cortical and subcortal areas, as determined by magnetic resonance imaging, is related to the compromised semantic retrieval and language control in schizophrenia.
Neuropsychologia, 2011
The contribution of the thalamus to the functioning of prospective memory (PM) is currently unkno... more The contribution of the thalamus to the functioning of prospective memory (PM) is currently unknown. Here we report an experimental investigation of the performance of two patients with bilateral infarcts in the anterior-mesial regions of the thalami on an event-based PM paradigm. One patient, G.P., had a pervasive declarative memory impairment but no significant executive deficit. The other patient, R.F., had a memory deficit limited to verbal material with associated behavioral abnormalities (inertia and apathy); she performed poorly on tests of executive functions. Although both patients performed poorly on the PM task, a qualitative analysis of performance revealed different mechanisms at the base of their impaired PM. G.P. had reduced declarative memory for target words compared with normal controls; but, unforgotten words were normally able to elicit his recall of the prospective intention. Conversely, R.F.'s declarative memory for target words was as accurate as that of normal controls, but she presented a dramatically reduced ratio between the number of target words she recalled and the number of times she activated the prospective intention on the PM task, suggesting that her deficit consisted of difficulty in activating the intention despite normal declarative memory for the target events. In conclusion, results of the present study demonstrate that thalamic structures have an important role in PM processes. They also document that damage to the anterior-mesial regions of the thalami affects PM abilities by two different mechanisms, respectively based on the relative disruption of declarative memory or executive processes functioning, which, in turn, is related to the specific intrathalamic structures involved by the lesions. Indeed, while G.P.'s pervasive declarative memory deficit was underlain by bilateral involvement of the mammillo-thalamic tract, R.F.'s executive and behavioral abnormalities were likely related to bilateral damage of the midline, intralaminar, and medio-dorsal nuclei.
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Papers by Carlo Caltagirone