Carlo Caltagirone

The Mental Deterioration Battery: Normative Data, Diagnostic Reliability and Qualitative Analyses of Cognitive Impairment

This study aimed at investigating the clinical usefulness of the Mental Deterioration Battery (MDB) in the neuropsychological diagnosis and characterization of the dementia syndrome. In this paper, we report: (a) normative data for various test scores derived from the analysis of performance of 340 normal subjects living in urban areas; (b) an evaluation of the reliability of the single tests and of the battery as a whole in differentiating normal subjects from patients affected by cognitive deterioration derived from the analysis of performance of 130 normal subjects living in rural areas and 134 patients affected by probable Alzheimers dementia; (c) a cluster analysis of performances of the 340 normal subjects in the standardization group to evaluate possible criteria of homogeneity according to which the various MDB scores tend to aggregate; (d) an analysis of performance profiles of 183 patients with right monohemispheric focal lesions, 159 patients with left unilateral lesions with aphasia and 131 left-lesioned nonaphasic patients to evaluate the specificity of the single tests of the battery in documenting a selective impairment of one of the two cerebral hemispheres. Results confirm the reliability of the MBD in discriminating between normal and demented patients and provide indications for use of the battery in differentiating qualitative patterns of cognitive impairment.

Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinsons disease and 22 control subjects underwent 3-T magnetic resonance imaging with T₂*-weighted, whole-brain T₁-weighted and diffusion tensor imaging scans. The mean R₂* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinsons disease and control subjects. Comparisons were also performed using voxel-based analysis of R₂*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinsons disease displayed significantly higher R₂* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinsons disease from controls. The markers comprising discriminating combinations were R₂* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinsons physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R₂*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinsons disease and, possibly, of other subcortical pathologies.

Effect of Collateral Blood Flow and Cerebral Vasomotor Reactivity on the Outcome of Carotid Artery Occlusion

Background and Purpose— Evidence suggests that an alteration in cerebral hemodynamics plays a relevant role in the occurrence of stroke in patients with carotid occlusion. The purpose of the present study was to evaluate the relationships among baseline characteristics, type and number of collateral pathways, cerebral vasomotor reactivity (VMR), and outcome of patients with carotid occlusion. Methods— One hundred four patients with symptomatic or asymptomatic internal carotid artery occlusion were followed up prospectively for a median period of 24 months. Cerebral VMR to apnea was calculated with transcranial Doppler ultrasonography by means of the breath-holding index (BHI) in the middle cerebral arteries. The patency of the 3 major intracranial collateral vessels was also evaluated. Results— During the follow-up period, 18 patients experienced an ischemic stroke ipsilateral to internal carotid artery occlusion. Among factors considered, only older age, number of collateral pathways, and BHI values in the middle cerebral artery ipsilateral to the occluded side were significantly associated with the risk of ipsilateral stroke (P <0.001, P =0.008, and P <0.001, respectively; multiple Cox regression analysis). A normal VMR and favorable prognosis characterized patients with full collateral development; in this group, no patient experienced an ischemic event. On the other hand, an impaired VMR and increased probability of experiencing a stroke were found in patients without collateral pathways; the annual risk of ipsilateral stroke in this group was 32.7%. Patients with 1 or 2 collateral pathways showed a different VMR ranging from normal to strongly reduced BHI values. The ipsilateral stroke event risk was 17.5% in patients with 1 collateral vessel and 2.7% in patients with 2 collateral pathways. In this case, the risk of cerebrovascular events occurring during the follow-up period was significantly related to VMR. Conclusions— These data suggest that cerebral hemodynamic status in patients with carotid occlusive disease is influenced by both individual anatomic and functional characteristics. The planning of strategies to define the risk profile and any attempt to influence patients’ outcome should be based on the evaluation of the intracranial hemodynamic adaptive status, with particular attention to the number of collateral vessels and the related VMR.

Left/right and cortical/subcortical dichotomies in the neuropsychological study of human emotions

Abstract Two main dichotomies have been put forth in the study of the anatomical substrates of emotional behaviour. The first, more classical and more firmly established, claims that the basic brain mechanisms for emotions are located in subcortical rather than in cortical structures. The second, more recent and still more hypothetical dichotomy, maintains that the right and the left hemispheres are not equally involved in emotional behaviour and that the right hemisphere plays a critical role in this regard. It is not clear, however, if these two dichotomies are independent or are somehow interconnected. The aim of this article is to discuss some aspects of the neuropsychology of human emotions, taking into account both the cortical/subcortical and the left/right dichotomy. First, we will review some well-established facts and some more recent models and data concerning the role played by cortical and subcortical structures in various aspects of emotional behaviour. Secondly, we will present a short summ...

Hippocampal Volume Reduction in First-Episode and Chronic Schizophrenia A Review and Meta-Analysis

Several magnetic resonance imaging studies have reported hippocampal volume reduction in patients with schizophrenia, but other studies have reported contrasting results. In this review and meta-analysis, the authors aim to clarify whether a reduction in hippocampal volume characterizes patients with schizophrenia by considering illness phase (chronic and first episode) and hippocampus side separately. They made a detailed literature search for studies reporting physical volumetric hippocampal measures of patients with schizophrenia and healthy control (HC) participants and found 44 studies that were eligible for meta-analysis. Individual meta-analyses were also performed on 13 studies of first-episode patients and on 22 studies of chronic patients. The authors also detected any different findings when only males or both males and females were considered. Finally, additional meta-analyses and analyses of variance investigated the role of the factors “illness phase” and “side” on hippocampal volume reduction. Overall, the patient group showed significant bilateral hippocampal volume reduction compared with HC. Interestingly, first-episode and chronic patients showed same-size hippocampal volume reduction. Moreover, the left hippocampus was smaller than the right hippocampus in patients and HC. This review and meta-analysis raises the question about whether hippocampal volume reduction in schizophrenia is of neurodevelopmental origin. Future studies should specifically investigate this issue.

Regional brain atrophy and functional disconnection across Alzheimer's disease evolution

Objective To assess the contribution of regional grey matter (GM) atrophy and functional disconnection in determining the level of cognitive decline in patients with Alzheimers disease (AD) at different clinical stages. Methods Ten patients with amnesic mild cognitive impairment (a-MCI), 11 patients with probable AD and 10 healthy controls were recruited. T1 volumes were obtained from each subject and postprocessed according to an optimised voxel based morphometry protocol. Resting state functional MRI data were also collected from the same individuals and analysed to produce connectivity maps after identification of the default mode network (DMN) by independent component analysis. Results Compared with healthy controls, both AD and a-MCI patients showed a similar regional pattern of brain disconnection between the posterior cingulate cortex (PCC) and the medial prefrontal cortex and the rest of the brain. Conversely, the distribution of GM atrophy was significantly more restricted in a-MCI than in AD patients. Interestingly, the PCC showed reduced connectivity in a-MCI patients in the absence of GM atrophy, which was, in contrast, detectable at the stage of fully developed AD. Conclusions This study indicates that disconnection precedes GM atrophy in the PCC, which is a critical area of the DMN, and supports the hypothesis that GM atrophy in specific regions of AD brains likely reflects a long term effect of brain disconnection. In this context, our study indicates that GM atrophy in PCC accompanies the conversion from MCI to AD.

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines.

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1β, TNF-α or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1β, TNF-α or even IL-18, in patients with poststroke depression.

Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex

Paired-pulse transcranial magnetic stimulation (TMS) has been applied as a probe to test functional connectivity within distinct cortical areas of the human motor system. Here, we tested the interaction between the posterior parietal cortex (PPC) and ipsilateral motor cortex (M1). A conditioning TMS pulse over the right PPC potentiates motor evoked-potentials evoked by a test TMS pulse over the ipsilateral motor cortex, with a time course characterized by two phases: an early peak at 4 ms interstimulus interval (ISI) and a late peak at 15 ms ISI. Activation of this facilitatory pathway depends on the intensity of stimulation, because the effects are induced with a conditioning stimulus of 90% resting motor threshold but not at lower or higher intensities. Similar results were obtained testing the ipsilateral interaction in the left hemisphere with a slightly different time course. In control experiments, we found that activation of this facilitatory pathway depends on the direction of induced current in the brain and is specific for stimulation of the caudal part of the inferior parietal sulcus (cIPS) site, because it is not observed for stimulation of adjacent scalp sites. Finally, we found that by using poststimulus time histogram analysis of single motor unit firing, the PPC conditioning increases the excitability of ipsilateral M1, enhancing the relative amount of late I wave input recruited by the test stimulus over M1, suggesting that such interaction is mediated by specific interneurons in the motor cortex. The described facilitatory connections between cIPS and M1 may be important in a variety of motor tasks and neuropsychiatric disorders.

Influence of the supplementary motor area on primary motor cortex excitability during movements triggered by neutral or emotionally unpleasant visual cues

The stronger anatomo-functional connections of the supplementary motor area (SMA), as compared with premotor area (PM), with regions of the limbic system, suggest that SMA could play a role in the control of movements triggered by visual stimuli with emotional content. We addressed this issue by analysing the modifications of the excitability of the primary motor area (M1) in a group of seven healthy subjects, studied with transcranial magnetic stimulation (TMS), after conditioning TMS of SMA, during emotional and non-emotional visually cued movements. Conditioning TMS of the PM or of contralateral primary motor cortex (cM1) were tested as control conditions. Single-pulse TMS over the left M1 was randomly intermingled with paired TMS, in which a conditioning stimulation of the left SMA, left PM or right M1 preceded test stimulation over the left M1. The subjects carried out movements in response to computerised visual cues (neutral pictures and pictures with negative emotional content). The amplitudes of motor-evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle after paired TMS were measured and compared with those obtained after single-pulse TMS of the left M1 under the various experimental conditions. Conditioning TMS of the SMA in the paired-pulse paradigm selectively enhanced MEP amplitudes in the visual-emotional triggered movement condition, compared with single-pulse TMS of M1 alone or with paired TMS during presentation of neutral visual cues. On the other hand, conditioning TMS of the PM or cM1 did not differentially influence MEP amplitudes under visual-emotional triggered movement conditions. This pattern of effects was related to the intensity of the conditioning TMS over the SMA, being most evident with intensities ranging from 110% to 80% of motor threshold. These results suggest that the SMA in humans could interface the limbic and the motor systems in the transformation of emotional experiences into motor actions.

Mapping local hippocampal changes in Alzheimer's disease and normal ageing with MRI at 3 Tesla

Histological studies have suggested differing involvement of the hippocampal subfields in ageing and in Alzheimers disease. The aim of this study was to assess in vivo local hippocampal changes in ageing and Alzheimers disease based on high resolution MRI at 3 Tesla. T(1)-weighted images were acquired from 19 Alzheimers disease patients [age 76 +/- 6 years, three males, Mini-Mental State Examination 13 +/- 4] and 19 controls (age 74 +/- 5 years, 11 males, Mini-Mental State Examination 29 +/- 1). The hippocampal formation was isolated by manual tracing. Radial atrophy mapping was used to assess group differences and correlations by averaging hippocampal shapes across subjects using 3D parametric surface mesh models. Percentage difference, Pearsons r, and significance maps were produced. Hippocampal volumes were inversely correlated with age in older healthy controls (r = 0.56 and 0.6 to the right and left, respectively, P < 0.05, corresponding to 14% lower volume for every 10 years of older age from ages 65 to 85 years). Ageing-associated atrophy mapped to medial and lateral areas of the tail and body corresponding to the CA1 subfield and ventral areas of the head corresponding to the presubiculum. Significantly increased volume with older age mapped to a few small spots mainly located to the CA1 sector of the right hippocampus. Volumes were 35% and 30% smaller in Alzheimers disease patients to the right and left (P < 0.0005). Alzheimers disease-associated atrophy mapped not only to CA1 areas of the body and tail corresponding to those also associated with age, but also to dorsal CA1 areas of the head unaffected by age. Regions corresponding to the CA2-3 fields were relatively spared in both ageing and Alzheimers disease. Hippocampal atrophy in Alzheimers disease maps to areas in the body and tail that partly overlap those affected by normal ageing. Specific areas in the anterior and dorsal CA1 subfield involved in Alzheimers disease were not in normal ageing. These patterns might relate to differential neural systems involved in Alzheimers disease and ageing.