The behavioral variant of frontotemporal dementia (bvFTD) is one of the most frequent neurodegene... more The behavioral variant of frontotemporal dementia (bvFTD) is one of the most frequent neurodegenerative disorders with a presenile onset. It is characterized by a long phase of subclinical behavioral changes and social conduct disorders, associated with a progressive modification of personality. Recently, an international consortium of experts developed revised guidelines for its clinical diagnosis, which highlight the supportive role of biomarkers in the diagnostic process. According to new criteria, bvFTD can be classified in "possible" (requiring three of six specific clinical features), "probable" (in the presence of functional disability and typical neuroimaging features), and "with definite frontotemporal lobar degeneration" (requiring the presence of a known causal mutation or a histopathological confirmation). Familial aggregation is frequently reported in bvFTD and frontotemporal lobar degeneration in general, with an autosomal dominant transmission in about 10 % cases. The aim of this paper is to review and discuss recent advances in the knowledge of clinical, neuropsychological, and imaging features of bvFTD. We also briefly summarize the available genetic information about the frontotemporal lobar degeneration spectrum.
Expression of 10 GABA, receptor subunit genes was examined in monkey thalamus by in situ hybridiz... more Expression of 10 GABA, receptor subunit genes was examined in monkey thalamus by in situ hybridization using cRNA probes specific for (Y,, (Ye, (Ye, (Ye, Q~, P,, P2, P3, yl, and y2 subunit mRNAs. These displayed unique hybridization patterns with significant differences from rodents. Q,, p2, and-y2 transcripts were expressed at high levels in all dorsal thalamic nuclei, but expression was significantly higher in sensory relay nucleiespecially the dorsal lateral geniculate nucleus. Other transcripts showed nucleus-specific differences in levels of expression and in the range expressed. (Ye and (Ye subunit transcripts were expressed in all nuclei except the intralaminar nuclei. Levels of (Ye, c+, p,, p3, and y, expression were very low, except in intralaminar nuclei. In the reticular nucleus, most subunit transcripts were not expressed, and only y2 transcripts were consistently detected at modest levels. Thalamic GABA, receptors may be assembled from nucleus-specific groupings of subunit polypeptides.
Spatial knowledge of an environment involves two distinct competencies: declarative spatial knowl... more Spatial knowledge of an environment involves two distinct competencies: declarative spatial knowledge, linked to where environmental cues are and where the subject is with respect to the cues, and, at the same time, procedural spatial knowledge, linked to how to move into the environment. It has been previously demonstrated that hemicerebellectomized (HCbed) rats are impaired in developing efficient exploration strategies, but not in building spatial maps or in utilizing localizing cues. The aim of the present study was to analyse the relationships between spatial procedural and declarative knowledge by using the open field test. HCbed rats have been tested in two different protocols of the open field task. The results indicate that HCbed animals succeeded in moving inside the arena, in contacting the objects and in habituating to the new environment. However, HCbed animals did not react to environmental changes, when their impaired explorative pattern was inappropriate to the environment, suggesting that they were not able to represent a new environment because they were not able to explore it appropriately. Nevertheless, when their altered procedures were favoured by object arrangement, they detected environmental changes as efficiently as did normal rats. This finding suggests that no declarative spatial learning is possible without appropriate procedural spatial learning.
Publisher Summary This chapter focuses on recent data on the laminar organization of intralaminar... more Publisher Summary This chapter focuses on recent data on the laminar organization of intralaminar nuclei (IL)-cortical fibers and provides evidence of anatomical compartmentation within IL. The functional significance of the structural IL organization is discussed in relation to a hypothesis of IL relay activity. The IL presents a precise structural organization capable of highly specific integration of the different inputs. On physiological grounds, the main difference between IL and relay nuclei is their different roles in affecting cortical functions. IL is classically considered as the thalamic system capable of affecting cortical behavioral states while the relay nuclei are considered as the site for conveying specific information to the cortex. At least in terms of thalamocortical relationships, recent data are against the existence of the differences between IL and relay nuclei. Lesion and recording studies have shown that the rhythmic oscillatory activity during cortical synchronization is present throughout the thalamus under the conditional activity of the nucleus reticularis thalami. Although some recent evidence suggests possible differences among thalamic nuclei in affecting cortical synchronization, no indication exists supporting a functional segregation between IL and relay nuclei.
Verbal fluency indicates the rate at which one produces words. It is measured by tasks that asses... more Verbal fluency indicates the rate at which one produces words. It is measured by tasks that assess phonological or semantic associative processes and strategic abilities in retrieving words from a lexicon under forced conditions. Impairments in verbal fluency tasks are common in adult patients who are affected by cerebellar pathology. Despite conflicting results with regard to the laterality and specificity of cerebellar involvement in verbal fluency, the ability to generate lists of words per the phonemic rule has been reported to be more affected than under the semantic rule, with specific damage to phonemic clustering and switching. Phonemic verbal fluency requires the use of an unusual and novel search strategy to process sequenced information correctly. Thus, we propose that the prevalent impairment in phonological verbal fluency tasks is consistent with the sequence detection model, which has been advanced as the basic operational mode of the cerebellum.
In the past 20 years, much has changed of our understanding of cerebellar functioning; neverthele... more In the past 20 years, much has changed of our understanding of cerebellar functioning; nevertheless, the clinical approach to cerebellar symptoms is remarkably similar to that in use at the beginning of 1900. In this article, a classical approach to signs and symptoms related to cerebellar damage is presented together with a modern interpretation of the pathophysiological mechanisms. The importance of the cerebellum in cognition is the focus, with emphasis on the clinical relevance of the understanding of cerebro–cerebellar interactions.
Essentials of Cerebellum and Cerebellar Disorders, 2016
In the last 15 years increasing evidence has been added on non-motor cerebellar functions. In 199... more In the last 15 years increasing evidence has been added on non-motor cerebellar functions. In 1998 Schmahmann and Sherman defined a new clinical entity, the “cerebellar cognitive affective syndrome” (also called Schmahmann’s syndrome). In 2011 Tedesco et al. characterized the cognitive profile of subjects affected by focal cerebellar damage. The most adversely affected functions in focal cerebellar damage are sequencing, language, executive function, and visuospatial abilities.
for a scientific commentary on this article. Detailed mapping of clinical dysfunctions to the cer... more for a scientific commentary on this article. Detailed mapping of clinical dysfunctions to the cerebellar lobules in disease populations is necessary to establish the functional significance of lobules implicated in cognitive and motor functions in normal subjects. This study constitutes the first quantitative examination of the lobular correlates of a broad range of cognitive and motor phenomena in cerebellar disease. We analysed crosssectional data from 72 cases with cerebellar disease and 36 controls without cerebellar disease. Cerebellar lobule volumes were derived from a graph-cut based segmentation algorithm. Sparse partial least squares, a variable selection approach, was used to identify lobules associated with motor function, language, executive function, memory, verbal learning, perceptual organization and visuomotor coordination. Motor dysfunctions were chiefly associated with the anterior lobe and posterior lobule HVI. Confrontation naming, noun fluency, recognition, and perceptual organization did not have cerebellar associations. Verb and phonemic fluency, working memory, cognitive flexibility, immediate and delayed recall, verbal learning, and visuomotor coordination were variably associated with HVI, Crus I, Crus II, HVII B and/or HIX. Immediate and delayed recall also showed associations with the anterior lobe. These findings provide preliminary anatomical evidence for a functional topography of the cerebellum first defined in task-based functional magnetic resonance imaging studies of normal subjects and support the hypotheses that (i) cerebellar efferents target frontal lobe neurons involved in forming action representations and new search strategies; (ii) there is greater involvement of the cerebellum when immediate recall tasks involve more complex verbal stimuli (e.g. longer words versus digits); and (iii) it is involved in spontaneous retrieval of long-term memory. More generally, they provide an anatomical background for studies that seek the mechanisms by which cognitive and motor dysfunctions arise from cerebellar degeneration. Beyond replicating these findings, future research should employ experimental tasks to probe the integrity of specific functions in cerebellar disease, and new imaging methods to quantitatively map atrophy across the cerebellum.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving... more Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, Diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher-order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar white matter microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that white matter (WM) diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients.
In the last few decades, an increasing number of studies have focused on better characterizing th... more In the last few decades, an increasing number of studies have focused on better characterizing the cerebellar functions beyond motor control, including emotional and social domains. Anatomic and functional evidence strongly contributes to delineating the cerebellar functional subdivisions and their integration with cerebral functional networks strictly related to emotional regulation and social functioning, thus suggesting a model of cerebellar organization that resembles that of the cerebral cortex. Overcoming the traditional segregation of cerebrocerebellar networks in sensorimotor/cognitive functional modules, during emotional/social processes, the cerebellar activity reflects a domain-specific mentalizing functionality that is strongly connected with corresponding mentalizing networks in the cerebrum. Additionally, the cerebrocerebellar organization has been shown to have a specific functional and maturational trajectory that is only in part dependent on a structural maturational process and that is protracted from an early stage of life through adolescence and adulthood, when the mature control networks involve both segregation and integration of the brain regions that comprise them. Altogether, these findings underscore the importance of regional functional differences within the cerebellum in relation to emotional and social processing and raise questions about the clinical implication of cerebellar injury on emotional/social behaviors, both in the developing and the adult brain.
The behavioral variant of frontotemporal dementia (bvFTD) is one of the most frequent neurodegene... more The behavioral variant of frontotemporal dementia (bvFTD) is one of the most frequent neurodegenerative disorders with a presenile onset. It is characterized by a long phase of subclinical behavioral changes and social conduct disorders, associated with a progressive modification of personality. Recently, an international consortium of experts developed revised guidelines for its clinical diagnosis, which highlight the supportive role of biomarkers in the diagnostic process. According to new criteria, bvFTD can be classified in "possible" (requiring three of six specific clinical features), "probable" (in the presence of functional disability and typical neuroimaging features), and "with definite frontotemporal lobar degeneration" (requiring the presence of a known causal mutation or a histopathological confirmation). Familial aggregation is frequently reported in bvFTD and frontotemporal lobar degeneration in general, with an autosomal dominant transmission in about 10 % cases. The aim of this paper is to review and discuss recent advances in the knowledge of clinical, neuropsychological, and imaging features of bvFTD. We also briefly summarize the available genetic information about the frontotemporal lobar degeneration spectrum.
Expression of 10 GABA, receptor subunit genes was examined in monkey thalamus by in situ hybridiz... more Expression of 10 GABA, receptor subunit genes was examined in monkey thalamus by in situ hybridization using cRNA probes specific for (Y,, (Ye, (Ye, (Ye, Q~, P,, P2, P3, yl, and y2 subunit mRNAs. These displayed unique hybridization patterns with significant differences from rodents. Q,, p2, and-y2 transcripts were expressed at high levels in all dorsal thalamic nuclei, but expression was significantly higher in sensory relay nucleiespecially the dorsal lateral geniculate nucleus. Other transcripts showed nucleus-specific differences in levels of expression and in the range expressed. (Ye and (Ye subunit transcripts were expressed in all nuclei except the intralaminar nuclei. Levels of (Ye, c+, p,, p3, and y, expression were very low, except in intralaminar nuclei. In the reticular nucleus, most subunit transcripts were not expressed, and only y2 transcripts were consistently detected at modest levels. Thalamic GABA, receptors may be assembled from nucleus-specific groupings of subunit polypeptides.
Spatial knowledge of an environment involves two distinct competencies: declarative spatial knowl... more Spatial knowledge of an environment involves two distinct competencies: declarative spatial knowledge, linked to where environmental cues are and where the subject is with respect to the cues, and, at the same time, procedural spatial knowledge, linked to how to move into the environment. It has been previously demonstrated that hemicerebellectomized (HCbed) rats are impaired in developing efficient exploration strategies, but not in building spatial maps or in utilizing localizing cues. The aim of the present study was to analyse the relationships between spatial procedural and declarative knowledge by using the open field test. HCbed rats have been tested in two different protocols of the open field task. The results indicate that HCbed animals succeeded in moving inside the arena, in contacting the objects and in habituating to the new environment. However, HCbed animals did not react to environmental changes, when their impaired explorative pattern was inappropriate to the environment, suggesting that they were not able to represent a new environment because they were not able to explore it appropriately. Nevertheless, when their altered procedures were favoured by object arrangement, they detected environmental changes as efficiently as did normal rats. This finding suggests that no declarative spatial learning is possible without appropriate procedural spatial learning.
Publisher Summary This chapter focuses on recent data on the laminar organization of intralaminar... more Publisher Summary This chapter focuses on recent data on the laminar organization of intralaminar nuclei (IL)-cortical fibers and provides evidence of anatomical compartmentation within IL. The functional significance of the structural IL organization is discussed in relation to a hypothesis of IL relay activity. The IL presents a precise structural organization capable of highly specific integration of the different inputs. On physiological grounds, the main difference between IL and relay nuclei is their different roles in affecting cortical functions. IL is classically considered as the thalamic system capable of affecting cortical behavioral states while the relay nuclei are considered as the site for conveying specific information to the cortex. At least in terms of thalamocortical relationships, recent data are against the existence of the differences between IL and relay nuclei. Lesion and recording studies have shown that the rhythmic oscillatory activity during cortical synchronization is present throughout the thalamus under the conditional activity of the nucleus reticularis thalami. Although some recent evidence suggests possible differences among thalamic nuclei in affecting cortical synchronization, no indication exists supporting a functional segregation between IL and relay nuclei.
Verbal fluency indicates the rate at which one produces words. It is measured by tasks that asses... more Verbal fluency indicates the rate at which one produces words. It is measured by tasks that assess phonological or semantic associative processes and strategic abilities in retrieving words from a lexicon under forced conditions. Impairments in verbal fluency tasks are common in adult patients who are affected by cerebellar pathology. Despite conflicting results with regard to the laterality and specificity of cerebellar involvement in verbal fluency, the ability to generate lists of words per the phonemic rule has been reported to be more affected than under the semantic rule, with specific damage to phonemic clustering and switching. Phonemic verbal fluency requires the use of an unusual and novel search strategy to process sequenced information correctly. Thus, we propose that the prevalent impairment in phonological verbal fluency tasks is consistent with the sequence detection model, which has been advanced as the basic operational mode of the cerebellum.
In the past 20 years, much has changed of our understanding of cerebellar functioning; neverthele... more In the past 20 years, much has changed of our understanding of cerebellar functioning; nevertheless, the clinical approach to cerebellar symptoms is remarkably similar to that in use at the beginning of 1900. In this article, a classical approach to signs and symptoms related to cerebellar damage is presented together with a modern interpretation of the pathophysiological mechanisms. The importance of the cerebellum in cognition is the focus, with emphasis on the clinical relevance of the understanding of cerebro–cerebellar interactions.
Essentials of Cerebellum and Cerebellar Disorders, 2016
In the last 15 years increasing evidence has been added on non-motor cerebellar functions. In 199... more In the last 15 years increasing evidence has been added on non-motor cerebellar functions. In 1998 Schmahmann and Sherman defined a new clinical entity, the “cerebellar cognitive affective syndrome” (also called Schmahmann’s syndrome). In 2011 Tedesco et al. characterized the cognitive profile of subjects affected by focal cerebellar damage. The most adversely affected functions in focal cerebellar damage are sequencing, language, executive function, and visuospatial abilities.
for a scientific commentary on this article. Detailed mapping of clinical dysfunctions to the cer... more for a scientific commentary on this article. Detailed mapping of clinical dysfunctions to the cerebellar lobules in disease populations is necessary to establish the functional significance of lobules implicated in cognitive and motor functions in normal subjects. This study constitutes the first quantitative examination of the lobular correlates of a broad range of cognitive and motor phenomena in cerebellar disease. We analysed crosssectional data from 72 cases with cerebellar disease and 36 controls without cerebellar disease. Cerebellar lobule volumes were derived from a graph-cut based segmentation algorithm. Sparse partial least squares, a variable selection approach, was used to identify lobules associated with motor function, language, executive function, memory, verbal learning, perceptual organization and visuomotor coordination. Motor dysfunctions were chiefly associated with the anterior lobe and posterior lobule HVI. Confrontation naming, noun fluency, recognition, and perceptual organization did not have cerebellar associations. Verb and phonemic fluency, working memory, cognitive flexibility, immediate and delayed recall, verbal learning, and visuomotor coordination were variably associated with HVI, Crus I, Crus II, HVII B and/or HIX. Immediate and delayed recall also showed associations with the anterior lobe. These findings provide preliminary anatomical evidence for a functional topography of the cerebellum first defined in task-based functional magnetic resonance imaging studies of normal subjects and support the hypotheses that (i) cerebellar efferents target frontal lobe neurons involved in forming action representations and new search strategies; (ii) there is greater involvement of the cerebellum when immediate recall tasks involve more complex verbal stimuli (e.g. longer words versus digits); and (iii) it is involved in spontaneous retrieval of long-term memory. More generally, they provide an anatomical background for studies that seek the mechanisms by which cognitive and motor dysfunctions arise from cerebellar degeneration. Beyond replicating these findings, future research should employ experimental tasks to probe the integrity of specific functions in cerebellar disease, and new imaging methods to quantitatively map atrophy across the cerebellum.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving... more Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, Diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher-order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar white matter microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that white matter (WM) diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients.
In the last few decades, an increasing number of studies have focused on better characterizing th... more In the last few decades, an increasing number of studies have focused on better characterizing the cerebellar functions beyond motor control, including emotional and social domains. Anatomic and functional evidence strongly contributes to delineating the cerebellar functional subdivisions and their integration with cerebral functional networks strictly related to emotional regulation and social functioning, thus suggesting a model of cerebellar organization that resembles that of the cerebral cortex. Overcoming the traditional segregation of cerebrocerebellar networks in sensorimotor/cognitive functional modules, during emotional/social processes, the cerebellar activity reflects a domain-specific mentalizing functionality that is strongly connected with corresponding mentalizing networks in the cerebrum. Additionally, the cerebrocerebellar organization has been shown to have a specific functional and maturational trajectory that is only in part dependent on a structural maturational process and that is protracted from an early stage of life through adolescence and adulthood, when the mature control networks involve both segregation and integration of the brain regions that comprise them. Altogether, these findings underscore the importance of regional functional differences within the cerebellum in relation to emotional and social processing and raise questions about the clinical implication of cerebellar injury on emotional/social behaviors, both in the developing and the adult brain.
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Papers by Maria Leggio