Different types of abstract concepts: evidence from two neurodegenerative patients.

The observation of neurological patients showing selective impairments for specific conceptual categories contributed in the development of semantic memory theories. Here, we studied two patients (P01, P02), affected, respectively, by the semantic variant of Primary Progressive Aphasia (sv-PPA) and Cortico-Basal Syndrome (CBS). An implicit lexical decision task, including concrete (animals, tools) and abstract (emotions, social, quantity) concepts, was administered to patients and healthy controls.P01 and P02 showed an abolished priming effect for social and quantity-related concepts, respectively. This double dissociation suggests a role of different brain areas in representing specific abstract categories, giving insights for current semantic memory theories.

Correction to: The Italian Dystonia Registry: rationale, design and preliminary findings.

In the original article, Gina Ferrazzano was affiliated to Department of Neurology and Psychiatry, Neuromed Institute IRCCS, Sapienza University of Rome, Pozzilli, Italy.The corrected affiliation should be: Neuromed Institute IRCCS, Pozzilli, IS, Italy.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation.

BACKGROUND AND PURPOSE: Performance on gambling tasks in Parkinson's disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD. METHODS: We assessed the effects of cathodal tDCS over the right DLPFC during the Iowa Gambling Task in 20 patients with PD, compared with sham stimulation. We then conducted a second experimental design, assessing the effects of anodal tDCS over the right DLPFC. RESULTS: We observed that cathodal tDCS over the right DLPFC increased Iowa Gambling Task scores compared with sham stimulation. In the second experimental design, we did not find significant differences between anodal and sham tDCS. CONCLUSIONS: Cathodal tDCS over the right DLPFC possibly reduces the pathological overdrive in frontostriatal networks in patients with PD on dopaminergic medication, thus modulating impulsive and risky decision-making.

The Italian Dystonia Registry: rationale, design and preliminary findings.

The Italian Dystonia Registry is a multicenter data collection system that will prospectively assess the phenomenology and natural history of adult-onset dystonia and will serve as a basis for future etiological, pathophysiological and therapeutic studies. In the first 6 months of activity, 20 movement disorders Italian centres have adhered to the registry and 664 patients have been recruited. Baseline historical information from this cohort provides the first general overview of adult-onset dystonia in Italy. The cohort was characterized by a lower education level than the Italian population, and most patients were employed as artisans, builders, farmers, or unskilled workers. The clinical features of our sample confirmed the peculiar characteristics of adult-onset dystonia, i.e. gender preference, peak age at onset in the sixth decade, predominance of cervical dystonia and blepharospasm over the other focal dystonias, and a tendency to spread to adjacent body parts, The sample also confirmed the association between eye symptoms and blepharospasm, whereas no clear association emerged between extracranial injury and dystonia in a body site. Adult-onset dystonia patients and the Italian population shared similar burden of arterial hypertension, type 2 diabetes, coronary heart disease, dyslipidemia, and hypothyroidism, while hyperthyroidism was more frequent in the dystonia population. Geographic stratification of the study population yielded no major difference in the most clinical and phenomenological features of dystonia. Analysis of baseline information from recruited patients indicates that the Italian Dystonia Registry may be a useful tool to capture the real world clinical practice of physicians that visit dystonia patients.

Subcortical matter in the α-synucleinopathies spectrum: an MRI pilot study.

α-Synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation from brainstem structures to the neocortex. PD and DLB are clinically distinguishable, while discrimination between Parkinson Disease Dementia (PDD) and DLB can be subtle and based on the temporal relationship between motor and cognitive symptoms. To explore patterns of subcortical atrophy in PD, PDD and DLB, and assess specific differences between PD and PDD, and between DLB and PDD. 16 PD, 11 PDD and 16 DLB patients were recruited and underwent 1.5 Tesla structural MRI scanning. Segmentation of subcortical structures was performed with a well-validated, fully-automated tool, and volume and shape for each structure were compared between groups. PDD and DLB patients showed global subcortical atrophy compared to PD patients. Greater hippocampal atrophy was the specific trait that distinguished PDD from PD, while greater atrophy of the pallidi discriminated DLB from PDD. Vertex analysis revealed specific shape differences in both structures. Our results suggest that automated, time-sparing, subcortical volumetry may provide diagnostically useful information in α-synucleinopathies. Future studies on larger samples and with iron-sensitive MRI contrasts are needed.

Left parietal cortex transcranial direct current stimulation enhances gesture processing in corticobasal syndrome.

BACKGROUND AND PURPOSE: Corticobasal syndrome (CBS) is a clinical entity characterized by higher cortical dysfunctions associated with asymmetric onset of levodopa-resistant parkinsonism, dystonia and myoclonus. One of the most typical and distressful features of CBS is limb apraxia, which affects patients in their everyday life. Transcranial direct current stimulation (tDCS) is a non-invasive procedure of cortical stimulation, which represents a promising tool for cognitive enhancement and neurorehabilitation. The present study investigated whether anodal tDCS over the parietal cortex (PARC), would improve ideomotor upper limb apraxia in CBS patients. METHODS: Fourteen patients with possible CBS and upper limb apraxia were enrolled. Each patient underwent two sessions of anodal tDCS (left and right PARC) and one session of placebo tDCS. Ideomotor upper limb apraxia was assessed using the De Renzi ideomotor apraxia test that is performed only on imitation. RESULTS: A significant improvement of the De Renzi ideomotor apraxia test scores (post-stimulation versus pre-stimulation) after active anodal stimulation over the left PARC was observed (χ(2) = 17.6, P = 0.0005), whilst no significant effect was noticed after active anodal stimulation over the right PARC (χ(2) = 7.2, P = 0.07). A post hoc analysis revealed a selective improvement in the De Renzi ideomotor apraxia score after active anodal stimulation over the left PARC compared with placebo stimulation considering both right (P = 0.03) and left upper limbs (P = 0.01). CONCLUSIONS: These findings indicate that tDCS to the PARC improves the performance of an ideomotor apraxia test in CBS patients and might represent a promising tool for future rehabilitation approaches.

Abnormalities in cortical gray matter density in borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a chronic condition with a strong impact on patients' affective, cognitive and social functioning. Neuroimaging techniques offer invaluable tools to understand the biological substrate of the disease. We aimed to investigate gray matter alterations over the whole cortex in a group of Borderline Personality Disorder (BPD) patients compared to healthy controls (HC). METHODS: Magnetic resonance-based cortical pattern matching was used to assess cortical gray matter density (GMD) in 26 BPD patients and in their age- and sex-matched HC (age: 38 ± 11; females: 16, 61%). RESULTS: BPD patients showed widespread lower cortical GMD compared to HC (4% difference) with peaks of lower density located in the dorsal frontal cortex, in the orbitofrontal cortex, the anterior and posterior cingulate, the right parietal lobe, the temporal lobe (medial temporal cortex and fusiform gyrus) and in the visual cortex (P<0.005). Our BPD subjects displayed a symmetric distribution of anomalies in the dorsal aspect of the cortical mantle, but a wider involvement of the left hemisphere in the mesial aspect in terms of lower density. A few restricted regions of higher density were detected in the right hemisphere. All regions remained significant after correction for multiple comparisons via permutation testing. CONCLUSIONS: BPD patients feature specific morphology of the cerebral structures involved in cognitive and emotional processing and social cognition/mentalization, consistent with clinical and functional data.

Late-Onset Glycogen Storage Disease Type 2.

Glycogenosis II (GSDII) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase (GAA) deficiency, subsequent lysosomal accumulation of glycogen in muscles, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The infantile form usually appears in the first month of life, progresses rapidly and presents with severe cardiac involvement and complete deficiency of alpha-glucosidase activity (< 1% of normal controls). The late-onset form is characterized by great variability of the phenotypical spectrum. Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. Residual GAA enzyme activity may correlate with severity of phenotype but many adult patients sharing the same mutations present with a wide variability in residual enzyme activity, age of onset and rate of disease progression, thus supporting a role for other factors, i.e., post-translational modifications and modifier genes, in modulating disease presentation. Enzyme replacement therapy (ERT) with alglucosidase alfa stabilizes the disease or improves muscle and/or respiratory function. However, efficacy of ERT may be influenced by several factors including age when ERT begins, extent of muscle damage, degree of defective autophagy, diversity in muscle fiber composition, difficulties in delivery of the therapeutic agent and antibody production. Further studies should be warranted to investigate factors determining the differences in clinical expression and therapeutic response in order to achieve better clinical and therapeutic management of these patients.

The brain in late-onset glycogenosis II: a structural and functional MRI study.

BACKGROUND: Late-onset glycogenosis type II (GSD II) is a rare, multisystem disorder mainly affecting limb and respiratory muscles due to acid alpha glucosidase deficiency. Despite evidence at autopsy of glycogen accumulation in the brain, no study exploring brain functions is yet available. OBJECTIVE: Our objective in this study was to assess brain changes in late-onset GSD II. METHODS: Each patient underwent a standardized neuropsychological assessment, regional grey-matter (GM) atrophy, and resting-state functional magnetic resonance imaging (RS-fMRI). Functional connectivity maps of the salience (SN) and default-mode (DMN) networks were considered. A group of age- and gender-matched healthy controls was enrolled for MRI comparisons. P values family-wise error (FWE) cluster level corrected inferior to 0.05 were considered. RESULTS: Nine GSD II patients (age 46.6 ± 8.0; 55% male) were recruited. No significant GM atrophy was found in patients compared with controls (n = 18; age 48.0 ± 9.8,;40% male). Functional connectivity within the SN was selectively reduced in patients, and cingulate gyrus and medial frontal cortex were mainly involved. Accordingly, patients had significant impairment of executive functions (as measured by Wisconsin Card Sorting test), whereas other cognitive domains were within mean normal ranges. CONCLUSIONS: Our findings extend the clinical spectrum of GSD II by indicating that brain changes occur in this muscular disorder. Above all, these results should lead to better examinations of therapeutic approaches and perspectives for the affected patients. Further studies evaluating in depth these issues are warranted.

Prefrontal cortex rTMS enhances action naming in progressive non-fluent aphasia.

BACKGROUND AND PURPOSE: Progressive non-fluent aphasia (PNFA) is a neurodegenerative disorder that is characterized by non-fluent speech with naming impairment and grammatical errors. It has been recently demonstrated that repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) improves action naming in healthy subjects and in subjects with Alzheimer's disease. PURPOSE: To investigate whether the modulation of DLPFC circuits by rTMS modifies naming performance in patients with PNFA. METHODS: Ten patients with a diagnosis of PNFA were enrolled. High-frequency rTMS was applied to the left and right DLPFC and the sham (i.e. placebo) condition during object and action naming. A subgroup of patients with semantic dementia was enrolled as a comparison group. RESULTS: A repeated-measure anova with stimulus site (sham, left and right rTMS) showed significant effects. Action-naming performances during stimulation of both the left and right DLPFC were better than during placebo stimulation. No facilitating effect of rTMS to the DLPFC on object naming was observed. In patients with a diagnosis of semantic dementia, no effect of stimulation was reported. CONCLUSIONS: Our study demonstrated that rTMS improved action naming in subjects with PNFA, possibly due to the modulation of DLPFC pathways and a facilitation effect on lexical retrieval processes. Future studies on the potential of a rehabilitative protocol using rTMS applied to the DLPFC in this orphan disorder are required.

The new Alzheimer's criteria in a naturalistic series of patients with mild cognitive impairment.

To test the validity of the new diagnostic criteria for Alzheimer's disease (AD) in a naturalistic series of patients with mild cognitive impairment (MCI). Ninety consecutive MCI patients were enrolled in a longitudinal study on the natural history of cognitive impairment. Medial temporal (MT) atrophy on MRI was defined as hippocampal volume below the fifth percentile of the distribution in healthy elders, abnormal CSF was based on Sjogren's cutoffs for Abeta42 and tau, and temporoparietal hypometabolism on 18F-FDG PET based on Herholz's t sum score. Patients were followed clinically to detect conversion to AD (MCI-AD), non-AD dementia (MCI-nAD), or no conversion (MCI-NC). The 24 MCI-AD and 15 MCI-nAD patients had sociodemographic, clinical, and neuropsychological baseline features similar to the 51 MCI-NC patients. All MCI patients with MT atrophy converted to AD, as did all those with abnormal CSF, but only 48 and 35% of those without MT atrophy or abnormal CSF converted (p on logrank test = 0.0007 and 0.001). Prediction of AD conversion was enhanced when positivity to either MT atrophy or abnormal CSF was considered, with only 15% of those MCI patients negative on both converting to AD (p < 0.0005). Markers were not predictive of non-AD dementia conversion. The accuracy of either MT atrophy or abnormal CSF in discriminating MCI-AD from MCI-NC was good (AUC 0.82, 95% CI 0.70-0.95). MT atrophy and abnormal CSF are the single most robust predictors of conversion to AD in MCI patients, and their combination enhances prediction. AD markers are not predictive of conversion to non-AD dementia.

Metabolic compensation and depression in Alzheimer's disease.

BACKGROUND/AIMS: The aim of this study was to map metabolic compensation and depression in Alzheimer's disease (AD) on a voxel-by-voxel basis. METHODS: Twenty-one healthy elderly subjects and 25 AD patients underwent cerebral MR and FDG-PET imaging. All images were processed with SPM2, and whole-brain gray matter (GM) atrophy and hypometabolism maps were computed. Metabolic compensation and depression were assessed using Biological Parametric Mapping software. RESULTS: GM atrophy and hypometabolism mapped to similar regions, with varying degrees of severity. Significant metabolic compensation was found in the amygdala, while exceeding hypometabolism was mainly located in the posterior cingulate cortex. CONCLUSION: Metabolic depression can be due to both distant effects of atrophy and to additional hypometabolism-inducing factors, such as amyloid deposition. Conversely, metabolic compensation could reflect spared synaptic plasticity of the surviving neurons. The investigation of the metabolic compensation mechanism could help in the comprehension of the AD underlying pathology.

The neural bases of word encoding and retrieval: A fMRI-guided transcranial magnetic stimulation study.

There is evidence that the human prefrontal cortex is asymmetrically involved in long-term episodic memory processing. Moreover, abstract and concrete words processing has been reported to differentially involve prefrontal and parietal areas. We implemented a two-stages functional magnetic resonance imaging (fMRI)-repetitive transcranial magnetic stimulation (rTMS) paradigm to investigate the role of the dorsolateral prefrontal cortices (DLPFCs) and parietal cortices (PARCs) in encoding and retrieval of abstract and concrete words. Using this paradigm we could select areas to be stimulated on the basis of single-subject (SS) anatomical and functional data, investigating the usefulness of this integration approach. With respect to fMRI, abstract and concrete words differed only for a greater left fusiform gyrus activation for concrete words. In turn, significant rTMS effects were found, but only for the retrieval of abstract words. Consistent with previous findings, repetitive stimulation of the right DLPFC had a specific impact on episodic retrieval. Memory retrieval performance was also disrupted when rTMS was applied to the left PARC. Finally, we found a significant positive correlation between the effect sizes of SS right PARC activations for abstract word retrieval and the consequent rTMS interference effects. Taken together these data provide for the first time evidence that also the PARC has a necessary role in episodic retrieval of abstract words. Importantly, from a methodological perspective, our data demonstrate that fMRI-guided rTMS with a SS approach provides a powerful tool to investigate the neural underpinnings of cognitive functions.

The role of the dorsolateral prefrontal cortex in retrieval from long-term memory depends on strategies: a repetitive transcranial magnetic stimulation study.

The ability to associate a name to a face is a crucially relevant task in daily life. In this study, we investigated the neuronal basis of face-name retrieval in young subjects using repetitive transcranial magnetic stimulation (rTMS) over the left or right dorsolateral prefrontal cortex (DLPFC). The experimental task was composed of two study phases: an encoding phase and a retrieval phase. During the encoding phase, subjects saw a face (familiar or unfamiliar) followed by a name. During the retrieval phase, they saw the face together with two names and had to choose the name that was correctly associated with the face. rTMS was delivered only during retrieval. In addition, we evaluated the use of memory strategies during the task. Accordingly, subjects were subdivided into two groups: strategy users (SU) and no-strategy users (NSU). No rTMS effects were present for familiar face-name pairs, probably due to a ceiling effect. However, for unfamiliar face-name pairs, the different use of memory strategies resulted in different rTMS effects. The SU group showed a selective interference effect after right DLPFC stimulation, whereas the NSU group showed an effect after left DLPFC stimulation. Importantly, the overall performance of the two groups was comparable. We suggest that during memory retrieval the left DLPFC might be recruited when the subject does not apply deliberately a retrieval strategy whereas there is a shift to the right DLPFC if cognitive control processes that are engaged by strategies are needed to guide episodic retrieval.

Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline.

OBJECTIVE: Word-finding difficulty (anomia) is commonly observed in Alzheimer's dementia (AD). The aim of this study was to assess the effect of repetitive transcranial magnetic stimulation (rTMS) applied to the dorso-lateral prefrontal cortex (dlPFC) on picture naming in 24 probable AD patients with different degrees of cognitive decline. METHODS: High-frequency rTMS was applied to the left and right dlPFC during object and action naming in AD patients. A sham stimulation was used as a control condition. RESULTS: Whilst, as previously reported, stimulation to both the left and the right dlPFC improved action, but not object naming in the mild AD group; an improved naming accuracy for both classes of stimuli was found in the moderate to severe group. CONCLUSIONS: Repetitive transcranial magnetic stimulation applied to the dlPFC improves naming performance also in the advanced stages of AD. Moreover, in the severe group the effect is not specific for action naming, as in the case of the mild AD group. These findings suggest that rTMS can affect the intrinsic ability of the brain to restore or compensate for damaged function and may represent an useful new tool for cognitive rehabilitation.

Dementia, delusions and seizures: storage disease or genetic AD?

We describe a case of a young patient suffering from a rapidly progressive cognitive decline, associated with delusions, myoclonus and seizures and with no family history for dementia. Clinical features, along with skin biopsy findings were overlapping storage disease; the genetic analysis, however, demonstrated a de novo presenilin 1 mutation. The present report suggests the usefulness of genetic determinations in early-onset cases of dementia, even without an autosomal dominant trait of inheritance; for these cases and their relatives an extensive genetic counselling should be recommended.

Action and object naming in Parkinson's disease without dementia.

The present study aimed to assess the ability in objects and actions naming in Parkinson's disease (PD) patients. Further, we wished to assess the effect of a particular conceptual dimension, i.e. manipulability, on the naming of object and actions. Patients were recruited from the Department of Neurology, University of Brescia. Thirty-two were diagnosed as PD, according to published criteria, and 15 healthy volunteers matched in age and education to patients' sample. All patients underwent a detailed clinical and neurological evaluation. The stimuli used in the action-object picture naming task were taken from the Center for Research in Language-International Picture Naming Project corpus. To assess the effect of manipulability (or the involvement of fine hand movements) the noun-verb stimuli were re-categorized into manipulable and non-manipulable items (i.e. objects which can or cannot be manipulated and actions which do or do not involve fine hand movements). Patients showed a deficit both in action and object naming, compared with controls. In addition, patients with PD but not controls were significantly more impaired in action than in object naming. The current study supports the view that action naming is affected in patients with PD, possibly reflecting the presence of prefrontal dysfunction.

The Frontal Behavioural Inventory (Italian version) differentiates frontotemporal lobar degeneration variants from Alzheimer's disease.

The objective was to evaluate the construct validity of the Italian version of the Frontal Behavioural Inventory (FBI) and its usefulness in the differential diagnosis of dementias. Standard criteria were used in the clinical diagnosis of dementias in 83 patients and 33 agematched healthy volunteers. The FBI scale was translated from English into Italian language and back-translated. Cronbach's alpha, inter-rater and test-retest reliability, FBI convergent validity and discriminant analysis were calculated. FBI profile was compared between patients affected by frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). The FBI showed a high internal consistency and inter-rater reliability and it distinguished normal behavioural conditions from those presented in FTLD or AD. An 86.8% diagnostic accuracy was calculated by the discriminant analysis, selecting only age at disease onset and FBI, and particularly distinguishing behavioural variants within the FTLD spectrum. FTLD patients showed a characteristic behavioural profile. The FBI might be a reliable and useful diagnostic tool for dementias in clinical practice.

Cognitive impairment in adult myotonic dystrophies: a longitudinal study.

The clinical relevance and extent of cognitive impairment in adult myotonic dystrophy type 1 (DM1) and 2 (DM2) is still unclear. The aim of this study was to determine whether previously reported cognitive abnormalities progress over time and if this occurs in DM2 as it does in DM1. Fifty-six patients with DM1 and 29 patients with DM2 were subjected to muscle strength assessment, and to a complete battery of neuropsychological tests. Repeated assessment was performed in 20 DM1 and 13 DM2 over time (DM1 mean follow-up: 7.3+/-2.7 years; DM2 mean follow- up: 9.5+/-2.4 years). Muscle strength and test scores for frontal lobe functions worsened significantly over time (p<0.01), in both DM1 and DM2. DM2 is a progressive muscle disorder, although less severe than DM1. In both DM1 and DM2 frontal cognitive impairment (attentional) worsens over time but does not extend to additional areas of cognition.