Monica Consonni

Emotional empathy in amyotrophic lateral sclerosis: a behavioural and voxel-based morphometry study

Abstract Amyotrophic lateral sclerosis (ALS) is a multisystem condition, in which executive and/or behavioural symptoms can occur. Deficits of social cognition, including defective cognitive and emotional empathy, have been recently reported in ALS subjects. The neurostructural correlates of these disorders in ALS are still unknown. The aims of this study were to evaluate two components of empathy in non-demented ALS subjects, and to associate performance with regional grey-matter density using voxel-based morphometry (VBM). Twenty non-demented sporadic probable or definite ALS patients and 56 matched healthy controls (HC) participated in a non-verbal task requiring the attribution of emotional versus cognitive states to identify the correct ending of comic strips, compared with a control condition requiring identifying causal relationships devoid of social components. A subgroup of 14 ALS and 20 HC joined the VBM study. Results demonstrated that, compared with controls, ALS patients showed defective emotional empathy attribution, related with reduced grey-matter density in the anterior cingulate cortex and right inferior frontal gyrus. Our study provided evidence of a specific impairment of emotional empathy in ALS patients, reflecting neural damage in a limbic prefrontal network involved in emotional processing. Social cognition disorders may represent a marker of cognitive dysfunction in ALS.

The cognitive and behavioural profile of Amyotrophic Lateral Sclerosis: Application of the consensus criteria

Objective: The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteria [9]. The study also intends to assess the impact of physical disability on cognitive and behavioural abnormalities. Methods: Detailed neurological, neuropsychological and neurobehavioral evaluations were administered to 23 ALS patients, 11 Lower Motor Neuron Disease (LMND) patients and 39 healthy controls. Strong et al.’s criteria [9] were applied to diagnose the presence of cognitive/behavioural impairment. Clinical and neuropsychological scores were used for group comparisons and correlation analyses. Results: In comparison with LMND and controls, a subgroup of ALS patients (∼30%) manifested executive dysfunction, which was severe enough to classify them as cognitively impaired. Action naming difficulties and short-term memory deficits were also observed. Aspontaneity, disorganization and mental rigidity reached clinical relevance in 20% of ALS patients. A small percentage of ALS patients (13%) also had comorbid dementia. The cognitive or behavioural status was not related to the clinical features of ALS. Conclusion: The use of consensus criteria for cognitive and behavioural impairment and the comparison with the LMND group proved useful in defining the spectrum of non-motor manifestations of ALS.

Neural convergence for language comprehension and grammatical class production in highly proficient bilinguals is independent of age of acquisition

In bilinguals, native (L1) and second (L2) languages are processed by the same neural resources that can be modulated by age of second language acquisition (AOA), proficiency level, and daily language exposure and usage. AOA seems to particularly affect grammar processing, where a complete neural convergence has been shown only in bilinguals with parallel language acquisition from birth. Despite the fact that proficiency-related neuroanatomical differences have been well documented in language comprehension (LC) and production, few reports have addressed the influence of language exposure. A still unanswered question pertains to the role of AOA, when proficiency is comparably high across languages, with respect to its modulator effects both on LC and production. Here, we evaluated with fMRI during sentence comprehension and verb and noun production tasks, two groups of highly proficient bilinguals only differing in AOA. One group learned Italian and Friulian in parallel from birth, whereas the second group learned Italian between 3 and 6 years. All participants were highly exposed to both languages, but more to Italian than Friulian. The results indicate a complete overlap of neural activations for the comprehension of both languages, not only in bilinguals from birth, but also in late bilinguals. A slightly extra activation in the left thalamus for the less-exposed language confirms that exposure may affect language processing. Noteworthy, we report for the first time that, when proficiency and exposure are kept high, noun and verb production recruit the same neural networks for L1 and L2, independently of AOA. These results support the neural convergence hypothesis.

Beyond the consensus criteria: multiple cognitive profiles in amyotrophic lateral sclerosis?

The Strong consensus recommendations (2009) propose behavioural (ALSbi) and/or dysexecutive (ALSci) impairment as the two main clinical profiles of non-motor manifestations in non-demented amyotrophic lateral sclerosis (ALS) patients. We aimed at assessing whether clustering pattern of neuropsychological performance of ALS patients suggest the existence of additional clinical syndromes beyond the currently recognized phenotypes. We applied principal component analysis (PCA) to a comprehensive neuropsychological evaluation of 71 non-demented ALS patients in order to identify clusters of variables correlating highly with each other, with the aim of detecting distinct patterns of neuropsychological test performance. The outcome of PCA demonstrated the existence of three main test clusters. Two, accounting for 27% of the patients, were compatible with the recognised ALSbi and ALSci profiles. An additional third cluster loaded on social cognition, language and memory tests and accounted for 24% of the patients. Of these, 15% had defective performance on at least two tests belonging to the latter non-executive cluster, and were thus unclassifiable according to current criteria. Our data-driven approach indicated a third dimension of cognitive impairment, including language, social cognition and episodic memory, as a distinct pattern of non-motor manifestations in ALS patients, in addition to the recognized ALSci and ALSbi profiles.

Auditory event-related potentials in non-demented patients with sporadic amyotrophic lateral sclerosis

OBJECTIVE To investigate the presence of sub-clinical cognitive dysfunction in non-demented patients with amyotrophic lateral sclerosis (ALS) using auditory event-related potentials (ERPs). METHODS Ten subjects with ALS and 10 age- and sex-matched controls performed a passive three-stimulus paradigm with standard (80%), deviant (16%) and distracter (4%) stimuli. To quantify the mismatch component, the evoked response to the standard tones was subtracted from the corresponding deviant stimuli and novel response; the P3a component was obtained by subtracting the response to the standard tone from that to the novel stimuli. The amplitude and latency for the N1 component obtained with the standard stimuli were also measured. Clinical features, disability, cognitive status and depression were evaluated with standardised scales. RESULTS There were no significant differences between patients and controls for latencies, while the N1, P3a and MMN (obtained by the subtraction Novel-Standard) were of lower amplitude in patients than in controls. In the patient group, the P3a latency correlated with months from disease onset and symptoms severity, measured with the amyotrophic lateral sclerosis severity scale. CONCLUSIONS Our findings confirm the hypothesis of a sub-clinical cognitive impairment in non-demented ALS patients, suggesting pathological involvement beyond the motor areas. SIGNIFICANCE ERPs seem to be a promising technique to detect the possible impairment of extra-motor sub-clinical dysfunction in ALS, and an appropriate technique for the cognitive follow-up, as passive tasks, not requiring motor responses, are particularly adequate in a disorder leading to severe loss of motor function.

Connected speech in neurodegenerative language disorders: A review

Language assessment has a crucial role in the clinical diagnosis of several neurodegenerative diseases. The analysis of extended speech production is a precious source of information encompassing the phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic levels of language organization. The knowledge about the distinctive linguistic variables identifying language deficits associated to different neurodegenerative diseases has progressively improved in the last years. However, the heterogeneity of such variables and of the way they are measured and classified limits any generalization and makes the comparison among studies difficult. Here we present an exhaustive review of the studies focusing on the linguistic variables derived from the analysis of connected speech samples, with the aim of characterizing the language disorders of the most prevalent neurodegenerative diseases, including primary progressive aphasia, Alzheimers disease, movement disorders, and amyotrophic lateral sclerosis. A total of 61 studies have been included, considering only those reporting group analysis and comparisons with a group of healthy persons. This review first analyzes the differences in the tasks used to elicit connected speech, namely picture description, story narration, and interview, considering the possible different contributions to the assessment of different linguistic domains. This is followed by an analysis of the terminologies and of the methods of measurements of the variables, indicating the need for harmonization and standardization. The final section reviews the linguistic domains affected by each different neurodegenerative disease, indicating the variables most consistently impaired at each level and suggesting the key variables helping in the differential diagnosis among diseases. While a large amount of valuable information is already available, the review highlights the need of further work, including the development of automated methods, to take advantage of the richness of connected speech analysis for both research and clinical purposes.

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

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

Event-related potentials in idiopathic rapid eye movements sleep behaviour disorder

OBJECTIVE To assess psychophysiological parameters in idiopathic rapid eye movements sleep behaviour disorder (RBD), in order to identify possible markers for pre or sub-clinical cognitive abnormalities. METHODS Sixteen consecutive unmedicated patients with idiopathic RBD and 16 age- and sex-matched controls performed active and passive auditory oddball paradigms and an attentional test. RESULTS There were no significant between-group latency and amplitude differences. The two groups showed a difference in the inter-peak interval between N100 and P200 in the active condition. A significant correlation between attentional matrices scores and N100 amplitude at Fz and Cz to standard stimuli in the passive condition was found in controls but not in patients. CONCLUSIONS In RBD there are minimal event-related potentials (ERPs) abnormalities involving the early stages of information processing. SIGNIFICANCE ERPs are not sensitive to pre or sub-clinical cognitive abnormalities in RBD. In alternative, these findings might support the existence of a truly idiopathic RBD syndrome.

Early-onset progressive spastic paraplegia caused by a novel TUBB4A mutation: brain MRI and FDG-PET findings.

A 21-year-old man was evaluated in 2010 because of a sporadic childhood-onset slowly progressive spastic paraplegia complicated by mild learning difficulties. Examination showed spastic gait with no need of support, lower limb spastic hypertonia, diffusely increased deep tendon reflexes, bilateral Babinski sign, equinovarus deformity of the feet, and mild intellectual disability (WAIS total IQ score = 60) which did not prevent him from having a nearnormal life. Brain MRI showed relatively diffuse, slight white matter T2-hyperintensity in combination with normal T1-weighted signal (Fig. 1a–c), unmodified on two repeat MRI scans 3 and 5 years apart, at age 24 and 26 (not shown). Hence, we suspected a hypomyelinating leukodystrophy (HLD). A bilateral globus pallidus hypointensity on T2*-weighted images, which was above the normal range for the age [2], suggested pathologic iron deposition (Fig. 1d). At last evaluation, in 2015, the patient was still able to walk without support, and brain FDG-PET principally showed hypometabolism in the central grey nuclei and cerebellum (Fig. 2). A genetic screening for HLDs identified a novel heterozygous c.1064A[T (p.Asp355Val) mutation in exon 4 of the TUBB4A (tubulin, beta 4A class IVa) gene. The mutation was absent in the parents and in his sister (suggesting that this is a de novo mutation), as well as in the 1000 Genomes Project, Exome Variant Server, and dbSNP databases, and it was predicted to be pathogenic by in silico analysis (see Electronic Supplementary Material for details). TUBB4A-related disorders encompass a wide clinical and neuroradiological spectrum, ranging from dystonia type 4 (DYT4) disease, which is characterized by adultonset dystonia and normal brain MRI [4], to hypomyelination with atrophy of the basal ganglia and cerebellum (HABC) disease, which is clinically characterized by earlyonset extrapyramidal movement abnormalities and other variable neurological features including spasticity, ataxia, cognitive impairment, and seizures [5]. The major findings of our report are as follows: first, our patient presented with a progressive spastic paraplegia complicated only by mild intellectual disability, as recently reported in a consanguineous Roma/Gypsy kindred [6]. No overt extrapyramidal sign was found even after a long history of disease, providing further evidence that the extrapyramidal movement abnormalities, which have been considered the core feature of the TUBB4A-related disorders [5, 7], can be absent. Second, brain MRI showed that: (1) basal ganglia were of normal size [8, 9], and white matter abnormalities were not so diffuse as usually found, in agreement with the relatively mild clinical phenotype [6]; (2) there was an unexpected iron deposition in the globi pallidi, which is likely an epiphenomenon of neurodegeneration [10]. Third, brain FDG-PET revealed cerebellar hypometabolism (in agreement with the presence of mild cerebellar atrophy on MRI), but also bilateral putamen hypometabolism. The latter suggests that subtle pathological changes are present in this region (which expresses high levels of TUBB4A [4]) also when no Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8020-8) contains supplementary material, which is available to authorized users.

Cortical markers of cognitive syndromes in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) can be associated with a spectrum of cognitive and behavioural symptoms, but the related patterns of focal cortical atrophy in non-demented ALS patients remain largely unknown. We enrolled 48 non-demented ALS patients and 26 healthy controls for a comprehensive neuropsychological assessment and a magnetic resonance exam. Behavioural and cognitive impairment was defined on the basis of a data-driven multi-domain approach in 21 ALS patients. Averaged cortical thickness of 74 bilateral brain regions was used as a measure of cortical atrophy. Cortical thinning in a fronto-parietal network, suggesting a disease-specific pattern of neurodegeneration, was present in all patients, independent of cognitive and behavioural status. Between-group and correlational analyses revealed that inferior frontal, temporal, cingular and insular thinning are markers for cognitive and behavioural deficits, with language impairment mainly related to left temporal pole and insular involvement. These specific correlates support the concept of a spectrum of deficits, with an overlap between the ALS cognitive phenotypes and the syndromes of frontotemporal dementia.