Cinzia Femiano

Microstructural changes across different clinical milestones of disease in amyotrophic lateral sclerosis.

Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis.

Apathy in amyotrophic lateral sclerosis: insights from Dimensional Apathy Scale

Abstract Objectives: Apathy is associated with cognitive decline and worse survival in amyotrophic lateral sclerosis (ALS); an accurate evaluation of this aspect is relevant in clinical settings. The aims of this study are to evaluate the prevalence of apathy in a large ALS sample, using published diagnostic criteria, and to explore the psychometric properties, the sensitivity and the specificity of the Dimensional Apathy Scale (DAS) as a screening tool for apathy. Methods: One hundred and thirty-one patients underwent clinical interview based on diagnostic criteria for apathy, DAS, Apathy Evaluation Scale, and assessment of depression, global cognitive functioning, and non-verbal intelligence. Results: According to diagnostic criteria, apathy occurred in 28.2% of the patients. The DAS showed high consistency, convergent, and discriminant validities. Apathetic and non-apathetic patients significantly differed on total DAS and executive and Behavioral/Cognitive Initiation subscales, indicating good criterion validity. Receiver operating characteristics analysis, considering diagnostic criteria for apathy as gold standard, revealed that a score of 26/27 was an optimal cut-off score for the identification of apathy. Conclusions: The DAS is a valid screening tool for apathy and its aspects in ALS through limiting the impact of physical disability. Executive and behavioral/cognitive aspects of apathy, rather than emotional aspects, are more frequent in ALS.

Amyotrophic lateral sclerosis and multiple sclerosis overlap: a case report.

The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear.

Theory of Mind and Its Neuropsychological and Quality of Life Correlates in the Early Stages of Amyotrophic Lateral Sclerosis

This study aims to explore the potential impairment of Theory of Mind (ToM; i.e., the ability to represent cognitive and affective mental states to both self and others) and the clinical, neuropsychological and Quality of Life (QoL) correlates of these cognitive abnormalities in the early stages of amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disease recently recognized as a part of the same clinical and pathological spectrum of frontotemporal lobar degeneration. Twenty-two consecutive, cognitively intact ALS patients, and 15 healthy controls, underwent assessment of executive, verbal comprehension, visuospatial, behavioral, and QoL measures, as well as of the ToM abilities by Emotion Attribution Task (EAT), Advanced Test of ToM (ATT), and Eyes Task (ET). ALS patients obtained significantly lower scores than controls on EAT and ET. No significant difference was found between the two groups on ATT. As regard to type of ALS onset, patients with bulbar onset performed worse than those with spinal onset on ET. Correlation analysis revealed that EAT and ET were positively correlated with education, memory prose, visuo-spatial performances, and “Mental Health” scores among QoL items. Our results suggest that not only “cognitive” but also “affective” subcomponents of ToM may be impaired in the early stages of ALS, with significant linkage to disease onset and dysfunctions of less executively demanding conditions, causing potential impact on patients’ “Mental Health.”

Neuropsychological assessment in different King's clinical stages of amyotrophic lateral sclerosis

Abstract Emerging evidence shows that cognitive deficits associated with frontal lobe dysfunction occur from early stages of amyotrophic lateral sclerosis (ALS). We aimed to assess neuropsychological functioning at different stages of ALS to further delineate the occurrence of cognitive impairment alongside the trajectory of ALS as defined by standard assessment procedures. We investigated several cognitive domains in 74 ALS patients classified into four different clinical stages of disease, according to a recently validated staging system for ALS (known as ‘Kings’ system), and evaluated and compared the corresponding cognitive profiles. We found that data derived from global cognitive assessment and several executive (i.e. Frontal Assessment Battery and Trail Making Test B-A) and long-term memory (i.e. memory prose) tests were significantly different among the subsets of ALS patients, showing poorer performances with increasing clinical disability. In conclusion, our preliminary results support the notion that mainly frontotemporal abilities may be impaired during the ALS course and suggest that neuropsychological information could supplement the current clinical staging of patients. However, ALS-specific multi-domain screening instruments, which allow to correct neuropsychological scores for physical disability, should be validated in larger populations worldwide and routinely introduced in clinical practice.

Impact on children of a parent with ALS: a case-control study

Background: Numerous studies have explored how patients and their caregivers cope with amyotrophic lateral sclerosis (ALS), but the literature completely lacks research on the psychological impact of the disease on patients’ children. The aim of our study was to investigate the emotional and psychological impact of a parent with ALS on school-age children and adolescents in terms of problem behavior, adjustment, and personality characteristics. Methods: The study involved 23 children (mean age = 10.62 years, six females) with a parent suffering from ALS, and both their parents. Children were matched for age, gender, and birth-order with a control group of children with healthy parents. They were administered the Youth Self Report (YSR) questionnaire and the Rorschach Comprehensive System, and their healthy parent completed the Child Behavior Checklist (CBCL). Results: Findings clearly showed that, compared with controls, children with a parent who had ALS had several clinically significant adverse emotional and behavioral consequences, with emotional and behavioral problems, internalizing problems, anxiety and depressive symptoms. Children of a parent with ALS scored higher than controls for the Total Problems, Internalizing Problems, Anxious/Depressed and Withdrawn/Depressed scales in the YSR. A relevant percentage of children fell within the clinical range (42.9%) and borderline range (28.6%) for Internalizing Problems. The Rorschach CS confirmed the substantial impact of ALS in a parent on their offspring in terms of internalizing behavior and depression, with adjustment difficulties, psychological pain, and thought problems. Conclusion: Our findings indicate that school-aged children and adolescents with a parent who has ALS are vulnerable and carry a substantially higher risk of internalizing behavior, depressive symptoms, and reactive problems than children with healthy parents. Families affected may need support to cope with such an overwhelming disease.

Coping strategies and psychological distress in caregivers of patients with Amyotrophic Lateral Sclerosis (ALS)

Abstract Background: Amyotrophic lateral sclerosis (ALS) causes distress in caregivers. The present study aims to examine the association between coping strategies and psychological distress in caregivers of ALS patients. Methods: Coping strategies were assessed in 96 ALS informal caregivers by means of the Coping Inventory for Stressful Situations. Data about caregivers’ demographic characteristics, levels of burden, depression and anxiety (psychological distress) were also gathered by standardised questionnaires. Patients’ clinical, cognitive and behavioural disturbances were evaluated by ALS specific assessment tools. Results: Sequential logistic regression analysis showed that emotion-oriented coping strategy was significantly associated with high levels of depressive (p < 0.01) and anxiety (p < 0.05) symptoms and high levels of burden (p < 0.05), after controlling for all other variables. Moreover, a significant relationship of patients’ functional dependence levels with burden experienced by caregivers was observed. No relationships were detected between task-oriented and avoidance-oriented coping strategies and caregivers’ levels of psychological distress. Conclusions: The present study supported the mediating effects of coping strategies on intensity of burden, depression and anxiety experienced by ALS caregivers. These findings suggest that interventions aimed at reducing utilisation of maladaptive coping strategies may improve well-being in ALS caregivers, and, possibly, management of symptoms in ALS patients.

Brain functional networks become more connected as amyotrophic lateral sclerosis progresses: a source level magnetoencephalographic study

This study hypothesizes that the brain shows hyper connectedness as amyotrophic lateral sclerosis (ALS) progresses. 54 patients (classified as “early stage” or “advanced stage”) and 25 controls underwent magnetoencephalography and MRI recordings. The activity of the brain areas was reconstructed, and the synchronization between them was estimated in the classical frequency bands using the phase lag index. Brain topological metrics such as the leaf fraction (number of nodes with degree of 1), the degree divergence (a measure of the scale-freeness) and the degree correlation (a measure of disassortativity) were estimated. Betweenness centrality was used to estimate the centrality of the brain areas. In all frequency bands, it was evident that, the more advanced the disease, the more connected, scale-free and disassortative the brain networks. No differences were evident in specific brain areas. Such modified brain topology is sub-optimal as compared to controls. Within this framework, our study shows that brain networks become more connected according to disease staging in ALS patients.

Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis

Apathy is recognized as the most common behavioral change in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder. Particularly, apathy has been reported to be associated with poor ALS prognosis. However, the brain microstructural correlates of this behavioral symptom, reported as the most common in ALS, have not been completely elucidated. Using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS), here we aimed to quantify the correlation between brain microstructural damage and apathy scores in the early stages of ALS. Twenty-one consecutive ALS patients, in Kings clinical stage 1 or 2, and 19 age- and sex-matched healthy controls (HCs) underwent magnetic resonance imaging and neuropsychological examination. Between-group comparisons did not show any significant difference on cognitive and behavioral variables. When compared to HCs, ALS patients exhibited a decreased fractional anisotropy (FA) [p < .05, threshold-free cluster enhancement (TFCE) corrected] in the corpus callosum and in bilateral anterior cingulate cortices. Self-rated Apathy Evaluation Scale (AES) scores and self-rated apathy T-scores of the Frontal Systems Behavior (FrSBe) scale were found inversely correlated to FA measures (p < .05, TFCE corrected) in widespread white matter (WM) areas, including several associative fiber tracts in the frontal, temporal, and parietal lobes. These results point towards an early microstructural degeneration of brain areas biologically involved in cognition and behavior regulation in ALS. Moreover, the significant correlations between apathy and DTI measures in several brain areas may suggest that subtle WM changes may be associated with mild behavioral symptoms in ALS even in the absence of overt cognitive and behavioral impairment.

High angular resolution diffusion imaging abnormalities in the early stages of amyotrophic lateral sclerosis

OBJECTIVE Using magnetic resonance (MR) high angular resolution diffusion imaging (HARDI), we aimed at revealing possible microstructural alterations in the early stage of amyotrophic lateral sclerosis (ALS), still not completely elucidated. METHODS We studied 22 patients with ALS, in stages 1 or 2 according to the Kings staging system, compared to 18 healthy controls (HCs). Statistical mapping of HARDI-derived parameters and tractography measures were performed using the Q-ball imaging diffusion data model. RESULTS When compared to HCs, the ALS group showed a highly significant decrease of generalized fractional anisotropy (GFA) and fiber length and density in the corticospinal tracts (CSTs) and in the corpus callosum (CC) (p<0.05, corrected level of significance). Moreover, stratifying the ALS population considering the disease phenotype, larger areas of decreased GFA were found in patients with bulbar phenotype compared to those with classic phenotype in several bilateral associative fiber tracts, such as superior and inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. CONCLUSIONS Our whole-brain HARDI results provided preliminary evidence of an early pattern of microstructural degeneration in ALS, mainly involving the CSTs and the CC, although divergent patterns of microstructural abnormalites could be related to different disease phenotypes.