Non-demented Amyotrophic Lateral Sclerosis Patients Research Articles

Emotional awareness in patients with amyotrophic lateral sclerosis.

It has been recently acknowledged that deficits in experiencing and processing one's own emotions, also termed alexithymia, may possibly feature the frontotemporal-spectrum disorders. This study aims to determine whether alexithymia could be included within the frontotemporal syndromes of amyotrophic lateral sclerosis (ALS). Alexithymic traits were estimated in a cohort of 68 non-demented ALS patients with the 20-item Toronto Alexithymia Scale (TAS-20). Patients were assessed for the identification of motor-phenotypes and frontotemporal syndromes based on current classification criteria. Spearman's coefficients explored the correlates of TAS-20 measures with motor-functional profiles, global cognitive, social-cognitive (emotion recognition and empathy) and behavioral status. Abnormal TAS-20 scores were found in 13% of patients, and their distribution did not vary within motor and frontotemporal phenotypes. Significant associations were detected between TAS-20 and executive (p ≤ .011), memory (p = .006), state-anxiety (p ≤ .013) and depression measures (p ≤ .010). By contrast, TAS-20 scores were unrelated to social-cognitive performances, dysexecutive and apathetic profiles. Disease duration was the only motor-functional feature being related to the TAS-20 (p ≤ .008). Alexithymia of potential clinical relevance occur in a minority of ALS patients, and its neuropsychological correlates mostly resemble those featuring the general population. Hence, it is unlikely that alexithymia is a specific feature of frontotemporal-spectrum characterizing ALS, rather it could be an expression of psychogenic factors as a reaction to the disease.

An exploratory study on counterfactual thinking in amyotrophic lateral sclerosis.

This study aimed at exploring (1) the motor and non-motor correlates of counterfactual thinking (CFT) abilities in non-demented amyotrophic lateral sclerosis (ALS) patients and (2) the ability of CFT measures to discriminate these patients from healthy controls (HCs) and patients with and without cognitive impairment. N = 110 ALS patients and N = 51 HCs were administered two CFT tasks, whose sum, resulting in a CFT Index (CFTI), was addressed as the outcome. Patients further underwent an in-depth cognitive, behavioral, and motor-functional evaluation. Correlational analyses were run to explore the correlates of the CFTI in patients. Logistic regressions were performed to test whether the CFTI could discriminate patients from HCs. The CFTI was selectively associated (p ≤ 0.005) with fluency and memory subscales of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), but not with other variables. CFTI scores discriminated patients from HCs (p < 0.001) with high accuracy (82%), but not patients with a normal vs. defective performance on the ECAS-Total. CFT measures in non-demented ALS patients were associated with verbal fluency and memory functions, and they were also able to discriminate them from HCs.

Frontotemporal-spectrum disorders and functional independence in non-demented ALS patients

BackgroundThe present study aimed at determining whether, net of motor confounders, neuropsychological features affect functional independence (FI) in activities of daily living (ADLs) in non-demented amyotrophic lateral sclerosis (ALS) patients.MethodsN = 88 ALS patients without frontotemporal dementia were assessed for FI—Katz’s Basic ADL Scale (BADL) and Lawton-Brody’s Instrumental ADL Scale (IADL)—, cognition—Edinburgh Cognitive and Behavioural ALS Screen (ECAS)—and behaviour—Beaumont Behavioural Inventory and Dimensional Apathy Scale. The association between cognitive and behavioural measures and BADL/IADL scores was assessed by covarying for demographics, anxiety and depression levels, disease duration and motor confounders—i.e. ALS Functional Rating Scale-Revised (ALSFRS-R) scores, progression rate and both King’s and Milano-Torino stages.ResultsHigher scores on the ECAS-Language were associated with higher IADL scores (p = 0.005), whilst higher apathetic features—as measured by the Dimensional Apathy Scale (DAS)—were inversely related to the BADL (p = 0.003). Whilst IADL scores were related to all ECAS-Language tasks, the DAS-Initiation was the only subscale associated with BADL scores. Patients with abnormal ECAS-Language (p = 0.023) and DAS (p = 0.008) scores were more functionally dependent than those without.DiscussionAmong non-motor features, language changes and apathetic features detrimentally affect FI in non-demented ALS patients.

Memory-guided navigation in amyotrophic lateral sclerosis

BackgroundPrevious studies have yielded inconsistent results about hippocampal involvement in non-demented patients with amyotrophic lateral sclerosis (ALS). We hypothesized that testing of memory-guided spatial navigation i.e., a highly hippocampus-dependent behaviour, might reveal behavioural correlates of hippocampal dysfunction in non-demented ALS patients.MethodsWe conducted a prospective study of spatial cognition in 43 non-demented ALS outpatients (11f, 32 m, mean age 60.0 years, mean disease duration 27.0 months, mean ALSFRS-R score 40.0) and 43 healthy controls (14f, 29 m, mean age 57.0 years). Participants were tested with a virtual memory-guided navigation task derived from animal research (“starmaze”) that has previously been used in studies of hippocampal function. Participants were further tested with neuropsychological tests of visuospatial memory (SPART, 10/36 Spatial Recall Test), fluency (5PT, five-point test) and orientation (PTSOT, Perspective Taking/Spatial Orientation Test).ResultsPatients successfully learned and navigated the starmaze from memory, both in conditions that forced memory of landmarks (success: patients 50.7%, controls 47.7%, p = 0.786) and memory of path sequences (success: patients 96.5%, controls 94.0%, p = 0.937). Measures of navigational efficacy (latency, path error and navigational uncertainty) did not differ between groups (p ≥ 0.546). Likewise, SPART, 5PT and PTSOT scores did not differ between groups (p ≥ 0.238).ConclusionsThis study found no behavioural correlate for hippocampal dysfunction in non-demented ALS patients. These findings support the view that the individual cognitive phenotype of ALS may relate to distinct disease subtypes rather than being a variable expression of the same underlying condition.

Clinical usability of the Story-Based Empathy Task (SET) in non-demented ALS patients.

This study aimed at assessing the clinical usability of the Story-Based Empathy Task (SET) in non-demented amyotrophic lateral sclerosis (ALS) patients. N = 106 non-demented ALS patients and N = 101 healthy controls (HCs) were administered the SET, which includes three subtests assessing Emotion Attribution (SET-EA), Intention Attribution (SET-IA) and causal inference (SET-CI) - the latter being a control task. Patients also underwent the Reading the Mind in the Eyes Test (RMET), the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and a thorough behavioural and motor-functional evaluation. The diagnostics of the SET-EA and -IA were tested against a defective performance on the RMET. The association between SET subtests and cognitive/behavioural outcomes was examined net of demographic and motor-functional confounders. Case-control discrimination was explored for each SET subtest. Demographically adjusted SET-EA and -IA scoresaccurately detected defective RMET performances at the optimal cutoffs of <3.04 (AUC = .84) and <3.61 (AUC = .88), respectively. By contrast, the SET-CI performed poorly in doing so (AUC = .58). The SET-EA converged with the RMET, as well as with ECAS-Executive and -Memory scores, whilst the SET-IA was unrelated to cognitive measures (including the RMET); the SET-CI was related to the ECAS-Language the ECAS-Executive. SET subscores were unrelated to behavioural outcomes. Only the SET-EA discriminated patients from HCs. The SET as a whole should not be addressed as a social-cognitive measure in this population. At variance, its subtest tapping on emotional processing - i.e., the SET-EA - is recommended for use as an estimate of social-cognitive abilities in non-demented ALS patients.

Prevalence and determinants of language impairment in non-demented amyotrophic lateral sclerosis patients.

This study aimed at estimating the prevalence of language impairment (LI) in a large, clinic-based cohort of non-demented amyotrophic lateral sclerosis (ALS) patients and assessing its underpinnings at motor and non-motor levels. Non-demented ALS patients (N=348) underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), as well as an assessment of behavioural/psychiatric and motor-functional features. The prevalence of LI was estimated based on the proportion of patients showing a performance below the age- and education-adjusted cut-off on the ECAS-Language. Multiple regression models were run to assess the determinants of language functioning and impairment. The prevalence of LI was 22.7%. 46.6% of the variance of ECAS-Language scores remained unexplained, with only the ECAS-Executive positively predicting them (p < 0.001; η2 =0.07). Similarly, only a lower score on the ECAS-Executive predicted a higher probability of a below cut-off ECAS-Language performance (p < 0.001). Spelling and Naming tasks were the major drivers of ECAS-Language performance. This study suggests that, in non-demented ALS patients, LI occurs in ≈23% of cases, is significantly driven by executive dysfunction but, at the same time, partially independent of it and is not associated with other motor or non-motor features.

Validity and diagnostics of the Reading the Mind in the Eyes Test (RMET) in non-demented amyotrophic lateral sclerosis (ALS) patients.

The aim of this study was to explore the construct validity and diagnostic properties of the Reading the Mind in the Eyes Test (RMET) in non-demented patients with amyotrophic lateral sclerosis (ALS). A total of 61 consecutive patients and 50 healthy controls (HCs) were administered the 36-item RMET. Additionally, patients underwent a comprehensive assessment of social cognition via the Story-Based Empathy Task (SET), which encompasses three subtests targeting Causal Inference, Emotion Attribution (SET-EA), and Intention Attribution (SET-IA), as well as global cognitive [the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and behavioral screening [the Frontal Behavioral Inventory (FBI); the Dimensional Apathy Scale (DAS); the Beck Depression Inventory (BDI); and the State and Trait Anxiety Inventory-Y]. The construct validity of the RMET was tested by regressing it within a stepwise model that encompassed as predictors the abovementioned cognitive and behavioral measures, covarying for demographic and motor confounders. Receiver-operating characteristics (ROC) analyses allowed exploring intrinsic and post-test properties of the RMET both in discriminating patients from HCs and in identifying patients with a defective SET-EA performance. The RMET was solely predicted by the SET-EA (p = 0.003) and SET-IA (p = 0.005). RMET scores showed high accuracy both in discriminating patients from HCs (AUC = 0.81) and in identifying patients with a defective SET-EA score (AUC = 0.82), with adequate-to-optimal both intrinsic and post-test properties. The RMET is a convergently and divergently valid measure of affective social cognition in non-demented ALS patients, also featuring optimal intrinsic and post-test diagnostic properties in both case-control and case-finding scenarios.

Iron quantitative analysis of motor combined with bulbar region in M1 cortex may improve diagnosis performance in ALS.

To explore whether the combined analysis of motor and bulbar region of M1 on susceptibility-weighted imaging (SWI) can be a valid biomarker for amyotrophic lateral sclerosis (ALS). Thirty-two non-demented ALS patients and 35 age- and gender-matched healthy controls (HC) were retrospectively recruited. SWI and 3D-T1-MPRAGE images were obtained from all individuals using a 3.0-T MRI scan. The bilateral posterior band of M1 was manually delineated by three neuroradiologists on phase images and subdivided into the motor and bulbar regions. We compared the phase values in two groups and performed a stratification analysis (ALSFRS-R score, duration, disease progression rate, and onset). Receiver operating characteristic (ROC) curves were also constructed. ALS group showed significantly increased phase values in M1 and the two subregions than the HC group, on the all and elderly level (p < 0.001, respectively). On all-age level comparison, negative correlations were found between phase values of M1 and clinical score and duration (p < 0.05, respectively). Similar associations were found in the motor region (p < 0.05, respectively). On both the total (p < 0.01) and elderly (p < 0.05) levels, there were positive relationships between disease progression rate and M1 phase values. In comparing ROC curves, the entire M1 showed the best diagnostic performance. Combining motor and bulbar analyses as an integral M1 region on SWI can improve ALS diagnosis performance, especially in the elderly. The phase value could be a valuable biomarker for ALS evaluation. • Integrated analysis of the motor and bulbar as an entire M1 region on SWI can improve the diagnosis performance in ALS. • Quantitative analysis of iron deposition by SWI measurement helps the clinical evaluation, especially for the elderly patients. • Phase value, when combined with the disease progression rate, could be a valuable biomarker for ALS.

A preliminary comparison between ECAS and ALS-CBS in classifying cognitive-behavioural phenotypes in a cohort of non-demented amyotrophic lateral sclerosis patients.

To define the presence and type of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS), different screening tools have been created. Currently, the most used screening tests are the Edinburgh cognitive and behavioural ALS screen (ECAS) and the ALS cognitive behavioural screen (ALS-CBS). The objective of this study was to compare the ability of ECAS and ALS-CBS in classifying non-demented ALS patients according to Strong criteria. One-hundred and fifty-four in- and out-patients with an age > 18 and a definite or probable ALS diagnosis were recruited between September 2019 and February 2020 at NeMO Clinical Centre and at Istituto Auxologico Italiano in Milan and underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioural Screen (ALS-CBS). Exclusion criteria involved patients with a diagnosis of FTD, with a severe cognitive deterioration and/or an important behavioural impairment, with a significant psychiatric disorder or with the co-presence of another significant illness. The distribution of patients according to Strong criteria was different for ECAS and ALS-CBS and the degree of agreement between the two tests in terms of Cohen's Kappa coefficient resulted equal to 0.2047 with a 95% confidence limits interval between 0.1122 and 0.2973. This study for the first time compares the ability of ECAS and ALS-CBS in stratifying ALS patients. Further studies will be conducted to better understand the reasons underlying the differences between these two tests in classifying the different subtypes of fronto-temporal dysfunction in ALS.

Hippocampal connectivity in Amyotrophic Lateral Sclerosis (ALS): more than Papez circuit impairment

Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p < .05, family-wise error corrected). Interestingly, changes of Digit Span forward performance were inversely related to RS-fMRI signal fluctuations in the cerebellum, while changes of both episodic and visual memory scores were inversely related to mean and radial diffusivity abnormalities in several WM fiber tracts, including middle cerebellar peduncles. Our findings revealed that ALS patients showed significant functional and structural connectivity changes across the regions comprising the Papez circuit, as well as more extended areas including cerebellum and frontal, temporal and parietal areas, supporting the theory of a multi-system pathology in ALS that spreads from cortical to subcortical structures.

Papez Circuit Gray Matter and Episodic Memory in Amyotrophic Lateral Sclerosis and Behavioural Variant Frontotemporal Dementia.

Amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia are two different diseases recognized to overlap at clinical, pathological and genetic characteristics. Both conditions are traditionally known for relative sparing of episodic memory. However, recent studies have disputed that with the report of patients presenting with marked episodic memory impairment. Besides that, structural and functional changes in temporal lobe regions responsible for episodic memory processing are often detected in neuroimaging studies of both conditions. In this study, we investigated the gray matter features associated with the Papez circuit in amyotrophic lateral sclerosis, behavioural variant frontotemporal dementia and healthy controls to further explore similarities and differences between the two conditions. Our non-demented amyotrophic lateral sclerosis patients showed no episodic memory deficits measured by a short-term delayed recall test while no changes in gray matter of the Papez circuit were found. Compared with the amyotrophic lateral sclerosis group, the behavioural variant frontotemporal dementia group had lower performance on the short-term delayed recall test and marked atrophy in gray matter of the Papez circuit. Bilateral atrophy of entorhinal cortex and mammillary bodies distinguished behavioural variant frontotemporal dementia from amyotrophic lateral sclerosis patients as well as atrophy in left cingulate, left hippocampus and right parahippocampal gyrus. Taken together, our results suggest that sub-regions of the Papez circuit could be differently affected in amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.

Microstructural correlates of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) changes in amyotrophic lateral sclerosis

Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was designed for testing patients with amyotrophic lateral sclerosis (ALS), a multi-system neurodegenerative disease characterized by progressive physical disability. In this study, we aim to explore the potential brain microstructural substrates associated with performance on ECAS in the early stages of ALS, using a whole-brain tract-based spatial statistics diffusion tensor imaging approach. Thirty-six non-demented ALS patients, assessed using ECAS, and 35 age-, sex- and education-matched healthy controls underwent magnetic resonance imaging at 3 Tesla. The ALS patients showed decreased fractional anisotropy (FA) in the cortico-spinal tracts and corpus callosum (CC) and significant association between verbal fluency score, among ALS-specific ECAS scores, and FA measures in several long association fiber tracts in the frontal, temporal and parietal lobes. Furthermore, the ALS non-specific total score was inversely related to axial diffusivity (AD) in the mediodorsal nucleus of the thalamus, with more extended areas of correlation in the CC, when considering only the memory subscore. Our results point towards microstructural degeneration across motor and extra-motor areas in ALS, underlining that alterations in verbal fluency performances may be related to impairment of frontotemporal connectivity, while alterations of memory may be associated with damage of thalamocortical circuits.

Regional Dynamics of the Resting Brain in Amyotrophic Lateral Sclerosis Using Fractional Amplitude of Low-Frequency Fluctuations and Regional Homogeneity Analyses.

Resting-state functional magnetic resonance imaging has been playing an important role in the study of amyotrophic lateral sclerosis (ALS). Although functional connectivity is widely studied, the patterns of spontaneous neural activity of the resting brain are important mechanisms that have been used recently to study a variety of conditions but remain less explored in ALS. Here we have used fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) to study the regional dynamics of the resting brain of nondemented ALS patients compared with healthy controls. As expected, we found the sensorimotor network with changes in fALFF and ReHo, and also found the default mode network (DMN), frontoparietal network (FPN), and salience network (SN) altered and the cerebellum, although no structural changes between ALS patients and controls were reported in the regions with fALFF and ReHo changes. We show an altered pattern in the spontaneous low-frequency oscillations that is not confined to the motor areas and reveal a more widespread involvement of nonmotor regions, including those responsible for cognition.

Episodic memory and learning rates in amyotrophic lateral sclerosis without dementia

In amyotrophic lateral sclerosis (ALS), memory deficits may be primary or secondary to executive dysfunction. We assessed episodic memory and executive function of nondemented ALS patients, comparing episodic memory profiles and learning rates of ALS patients with those of mild cognitive impairment (MCI) subjects and cognitively healthy controls (HC). In a multidisciplinary tertiary centre for motor neuron disease, 72 nondemented ALS patients, 57 amnestic MCI (aMCI), 89 single non amnestic MCI with compromised executive functions (dysexecutive MCI), and 190 HC were enrolled. They were screened using the Frontal Assessment Battery and Mini Mental State Examination. Episodic memory performances and learning rates were tested using the Rey Auditory Verbal Learning Test (RAVLT). Episodic memory dysfunction (immediate recall) was found in 14 ALS patients (19.4%). The ALS group had lower performance than HC on immediate recall, without differences in learning rate, and better performance than aMCI subjects on all RAVLT measures. Compared to dysexecutive MCI subjects, ALS patients had only better verbal learning abilities. ALS patients with executive dysfunction had a lower score on immediate and delayed recalls, verbal learning, and primacy effect than ALS patients without executive dysfunction. The immediate recall among couples of diagnostic groups differed in a statistically significant way except for the ALS/dysexecutive MCI groups. In ALS patients, episodic memory performances and learning rates appeared to be better than in aMCI subjects and similar to those with dysexecutive MCI, suggesting also a secondary functional damage due to executive impairment.

Radial diffusivity as an imaging biomarker for early diagnosis of non-demented amyotrophic lateral sclerosis.

To explore the sensitivity of potential DTI-based biomarkers in detecting microstructural changes for whole-brain white matter in early stage amyotrophic lateral sclerosis (ALS), analyze the relationship between the DTI indices and disease status, and further clarify potential brain regions for disease monitoring and clinical assessment. Thirty-three non-demented ALS patients and 32 age- and gender-matched subjects participated in this study. DTI data were acquired via 3.0T MRI scanner. Maps of diffusion-related indices including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were obtained. Tract-based spatial statistics (TBSS) were used to investigate whole-brain white matter changes of each index. Correlation analyses between both brain-wide and volume-of-interest (VOI)-wide white matter alterations and clinical factors including ALSFRS-R scores, disease duration, and progression rate were performed. Compared to healthy subjects, ALS patients showed significantly increased RD, MD and reduced FA, mainly along the corticospinal tract (CST) and the body of corpus callosum (CC). Increases in RD were broader than decreases in FA, in CST of both hemispheres. Meanwhile, involvement of several extra-motor regions was also revealed by RD. Significant positive correlation between ALSFRS-R scores and FA, negative correlation between ALSFRS-R and RD were found in left CST. RD may be the most sensitive biomarker for the detection of early demyelination of white matter. Both RD and FA may serve as objective biomarkers for disease severity assessment. CST may be the most affected brain region in non-demented ALS. • Changes in RD were broader than those in FA in bilateral CST. • Involvement of extra-motor regions was uncovered by RD. • FA and RD in CST were related to ALSFRS-R scores.

The Primitive Palmomental Reflex in Amyotrophic Lateral Sclerosis

Background and Purpose: The palmomental reflex (PMR) is a primitive reflex that might be released due to inhibition in adulthood. It has been associated with several neurodegenerative conditions. The aim of the present study was to evaluate the frequency of PMR in amyotrophic lateral sclerosis (ALS). Patients and Methods: Non-demented ALS patients (n = 179) were recruited. Two groups of disease controls were enrolled: (a) non-demented patients with other neurological disorders (NC; n = 86, mean age 60 ± 14 years); (b) healthy subjects, healthy controls (HC; n = 175, mean age 61 ± 12 years). PMR was elicited by a brisk stroke along the thenar eminence of the right hand with a key or a pen. Results: The PMR could be elicited in 46% of the ALS patients, compared to 29% of NC and 16% of HC (p < 0.001). A multivariate analysis showed that bulbar-onset and female gender are associated with an increased risk of PMR. Conclusion: We demonstrate a higher frequency of the PMR in ALS patients compared to NC or HC. Its expression increases with age, being higher in bulbar-onset patients. Given that the reflex circuit is located in the brain stem, its release due to inhibition might be associated to the presence of a cortico-bulbar tract dysfunction in ALS.

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.

Brain signature of mild stages of cognitive and behavioral impairment in amyotrophic lateral sclerosis

We aimed to assess the brain signature of cognitive and behavioral impairment in C9orf72-negative non-demented ALS patients. The study included 50 amyotrophic lateral sclerosis (ALS) patients (out of 75 initially recruited) and 38 healthy controls. High-resolution T1-weighted and spin-echo diffusion tensor images were acquired in a 3T MRI scanner. The multi atlas-based analysis protocol and the FreeSurfer tool were employed for gray matter assessment, and fiber tractography for white matter evaluation. Cognitively impaired ALS patients (n = 12) had bilateral amygdalae and left thalamic volumetric reduction compared to non-impaired ALS patients. Behaviorally impaired ALS patients (n = 14) had lower fractional anisotropy (FA) at the fornix in comparison with healthy subjects. These parameters did correlate with cognitive/behavioral scores, but not with motor-functional parameters in the ALS cohort. We believe that basal ganglia and fornix damage might be related to cognitive and behavioral impairment across ALS-frontotemporal dementia continuum. Also, distinct anatomical areas seem to influence the behavioral and cognitive status of these individuals.

Investigating the neuroanatomical substrate of pathological laughing and crying in amyotrophic lateral sclerosis with multimodal neuroimaging techniques

Objective: Pathological laughing and crying (PLC) is common in several neurological and psychiatric diseases and is associated with a distributed network involving the frontal cortex, the brainstem and cortico-pontine-cerebellar circuits. By applying multimodal neuroimaging approach, we examined the neuroanatomical substrate of PLC in a sample of patients with amyotrophic lateral sclerosis (ALS). Methods: We studied 56 non-demented ALS patients and 25 healthy controls (HC). PLC was measured in ALS using the Center of Neurologic Study Lability Scale (CNS-LS; cutoff score: 13). All participants underwent 3D-T1-weighted and 30-directional diffusion-weighted imaging at 3T. Voxel-based morphometry and tract-based spatial-statistics analysis was used to examine gray matter (GM) and white matter (WM) differences between ALS patients with and without PLC (ALS-PLC and ALS-nonPLC, respectively). Comparisons were restricted to regions with detected differences between ALS and HC, controlling for age, gender, total intracranial volume and depressive symptoms. Results: In regions with significant differences between ALS and HC, ALS-PLC patients showed decreased GM volume in left orbitofrontal cortex, frontal operculum, and putamen and bilateral frontal poles, compared to ALS-nonPLC. They also had decreased fractional anisotropy in left cingulum bundle and posterior corona radiata. WM abnormalities were additionally detected in WM associative and ponto-cerebellar tracts (using a more liberal threshold). Conclusions: PLC in ALS is driven by both GM and WM abnormalities which highlight the role of circuits rather than isolated centers in the emergence of this condition. ALS is suggested as a useful natural experimental model to study PLC.

Pathologic Involvement of Glutamatergic Striatal Inputs From the Cortices in TAR DNA-Binding Protein 43 kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis.

In frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), recent studies have presumed relationships between cognitive declines and striatal dysfunctions. The striatum contributes to socio-cognitive functions by receiving glutamatergic inputs from the cerebral cortices. However, the vulnerability of these cortico-striatal inputs is unclear in these diseases. This study aimed to evaluate the glutamatergic inputs to the striatum from the cerebral cortices in patients with sporadic TDP-43-related FTLD (FTLD-TDP) and ALS (ALS-TDP). We examined 46 consecutively autopsied patients (31 FTLD-TDP and 15 ALS patients) and 10 normal controls. The axon terminals of the glutamatergic cortico-striatal projection neurons were quantified at the striatum using antivesicular glutamate transporter-1 (VGLUT-1) immunohistochemistry. In results, all FTLD-TDP patients displayed marked depletion of VGLUT-1-positive axon terminals in the caudate head and putamen. Particularly, the patients with type C pathology showed a severe loss. The nondemented ALS patients displayed loss of VGLUT-1-positive axon terminals in the putamen, but those were relatively spared in the caudate head. Confocal microscopy revealed TDP-43 aggregations within VGLUT-1-positive axon terminals in a subset of the patients. Our results indicate marked involvement of glutamatergic striatal inputs from the cerebral cortices in association with socio-cognitive declines in a disease spectrum of TDP-43 proteinopathy.