Non-demented Amyotrophic Lateral Sclerosis Patients Research Articles

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.

An eye-tracker controlled cognitive battery: overcoming verbal-motor limitations in ALS.

We assessed language, attention, executive, and social cognition abilities in a sample of patients with Amyotrophic Lateral Sclerosis (ALS) by means of a recently developed cognitive battery based on oculomotor control with eye-tracking (ET) technology. Twenty-one ALS patients and 21 age- and education-matched healthy subjects underwent the ET-based cognitive assessment, together with the standard cognitive screening tools [Frontal Assessment Battery (FAB); Montreal Cognitive Assessment (MoCA); and Digit Sequencing Task]. Psychological measures of anxiety (State-Trait Anxiety Inventory-Y) and depression (Beck Depression Inventory) were also collected, and an ET usability questionnaire was administered. For patients, clinical and respiratory examinations were also performed, together with behavioural assessment (Frontal Behavioural Inventory). The developed battery discriminated among patients and controls with regard to measures of verbal fluency, frontal abilities, and social cognition. Measures of diagnostic utility confirmed a higher diagnostic accuracy of such ET-based tests with respect to FAB; similar diagnostic accuracy emerged when comparing them to the other standard cognitive tools (MoCA, WM). Usability ratings about the ET tests were comparable among the two groups. The ET-based neuropsychological battery demonstrated good levels of diagnostic accuracy and usability in a clinical population of non-demented ALS patients, compared to matched healthy controls. Future studies will be aimed at further investigate validity and usability components by recruiting larger sample of patients, both in moderate-to-severe stages of the disease and affected by more severe cognitive impairment.

Widespread temporo-occipital lobe dysfunction in amyotrophic lateral sclerosis

Recent studies suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a single clinical continuum. However, previous neuroimaging studies have found only limited involvement of temporal lobe regions in ALS. To better delineate possible temporal lobe involvement in ALS, the present study aimed to examine changes in functional connectivity across the whole brain, particularly with regard to extra-motor regions, in a group of 64 non-demented ALS patients and 38 healthy controls. To assess between-group differences in connectivity, we computed edge-level statistics across subject-specific graphs derived from resting-state functional MRI data. In addition to expected ALS-related decreases in functional connectivity in motor-related areas, we observed extensive changes in connectivity across the temporo-occipital cortex. Although ALS patients with comorbid FTD were deliberately excluded from this study, the pattern of connectivity alterations closely resembles patterns of cerebral degeneration typically seen in FTD. This evidence for subclinical temporal dysfunction supports the idea of a common pathology in ALS and FTD.

Executive dysfunction and survival in patients with amyotrophic lateral sclerosis: Preliminary report from a Serbian centre for motor neuron disease

Our objective was to determine whether the presence of executive dysfunction in non-demented amyotrophic lateral sclerosis (ALS) patients might affect the longevity of survival. Forty-eight consecutive non-demented ALS patients (mean age = 52.93 ± 12.37) were followed for five years. All patients underwent clinical and neuropsychological assessments at baseline visit. Further, a yearly follow-up check for associated dementia (ALS-Dem) was completed and the time of death was recorded, when applicable. Executive deficits were shown in 49.5% of ALS patients, with the most striking differences found on the tests of verbal fluency (both phonemic and category, p < 0.01); as well as inefficient strategy on a working memory test (p < 0.05); as on the more demanding levels of the planning and problem solving task (p < 0.01). It appears that the baseline executive status might predict survival in ALS (p = 0.075), and the patients presenting executive dysfunction could have up to three times greater risk of death, after adjustment by several potential confounding factors. In conclusion, this study suggests that executive dysfunction could potentially influence survival in ALS patients. The cognitive testing might give us important clues about the prognosis of the disease. Further studies with larger sample size are necessary.

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.

Communication and pragmatic breakdowns in amyotrophic lateral sclerosis patients

While there is increasing attention toward cognitive changes in amyotrophic lateral sclerosis (ALS), the domain of pragmatics, defined as the ability to integrate language and context to engage in successful communication, remains unexplored. Here we tested pragmatic abilities in 33 non-demented ALS patients and 33 healthy controls matched for age and education through 6 different tasks, ranging from discourse organization to the comprehension of figurative language, further grouped in three composite measures for pragmatic production, pragmatic comprehension and global pragmatic abilities. For a subgroup of patients, assessment included executive functions and social cognition skills. ALS patients were impaired on all pragmatic tasks relative to controls, with 45% of the patients performing below cut-off in at least one pragmatic task, and 36% impaired on the global pragmatic score. Pragmatic breakdowns were more common than executive deficit as defined by the consensus criteria, and approximately as prevalent as deficits in social cognition. Multiple regression analyses support the idea of an interplay of executive and social cognition abilities in determining the pragmatic performance, although all these domains show some degree of independence. These findings shed light on pragmatic impairment as a relevant dimension of ALS, which deserves further consideration in defining the cognitive profile of the disease, given its vital role for communication and social interaction in daily life.

Brain Parenchymal Fraction: A Relatively Simple MRI Measure to Clinically Distinguish ALS Phenotypes.

Even though neuroimaging and clinical studies indicate that amyotrophic lateral sclerosis (ALS) manifests with distinct clinical phenotypes, no objective test exists to assess upper motor degeneration in ALS. There is great interest in identifying biomarkers of ALS to allow earlier diagnosis and to recognize disease subtypes. Current quantitative neuroimaging techniques such as T2 relaxometry and diffusion tensor imaging are time-consuming to use in clinical settings due to extensive postprocessing requirements. Therefore, we aimed to study the potential role of brain parenchymal fraction (BPF) as a relatively simple quantitative measure for distinguishing ALS phenotypes. T1-weighted MR images of brain were obtained in 15 neurological controls and 88 ALS patients categorized into 4 distinct clinical phenotypes, upper motor neuron- (UMN-) predominant ALS patients with/without corticospinal tract (CST) hyperintensity on T2/PD-weighted images, classic ALS, and ALS with frontotemporal dementia (ALS-FTD). BPF was calculated using intracranial grey matter, white matter, and cerebrospinal fluid volumes obtained in control and ALS subgroups using SPM8 software. Only ALS-FTD patients had significant reduction in BPF when compared to controls and nondemented ALS patients. Correlation of clinical measures such as disease duration with BPF further supports the view that the BPF could be a potential biomarker for clinical diagnosis of ALS-FTD patients.

Microstructural white matter changes underlying cognitive and behavioural impairment in ALS--an in vivo study using DTI.

BackgroundA relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients.MethodsWe assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures.ResultsPatients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts.ConclusionIn non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients.

Cognitive deterioration and functional compensation in ALS measured with fMRI using an inhibitory task.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, resulting in progressive weakness and muscle atrophy. Recent studies suggest that nondemented ALS patients can show selective cognitive impairments, predominantly executive dysfunction, but little is known about the neural basis of these impairments. Oculomotor studies in ALS have described deficits in antisaccade execution, which requires the implementation of a task set that includes inhibition of automatic responses followed by generation of a voluntary action. It has been suggested that the dorsolateral prefrontal cortex (DLPFC) contributes in this process. Thus, we investigated whether deterioration of executive functions in ALS patients, such as the ability to implement flexible behavior during the antisaccade task, is related to DLPFC dysfunction. While undergoing an fMRI scan, 12 ALS patients and 12 age-matched controls performed an antisaccade task with concurrent eye tracking. We hypothesized that DLPFC deficits would appear during the antisaccade preparation stage, when the task set is being established. ALS patients made more antisaccade direction errors and showed significant reductions in DLPFC activation. In contrast, regions, such as supplementary eye fields and frontal eye fields, showed increased activation that was anticorrelated with the number of errors. The ALS group also showed reduced saccadic latencies that correlated with increased activation across the oculomotor saccade system. These findings suggest that ALS results in deficits in the inhibition of automatic responses that are related to impaired DLPFC activation. However, they also suggest that ALS patients undergo functional changes that partially compensate the neurological impairment.

G.P.310: The cognitive profile of ALS: update of a meta-analysis

There is a clinical, genetic and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In 2008, our meta-analysis on the cognitive profile of ALS showed that fluency deficits, executive dysfunction and impairment of language and memory can be present in non-demented ALS patients. To further elucidate the cognitive profile of ALS we aimed to update the meta-analysis. We searched Embase, Medline and PsycInfo. Articles were selected if healthy volunteers and non-demented ALS patients, fulfilling El Escorial criteria, underwent at least one validated cognitive test. All tests were categorized in cognitive domains and effect sizes were calculated per domain. Demographic and clinical data were also extracted. We included 29 new articles, resulting in a total of 45 articles (n = 1292 patients and 1144 controls). The median number of neuropsychological (sub) tests administered to patients and controls was 8 (1–34). Patients (63% men, 33% bulbar onset) had a mean age of 59.1 years, a mean educational level of 11.8 years and a mean disease duration of 24 months. Most patients had mild to moderate disability (mean ALSFRS-R 33.1). The domains with the largest, significant effect sizes (Hedges’ g > 0.50) were visuoconstructive functions (0.63), global cognition (0.59), fluency (0.58), language (0.56), social cognition (0.55) and delayed verbal memory (0.52). Executive function had a significant effect size of 0.44. The update of the meta-analysis revealed a new cognitive domain with a large effect size, i.e. social cognition, which encompasses insight into social situations and recognition of emotional states of others. This highlights the clinical overlap between ALS and FTD. The update further reinforces that the cognitive profile extends beyond executive dysfunction and includes language and memory impairment and deficits in social cognition. In the visuoconstructive domain bias due to motor impairment could not be ruled out.

Microstructural white matter correlates of emotion recognition impairment in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is associated in about half of the cases with behavioral and cognitive disorders, including impairments in socio-emotional processing, considered as key-features for the diagnosis of the behavioral variant of frontotemporal dementia (bv-FTD). The neurostructural bases of emotional deficits in ALS, however, still remain largely unexplored. Here we aim to assess emotion recognition in non-demented sporadic ALS patients compared with healthy controls, and to explore for the first time its microstructural white-matter correlates. Twenty-two subjects with either probable or definite diagnosis of ALS and 55 age-, gender-, and education-matched healthy controls were recruited in the study. All participants performed the Ekman 60-Faces Test, assessing the recognition of six basic emotions (i.e., anger, disgust, fear, sadness, surprise and happiness). A subgroup of subjects, comprising 19 patients and 20 healthy controls, also underwent a Diffusion Tensor Imaging scanning. Behavioral analysis highlighted a significant decline of emotion recognition skills in patients compared to controls, particularly affecting the identification of negative emotions. Moreover, the Diffusion Tensor Imaging analyses revealed a correlation between this impairment and the alteration of white-matter integrity along the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus. Our findings indicate the presence of an early emotion recognition deficit in non-demented sporadic ALS patients, associated with microstructural changes in ventral associative bundles connecting occipital, temporo-limbic and orbitofrontal regions in the right hemisphere. These changes may represent a frontotemporal-limbic microstructural marker of socio-emotional impairment in ALS.

Attentional processing in bulbar- and spinal-onset amyotrophic lateral sclerosis: Insights from event-related potentials

Our objective was to evaluate attentional processing with respect to the clinical-onset subtype in amyotrophic lateral sclerosis (ALS) using event-related potentials (ERPs). Thirty-three non-demented ALS patients (22 spinal onset, 11 bulbar onset) and 32 age- and gender-matched controls underwent a psychophysiological evaluation. Mismatch Negativity (MMN), P300 components and Contingent Negative Variation (CNV) were obtained. Latencies and amplitudes of the MMN, P3a and P3b waves and CNV amplitude were then evaluated. Clinical parameters were correlated with ERP data. No differences emerged between ALS patients and controls with regard to the MMN and P3b components. N1-P3a inter-peak latency (Fz, p = 0.003; Cz, p = 0.001; Pz, p = 0.002) was longer in ALS-b than in ALS-s. Total CNV area (Cz, p = 0.01) and W1-CNV area were significantly reduced (Cz, p = 0.05; Pz, p = 0.03) in ALS-b with respect to the one of the controls, while no differences were found between ALS-s patients and controls. In conclusion, automatic pre-attentive processing of stimuli seems to be preserved in ALS. However, a significant delay in the time-course of selective attentive processing and a difficulty in initiating and sustaining attention may be present in ALS-b, which points to a possible dysfunction in the frontal neural network that responds to novelty and to abnormal integration of associative functions. This attentional impairment should be taken in account while developing alternative communicative strategies in ALS patients.

Different Frontal Involvement in ALS and PLS Revealed by Stroop Event-Related Potentials and Reaction Times

Background: A growing body of evidence suggests a link between cognitive and pathological changes in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobar degeneration (FTLD). Cognitive deficits have been investigated much less extensively in primary lateral sclerosis (PLS) than in ALS.Objective: To investigate bioelectrical activity to Stroop test, assessing frontal function, in ALS, PLS, and control groups.Methods: Thirty-two non-demented ALS patients, 10 non-demented PLS patients, and 27 healthy subjects were included. Twenty-nine electroencephalography channels with binaural reference were recorded during covert Stroop task performance, involving mental discrimination of the stimuli and not vocal or motor response. Group effects on event-related potentials (ERPs) latency were analyzed using statistical multivariate analysis. Topographic analysis was performed using low-resolution brain electromagnetic tomography (LORETA).Results: Amyotrophic lateral sclerosis patients committed more errors in the execution of the task but they were not slower, whereas PLS patients did not show reduced accuracy, despite a slowing of reaction times (RTs). The main ERP components were delayed in ALS, but not in PLS, compared with controls. Moreover, RTs speed but not ERP latency correlated with clinical scores. ALS had decreased frontotemporal activity in the P2, P3, and N4 time windows compared to controls.Conclusion: These findings suggest a different pattern of psychophysiological involvement in ALS compared with PLS. The former is increasingly recognized to be a multisystems disorder, with a spectrum of executive and behavioral impairments reflecting frontotemporal dysfunction. The latter seems to mainly involve the motor system, with largely spared cognitive functions. Moreover, our results suggest that the covert version of the Stroop task used in the present study, may be useful to assess cognitive state in the very advanced stage of the disease, when other cognitive tasks are not applicable.

The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study

BackgroundDespite considerable interest, the population-based frequency, clinical characteristics and natural history of cognitive impairment in amyotrophic lateral sclerosis (ALS) are not known.MethodologyThe authors undertook a prospective population-based study of cognitive...

Right hemisphere dysfunction and emotional processing in ALS: an fMRI study

Emotional processing may be abnormal in amyotrophic lateral sclerosis (ALS). Our aim was to explore functional anatomical correlates in the processing of aversive information in ALS patients. We examined the performance of nine non-demented ALS patients and 10 healthy controls on two functional MRI (fMRI) tasks, consisting of an emotional attribution task and a memory recognition task of unpleasant versus neutral stimuli. During the emotional decision task, subjects were asked to select one of three unpleasant or neutral words. During the memory task, subjects were asked to recognize words presented during the previous task. Controls showed, as expected, greater activation in the right middle frontal gyrus during selection of unpleasant than neutral words, and a greater activation mainly in right-sided cerebral areas during the emotional recognition task. Conversely, patients showed a general increase in activation of the left hemisphere, and reduced activation in right hemisphere in both emotional tasks. Such findings may suggest extra-motor neurodegeneration involving key circuits of emotions, mostly negative, commonly involved in FTD.

Insight in ALS: Awareness of behavioral change in patients with and without FTD

Although impaired insight is a core diagnostic criterion for establishing the diagnosis of frontotemporal dementia (FTD), insight has rarely been studied in amyotrophic lateral sclerosis (ALS). To determine differences between patient and informant (caregiver) reports of behavior and behavioral change in amyotrophic lateral sclerosis. Behavioral data for 17 patients with ALS and 4 patients with ALS-FTD were analyzed. Behavioral changes were evaluated using the Frontal Systems Behavior Scale (FrSBe). We compared premorbid to current behavioral profiles and patient self-reports with those of their informants to determine the level of awareness regarding behavioral changes since the onset of ALS. ALS patients without FTD had normal insight, as defined by this study, although self-reports suggested mild behavioral abnormalities. In contrast, patients with ALS-FTD revealed a marked loss of insight regarding profound changes in behavior. Patients with ALS-FTD exhibit a profound lack of insight, which is not found in non-demented ALS patients. Patients without dementia have normal insight, although they report mild behavioral changes that might reflect a psychological response to the disease.

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.

Frontotemporal white matter changes in amyotrophic lateral sclerosis

Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.