Continuum of Frontal Lobe Impairment in Amyotrophic Lateral Sclerosis

Department of Neurology, ALS Center, University of California, San Francisco, CA 94117, USA.
JAMA Neurology (Impact Factor: 7.01). 05/2007; 64(4):530-4. DOI: 10.1001/archneur.64.4.530
Source: PubMed

ABSTRACT To identify the nature and prevalence of cognitive and behavioral abnormalities in patients with amyotrophic lateral sclerosis (ALS).
Survey of clinical characteristics.
Multidisciplinary clinic within a university medical center. Patients A volunteer sample of 30 new patients with ALS were recruited consecutively. Of those invited, 23 participants (20 with sporadic ALS and 3 with familial ALS) enrolled. Participants ranged in age from 27 to 80 years (mean age, 56.5 years); the education level ranged from 12 to 21 years (mean education level, 3.5 years of college); and 17 participants (74%) were male.
Neuropsychological tests, neurobehavioral interviews, and structured magnetic resonance imaging.
Patients were classified into subtypes of frontotemporal lobar degeneration (n = 5), suspected Alzheimer disease (n = 1), and subthreshold variants of cognitive impairment (n = 2), behavioral impairment (n = 4), and cognitively and behaviorally normal (n = 11). Five neuropsychological tests, 2 behavioral abnormalities, and right hemisphere gray matter reductions differentiated patients into normal and abnormal groups.
In this sample, a sizable proportion of patients with ALS possess a range of behavioral and cognitive changes that lie on a spectrum of frontotemporal impairment. Right hemisphere atrophy may be a biomarker for cognitive impairment in patients with ALS.

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    • "Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are multisystem neurodegenerative disorders, which have been found highly related, occupying 2 poles of a disease spectrum, with a predominance of motor dysfunction at one end and cognitive symptoms at the other (Clark and Forman, 2006; Neumann et al., 2006). In fact, the 2 disorders have been recognized as representative of a neuropathologic continuum because they share several clinical, genetic, and pathogenetic characteristics (Ling et al., 2013; Lomen-Hoerth et al., 2002; Murphy et al., 2007). Genetic and pathologic analyses have demonstrated that mutations of trans-active response DNA binding protein (TARDBP) of 43 kD (Benajiba et al., 2009), fused in sarcoma/translocated in liposarcoma (FUS/TLS) (Blair et al., 2010), ubiquilin-2 (UBQLN2) (Deng et al., 2011), and c9orf72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011) have a key role in the pathogenesis of the ALS-FTD spectrum. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) and behavioral variant frontotemporal dementia (bvFTD) lie on a clinical, pathologic, and genetic continuum. Neuroimaging techniques have proven to be potentially useful to unravel the shared features of these syndromes. Using resting-state functional magnetic resonance imaging (RS-fMRI), we investigated functional connectivity of brain networks in 15 ALS and 15 bvFTD patients in early stages of disease and 15 healthy controls, looking expressly for connectivity pattern divergence or overlap between the 2 disorders. Compared with controls, we found decreased RS-fMRI signals within sensorimotor, right frontoparietal, salience, and executive networks in both patient groups. Within the default mode network (DMN), divergent connectivity patterns were observed, with RS-fMRI signals in the posterior cingulate cortex enhanced in bvFTD patients and suppressed in ALS patients. Our findings confirm that ALS and bvFTD not only broadly share common RS-fMRI connectivity patterns, probably representing different phenotypical expressions of the same neurodegenerative process, but also differ in the DMN, probably reflecting a different stage of neurodegeneration.
    Neurobiology of Aging 06/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.06.025 · 4.85 Impact Factor
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    • "The dysfunction of higher cognitive abilities, from mild cognitive impairment to frank dementia, is common in ALS (Ringholz et al., 2005), with a prevalence that ranges from 10 to 75% in patients (Miller et al., 2009), mainly involving cognitive and behavioral frontotemporal functions (Strong et al., 2009). In recent years, a growing body of evidence (Neary et al., 2000; Lomen-Hoerth et al., 2003; Rippon et al., 2006; Murphy et al., 2007) has suggested a link between ALS and frontotemporal lobar degeneration (FTLD). Previous studies that assessed subjects at rest (Kew et al., 1993; Abe et al., 1997) or during the performance of executive tasks (Ludolph et al., 1992; Abrahams et al., 1995) reported a significant decrease in frontal lobe activation in non-demented ALS patients who presented cognitive deficits. "
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    ABSTRACT: BACKGROUND: A growing body of evidence suggests a link between cognitive and pathological changes in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobar dementia (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: 32 non-demented ALS patients, 10 non-demented PLS patients and 27 healthy subjects were included. Twenty-nine electroencephalography (EEG) 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: ALS 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 behavioural 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.
    Frontiers in Aging Neuroscience 12/2013; 5:82. DOI:10.3389/fnagi.2013.00082 · 2.84 Impact Factor
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    • "The traditional assumption that ALS spares cognitive function is now considered to be incorrect (Strong et al., 2009; Phukan et al., 2012). Research consistently reports functional and structural changes in the frontotemporal region, manifesting as executive dysfunction, including behavioral dysinhibition; a pattern of deficits similar to that observed in frontotemporal dementia (FTD; Lomen-Hoerth et al., 2000; Ringholz et al., 2005; Murphy et al., 2007; Meier et al., 2010; Girardi et al., 2011). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive condition involving degeneration of both upper and lower motor neurons. Recent research suggests that a proportion of persons with ALS show a profile similar to that of frontotemporal dementia (FTD), with this group of ALS patients exhibiting social cognitive deficits. Although social cognitive deficits have been partially explored in ALS, research has yet to investigate such changes using ecologically valid measures. Therefore, this study aimed to further characterize the scope of social cognitive and emotion recognition deficits in non-demented ALS patients using an ecologically valid measure of social cognition. A sample of 35 ALS patients and 30 age-and-education matched controls were assessed using the Addenbrooke's Cognitive Examination, the Brixton Spatial Anticipation Test, and The Awareness of Social Inference Test, where participants were required to discriminate between various emotions and decipher socially challenging scenarios enacted in video vignettes. Participants with ALS showed significant difficulties in recognizing both sarcastic and paradoxical sarcastic statements, but not sincere statements, when compared to controls. After controlling for executive difficulties, ALS patients still displayed significant difficulties on tasks that assessed their comprehension of both sarcastic and paradoxical sarcastic statements. The inability to read social cues and make social inferences has the potential to place significant strain on familial/interpersonal relationships in ALS. The findings of this study highlight the importance of employing a broader range of neuropsychological assessment tools to aid in early detection of frontal lobe impairment in non-demented ALS patients.
    Frontiers in Human Neuroscience 05/2013; 7:178. DOI:10.3389/fnhum.2013.00178 · 2.90 Impact Factor
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