Cognitive impairment in amyotrophic lateral sclerosis (ALS) is correlated with pathologic and radiographic changes in cerebral cortex beyond the motor regions. Clinically, evidence of impairment can be detected in up to 50 percent of patients through direct neuropsychological testing, although frank frontotemporal dementia (FTD) occurs in a limited percentage. Behavioral changes are also common and can be characterized primarily by the presence of increased apathy. Determining the underlying causes of cognitive or behavioral change may be confounded by several disease-related factors, including fatigue, respiratory compromise, depression, and treatment with medications such as riluzole. Studies assessing the evolution and relative risk for cognitive and behavioral impairment in ALS suggest at least two types of patients: those who have clear FTD in whom cognitive decline develops gradually and those who have mild cognitive or behavioral impairments in whom progression either does not occur or is difficult to detect. Limited data suggest that cognition and behavior influence compliance, management, and survival, although this requires further assessment.
Overview
The study of cognition and behavior as a feature of amyotrophic lateral sclerosis (ALS) is an evolving field that still lacks consensus on terminology, diagnostic criteria, and the clinical significance of any detected abnormalities. Currently, fairly marked discrepancies remain regarding the incidence of abnormalities and characteristics of the impairments that define the disease. Although substantial pathologic and genetic evidence shows an overlap between ALS and frontotemporal dementia (FTD), cognitive and behavioral syndromes also occur among patients who have ALS that cannot be characterized as frank FTD.
The terms ALSci (ALS with cognitive impairment), ALSbi (ALS with behavioral impairment), and ALS-FTD are developing concepts that aim to capture the key differences between various phenotypes. Whether these conditions fall into a single disease spectrum or represent distinct clinical syndromes is still debated.
Cognitive impairment in amyotrophic lateral sclerosis
Most patients who have ALS diagnosed with a cognitive disorder are characterized as having ALSci. The impairment reflects frontal lobe dysfunction but is not considered synonymous with the more severe and disabling dementia associated with FTD. Numerous studies show that the primary deficits in ALSci occur in the domains of attention , cognitive flexibility , word generation, and retrieval ( Box 1 ) .
Cognitive domain
Attention and concentration
Working memory
Cognitive flexibility
Response inhibition
Planning/problem solving/abstract reasoning
Visual-perceptual skills
Memory
Intrinsic response generation (ie, fluency)
Many studies have identified impaired intrinsic response generation and particularly abnormalities in verbal fluency . Consistent with a frontal syndrome, visuospatial functions, praxis, and memory storage are typically spared , whereas reports suggesting that impaired memory may be found probably reflect deficiencies in retrieval processes associated with frontal lobe dysfunction rather than an amnestic process.
Estimates of the prevalence of cognitive impairment in patients who have ALS range from 10% to 75% . This wide range probably reflects differences in the selection of patients and methods used for diagnosis.
Where neuropsychological testing is the gold standard for diagnosis, reports have used varied cognitive tests and different cutoffs for distinguishing normal from abnormal, resulting in different conclusions about the nature of the disease. A single consensus on diagnostic criteria for ALSci has not been reached, but an increasingly common threshold used in the field requires the presence of two or more neuropsychological scores at or below the fifth percentile compared with a normative group. This requirement assumes the tests are part of a comprehensive battery including measures that are distinct and sensitive to executive functioning and language processing. With this methodology, the incidence of ALSci within a typical multidisciplinary clinic seems to be approximately 50% .
Whether a specific clinical presentation predicts ALSci is not entirely clear. Several studies have indicated an association of ALSci with bulbar involvement . Studies suggesting a correlation between dysarthria and higher levels of distractibility or between pseudobulbar affect and cognitive impairment reflect similar conclusions.
The authors have identified a distinct clinical syndrome marked by ocular apraxia and upper motor neuron bulbar involvement in a group of patients who have relatively obvious cognitive deficits . Pathologic studies have also found that patients who have bulbar palsy may have a degenerative process that extends beyond the motor cortex into frontotemporal lobar regions . The relationship is not entirely clear, however, as other studies have failed to find strong correlations between ALSci and bulbar involvement . Any discrepancies across studies may reflect the measures used for diagnosis of impairment, and depend on whether bulbar onset versus bulbar involvement was used for the comparison.
Cognitive impairment in amyotrophic lateral sclerosis
Most patients who have ALS diagnosed with a cognitive disorder are characterized as having ALSci. The impairment reflects frontal lobe dysfunction but is not considered synonymous with the more severe and disabling dementia associated with FTD. Numerous studies show that the primary deficits in ALSci occur in the domains of attention , cognitive flexibility , word generation, and retrieval ( Box 1 ) .
Cognitive domain
Attention and concentration
Working memory
Cognitive flexibility
Response inhibition
Planning/problem solving/abstract reasoning
Visual-perceptual skills
Memory
Intrinsic response generation (ie, fluency)
Many studies have identified impaired intrinsic response generation and particularly abnormalities in verbal fluency . Consistent with a frontal syndrome, visuospatial functions, praxis, and memory storage are typically spared , whereas reports suggesting that impaired memory may be found probably reflect deficiencies in retrieval processes associated with frontal lobe dysfunction rather than an amnestic process.
Estimates of the prevalence of cognitive impairment in patients who have ALS range from 10% to 75% . This wide range probably reflects differences in the selection of patients and methods used for diagnosis.
Where neuropsychological testing is the gold standard for diagnosis, reports have used varied cognitive tests and different cutoffs for distinguishing normal from abnormal, resulting in different conclusions about the nature of the disease. A single consensus on diagnostic criteria for ALSci has not been reached, but an increasingly common threshold used in the field requires the presence of two or more neuropsychological scores at or below the fifth percentile compared with a normative group. This requirement assumes the tests are part of a comprehensive battery including measures that are distinct and sensitive to executive functioning and language processing. With this methodology, the incidence of ALSci within a typical multidisciplinary clinic seems to be approximately 50% .
Whether a specific clinical presentation predicts ALSci is not entirely clear. Several studies have indicated an association of ALSci with bulbar involvement . Studies suggesting a correlation between dysarthria and higher levels of distractibility or between pseudobulbar affect and cognitive impairment reflect similar conclusions.
The authors have identified a distinct clinical syndrome marked by ocular apraxia and upper motor neuron bulbar involvement in a group of patients who have relatively obvious cognitive deficits . Pathologic studies have also found that patients who have bulbar palsy may have a degenerative process that extends beyond the motor cortex into frontotemporal lobar regions . The relationship is not entirely clear, however, as other studies have failed to find strong correlations between ALSci and bulbar involvement . Any discrepancies across studies may reflect the measures used for diagnosis of impairment, and depend on whether bulbar onset versus bulbar involvement was used for the comparison.
Frontotemporal dementia in amyotrophic lateral sclerosis
Frontotemporal lobar degeneration (FTLD) describes a group of disorders caused by frontal and temporal lobe degeneration sharing common pathologic features. FTD, also known as the frontal or behavioral variant FTLD, tends to be caused by bilateral or right-sided degeneration and manifests primarily as a behavior disorder. Left-sided involvement leads to disorders of language that include progressive nonfluent aphasia (PNFA) and semantic dementia.
Outside of ALS, the Neary criteria are most commonly used for diagnosing FTD . These criteria use a behavioral rather than cognitive approach, defining FTD through an insidious onset and gradual progression, altered social conduct, impaired regulation of personal conduct, emotional blunting, and loss of insight. All five core features are required for the diagnosis, whereas secondary findings may include disinhibition; restlessness; reduced empathy or lack of concern for others; lack of foresight; impulsiveness; social withdrawal; verbal stereotypes or echolalia; verbal or motor perseveration; or sexual hyperactivity . A diagnostic approach that relies solely on cognitive testing may fail to detect patients who have early or mild ALS-FTD, in whom these behavioral abnormalities can occur in the context of intact cognition .
The literature reflects varied frequencies of FTLD subtypes within the ALS population. Again, these discrepancies likely reflect biases introduced by the methodology used for diagnosis and subjectivity in behavioral assessment. Similarly, discrepancies can be found in the estimates of the FTLD subtypes frequencies. In one study that used a combination of cognitive testing and the Neary criteria , 65% of patients who where diagnosed with ALS-FTLD had the behavioral (frontal) variant, characterized by apathy, disinhibition, and poor social monitoring. In contrast, a subsequent study found that 63% of patients who had ALS and dementia had a language variant of FTLD, more consistent with PNFA or semantic dementia.
A population-based sample of patients who had ALS estimated that 17% had frank dementia and 11% had clear aphasia , whereas in tertiary care clinics, the prevalence of impairment meeting criteria for frank dementia has ranged from 15% to 41% . Rippon and colleagues reported dementia in 23% of their ALS cohort but used Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, which uses memory impairment as the defining feature of dementia.
In the authors’ experience, only a small subset of patients, perhaps as low as approximately 5%, presents to a multidisciplinary clinic with clear FTD. These patients differ dramatically from those who have ALSci because of vast behavioral alterations, which usually begin before motor weakness becomes apparent. Many of these patients present initially to centers that focus on cognition, and they may be underrepresented in a center focusing specifically on ALS.
In contrast to ALSci, FTD symptoms typically occur before ALS symptoms. For example, a recent study of 24 patients who had motor neuron disease–FTD (MND-FTD) showed that 58% experienced the onset of FTD more than 3 years before MND, whereas 38% reported simultaneous onset. A prospective study of patients who had ALS found that those who met criteria for a dementia exhibited cognitive or behavioral decline an average of 7 years and 7 months before motor symptoms .
Although the incidence of clinical or EMG abnormalities suggestive of motor neuron disease within an FTD clinic was approximately 15% , no clear reports exist of patients in ALS centers developing frank FTD during the course of motor degeneration. Some experts hypothesize that patients who have ALS die before cognitive or behavioral impairments become apparent, in contrast to patients who develop FTD and have years to develop ALS. The loss of speech and movement in ALS may also mask the cognitive and behavioral degradation if it occurs. An alternative explanation would be that patients who have typical ALS rarely develop FTD.
Reports have suggested that FTD reflects one end of a disease continuum, with ALSci as the more benign, initial manifestation. However, the argument is difficult to support when considering temporal data. Prospective studies have failed to detect significant progression of ALSci over time . Only Robinson and colleagues reported declines in cognitive test scores, defined by a 1 SD change, but they did not specify whether performances declined to levels consistent with clinical impairment (ie, below the fifth percentile).
Strong and colleagues documented cognitive changes over 6 months in a small cohort of patients who had bulbar-onset but experienced no progression to typical FTD. In contrast, patients who present to ALS clinics with frank FTD show clear progression of dementia along with motor decline. A report by Moretti and colleagues found that among a cohort of patients documented at baseline to have varying degrees of cognitive and behavioral impairment, progression was only evident in those initially diagnosed with FTD.
Behavioral changes in amyotrophic lateral sclerosis
The term ALSbi describes behavioral impairment that does not meet diagnostic criteria for FTD, yet reflects a mood-independent change since ALS onset. Estimates of the prevalence of ALSbi vary depending on methodology and diagnostic criteria.
One feature consistent across several studies is the presence of marked apathy that can occur despite whether significant cognitive impairments are present ( Fig. 1 ) . One multicenter study found abnormal levels of apathy in 55% of patients who had ALS . The apathy correlated with deficits in verbal fluency but not depression, disease duration, forced vital capacity, or ALS-FRS scores. Similar to cognitive impairment in ALS, no current evidence shows that ALSbi progresses to ALS-FTD or that it is part of a continuum. However, disinhibition, which is a common feature in FTD, is not seen with high frequency as a behavioral manifestation of ALS.
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