Archives of Clinical Neuropsychology 32 (2017) 906–916 Considerations for Clinical Neuropsychological Evaluation in Amyotrophic Lateral Sclerosis Susan C. Woolley1, Beth K. Rush2,* 2 1 Sutter Paciﬁc Medical Foundation, CA, USA Mayo Clinic Florida, Department of Psychiatry and Psychology, 4500 San Pablo Road, Jacksonville, FL 32224, USA *Corresponding author at: Mayo Clinic Florida, Department of Psychiatry and Psychology, 4500 San Pablo Road, Jacksonville, FL32224, USA. E-mail address: firstname.lastname@example.org (B.K. Rush). Editorial Decision 25 August 2017; Accepted 14 September 2017 Abstract The clinical neuropsychologist has the opportunity to be uniquely involved in the evaluation and treatment of individuals with amyotrophic lateral sclerosis (ALS). We review the current literature that deﬁnes cognitive and behavioral symptoms in ALS, including current knowledge of the neuropathological and genetic underpinning for these symptoms. There are unique considerations for clinical neuropsychological evaluation and clinical research in ALS and we highlight these in this review. Speciﬁcally, we shed light on special factors that contribute to our understanding of cognitive and behavioral impairment in ALS, including co-morbid symptoms, differential diagnosis, and considerations for longitudinal tracking of phenotypes. We discuss the rationale for proposing a speciﬁc approach to such as cognitive screening, test selection, response modality consideration, and test–retest intervals. With this didactic overview, the clinical neuropsychologist has the potential to learn more about the heterogeneous presentation of motor and neuropsychological symptoms in ALS. Furthermore, the reader has the opportunity to understand what it takes to develop a valid assessment approach particularly when the phenotype of ALS remains undeﬁned in some regards. This clinical practice review sets the stage for the clinical neuropsychologist to further contribute to our clinical and scientiﬁc understanding of ALS and cognition. Keywords: Amyotrophic lateral sclerosis; neuropsychological assessment Introduction Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular disease ﬁrst described by Charcot in 1869. In the U.S., it is commonly referred to as Lou Gehrig’s disease, and throughout Europe, it is characterized as a form of motor neuron disease (MND). Deﬁned by the progressive death of motor neurons in the brain and spinal cord, initial symptoms can include muscle atrophy, weakness, fasciculations, or spasticity. Symptoms can begin unilaterally in one limb, with disease spread across the midline to other limbs. In contrast to the more common limb-onset type, bulbar-onset ALS initially impacts speech and swallowing. A third onset type, thoracic, initially impacts respiration. Approximately 6,000 people in the U.S. are diagnosed annually with ALS. In the U.S., ALS incidence is 2/100,000, with prevalence of approximately 20,000 individuals. Mean age of onset is 55 years and ranges between 40 and 70, with occasional onset in adolescence and young adulthood. ALS is slightly more predominant in men, but incidence rates are more comparable across genders in later-onset cases. The duration between symptom onset and diagnosis is approximately 12 months, and average survival time is 3 years from the time of diagnosis. Risk factors are unknown but likely reﬂect a combination of genetic and environmental factors. Only 10% of all ALS cases are familial, although new genetic mutations are being discovered with regularity. Although ALS was once considered a pure neuromuscular condition, a wide range of cognitive and behavioral changes occur in people with ALS which have important prognostic implications. Up to one-half of people with ALS demonstrate changes in cognition or behavior, with 15% meeting criteria for dementia, and speciﬁcally, frontotemporal dementia (FTD) © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: email@example.com. doi:10.1093/arclin/acx089 Advance Access publication on 28 September 2017 S.C. Woolley, B.K. Rush / Archives of Clinical Neuropsychology 32 (2017); 906–916 907 (Lomen-Hoerth et al., 2003; Ringholz et al., 2005). Region of motor disease onset does not predict who develops cognitive and behavioral impairment. The presence of FTD or executive dysfunction signiﬁcantly impacts survival, reducing mean survival time by 12 months. The presence of behavioral symptoms like severe apathy also negatively impacts survival to a significant extent (Caga et al., 2016). Cognitive and behavioral symptoms can begin prior to motor disease onset, or can develop concurrently or after motor neuron denervation. Although the behavioral variant of FTD (bvFTD) is most commonly reported in ALS, other FTD variants (e.g., semantic dementia, progressive non-ﬂuent aphasia) have been documented in ALS (M. Grossman et al., 2008). The estimated interval between the onset of FTD and the diagnosis of ALS ranges from less than 2 years to more than 7 years. Median survival from disease onset for ALS-FTD patients ranges from 2 to 3 years, which is shorter than survival rates for bvFTD without ALS (6 years on average) (Lillo, Garcin, Hornberger, Bak, & Hodges, 2010). Accurate neuropsychological evaluation directly informs symptom management, treatment decisions, education, and scientiﬁc discovery. For individuals with ALS and cognitive/behavioral impairment, neuropsychologists have the potential to make a profound impact related to determination of decisional capacity and end of life care. Neuropsychological assessment can also provide reassurance when dementia is ruled out. Because of this, accurate and informed neuropsychological assessment is crucial. Neuropathology The general neuropathology of ALS is distinctive (Saberi, Stauffer, Schulte, & Ravits, 2015). Importantly, neuropathological ﬁndings are discovered along the entire neuro-axis, including the brain, brainstem motor nuclei, cranial nerves, and spinal cord. In the spinal cord, hallmark features of disease include atrophy of the anterior horn cells, corresponding sclerosis of the spinal cord lateral columns, and even atrophy of spinal nerve endings innervating muscles. In the brain and spinal cord, Bunina bodies are present. The brain is uniquely compromised by the loss of Betz cells in motor cortex, ubiquinated cytoplasmic inclusions composed of TDP-43, atrophy in the frontal and temporal cortices, atrophy of the corticospinal tract, and generalized loss of white matter volume. Ubiquitin-positive inclusions are found in the neurons, and occasionally the glial cells, of individuals with ALS. In ALS, these inclusions are uniquely distributed in the frontal cortex, temporal cortex, hippocampus, and striatum at different stages of disease progression. Importantly, these inclusions are negative for tau, alpha-synuclein, and other markers of neurodegeneration. TDP-43 is the main component of these ubiquinated inclusions and is uniquely found in people with ALS as well as people with FTD. Although there are different neuropathological etiologies of FTD, a major portion of FTD cases are characterized by ubiquitin-positive, tau-negative inclusions (also known as Frontal Temporal Lobar Degeneration—Ubiquinated, or FTLD-U). In 2006, this discovery scientiﬁcally linked ALS and FTLD-U, leading to a new taxonomic designation now known as the TDP-43 proteinopathies (Neumann et al., 2006). Despite various nuances to the clinical presentations, TDP-43 proteinopathies commonly involve loss of nuclear TDP-43 and the formation of pathological aggregates in cytoplasm. The presence of TDP-43 inclusions is not pathognomic for ALS or FTLD-TDP-43. In fact, such inclusions can be observed in people with Alzheimer’s dementia, Lewy Body Disease, Guamanian Parkinson’s dementia complex, chronic traumatic encephalopathy, and more generalized neurodegeneration. It is quite possible that the aggregation and mis-folding of TDP-43 occurs as a natural consequence of the healthy aging process. It is the speciﬁc distribution of TDP-43 inclusions in ALS and FTLD that is relevant and linked to speciﬁc clinical presentations and clinical phenotypes. Almost 90% of ALS cases are sporadic, or non-hereditary, but at least 10% of cases are familial (fALS). The most common mutations identiﬁed in familial ALS include SOD-1 TARDP/TDP-43 mutation, FUS (5% of fALS cases), and C9ORF72 repeat expansions. In fALS cases, neuropathological changes with disease progression are somewhat distinctive. For instance, individuals with SOD-1 mutations have demonstrated greater lower motor neuron than upper motor neuron neurodegeneration. Individuals with fALS and TARDP/TDP-43 mutation appear to have a greater number of pre-inclusions than occur in sporadic cases of ALS. FUS mutation carriers account for cases of FTLD-U that are TDP-43 negative (Mackenzie et al., 2010). And ﬁnally, C9ORF72 repeat expansion carriers demonstrate TDP-43 pathology seen in other cases of ALS, but also have highly speciﬁc ubiquitin-positive, p62 positive pathology that is TDP-43 negative. This very speciﬁc neuropathological feature leads to dipeptide repeat protein generation most abundant in the cerebellum, hippocampus, and neocortex (Mackenzie, Frick, & Neumann, 2014). The cerebellar burden of pathology appears to be unique to C9ORF72 repeat expansion carriers, be they individuals with familial or sporadic ALS. 908 S.C. Woolley, B.K. Rush / Archives of Clinical Neuropsychology 32 (2017); 906–916 A Word About ALS Variants and Neuropathology ALS is a clinical diagnosis contingent upon the presence of both upper and lower motor neuron signs and symptoms. Variants of ALS, with exclusively upper or lower motor neuron involvement include primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA). PLS is characterized by the presence of upper motor neuron signs and symptoms and the absence of lower motor neuron signs and symptoms. The same neuropathological characteristics exist in PLS and ALS, but the distribution of the neuropathological burden typically differs in intensity and location. For example, whereas the greatest demyelination in ALS appears to occur in the superior frontal gyrus, the greatest demyelination in PLS appears in the corpus callosum. PMA is diagnosed when an individual demonstrates lower motor neuron signs and symptoms in the absence of upper motor signs and symptoms. Individuals with PMA that are studied at autopsy frequently present with inclusions positive for ubiquitin, TDP-43, and FUS. Despite, the fact that lower motor neuron clinical symptoms deﬁne the presentation of PMA, neuropathological studies have demonstrated degeneration in the corticospinal tract of individuals with PMA (Ince et al., 2003). Thus, ALS neuropathology has been observed in PMA, even in the absence of upper motor neuron clinical symptoms. Taken together, these data suggest that ALS, PLS, and PMA may represent different stages or pathological trajectories of the same continuum. Please note that the upcoming discussion of the cognitive and behavioral features of ALS is inclusive of cases of PLS and PMA. Cognitive/Neuropsychological Features of ALS Given the neuropathological and radiological evidence of frontal and temporal lobe pathology in ALS, it is logical to expect neuropsychological deﬁcits in this population. A recent revision of the diagnostic criteria for frontotemporal spectrum disorders in ALS was published in 2017 (Strong et al., 2017), and Table 1 presents the core criteria. These primarily focus on the detection of behavioral disorders, and executive/language impairment, however; clinical and scientiﬁc discovery is ongoing, and the diagnostic criteria recognize that other cognitive domains may be important to evaluate, with documentation of function at different stages of disease progression. The presentation of cognitive and behavioral symptoms in ALS can be very heterogeneous and the core diagnostic criteria reﬂect this. An individual with ALS can have cognitive impairment without meeting criteria for dementia (ALSci), behavioral impairment without meeting criteria for dementia (ALSbi), cognitive and behavioral impairments without meeting criteria for dementia (ALScbi), or features of ALS and dementia (ALS-FTD). Below, we describe the literature of cognitive and behavioral symptoms in ALS in detail. Executive Dysfunction Phonemic verbal ﬂuency is the hallmark of executive dysfunction in ALS, and is seen early in the disease (Abrahams et al., 2000, 2004). Fluency dysfunction in ALS correlates with dorsolateral prefrontal cortex dysfunction, may be more severe in patients with bulbar palsy, and associates with ocular abnormalities (Donaghy et al., 2009). The dysfunction remains detectable even when motor slowing and dysarthria are controlled for, and is also documented on written verbal ﬂuency measures. Multiple studies have conﬁrmed deﬁcits in phonemic ﬂuency, making this an accepted indicator of cognitive dysfunction in demented and non-demented individuals with ALS. Other executive-type deﬁcits have been reliably identiﬁed on standard assessments measuring attention monitoring and switching, working memory, cognitive ﬂexibility, and mental control (Evans et al., 2015; Ringholz et al., 2005). People with ALS may make more errors and take longer to learn new rules on the Wisconsin Card Sorting Test, for example (Lange et al., 2016). Similar impairments have been shown on other card sorting concept formation tasks such as Delis Kaplan Executive Function System Card Sorting Test (Libon et al., 2012). Individuals with ALS perform poorly compared to healthy individuals on the Iowa Gambling Task (Girardi, Macpherson, & Abrahams, 2011); the poor performance suggests that individuals with ALS either fail to learn or fail to execute an effective approach. Other ALS studies employing ecologically valid measures of executive functions demonstrate deﬁcits in reasoning and coordinating rules (Stukovnik, Zidar, Podnar, & Repovs, 2010). Impairments in social cognition are integral to the diagnosis of FTD, and recent studies of people with ALS also detect dysfunction in this domain. A meta-analysis (Beeldman et al., 2016) identiﬁed social cognition as a signiﬁcant deﬁcit within the cognitive proﬁle of ALS. A recent study of people with ALS and no dementia (Andrews, Staios, Howe, Reardon, & Fisher, 2017) detected impairments in complex facial affect recognition, affective prosody recognition, and cross-modal integration. The later deﬁcit correlated with performance on executive measures, but the majority of results were not explained by cognitive impairment, mood, or disease severity. A particular deﬁcit in processing negative facial emotions may exist S.C. Woolley, B.K. Rush / Archives of Clinical Neuropsychology 32 (2017); 906–916 909 Table 1. Revised consensus criteria for the diagnosis of frontotemporal spectrum disorders in ALS (Strong et al., 2017) Diagnosis Criteria ALS Cognitive Impairment ALSci Evidence of either executive dysfunction (including social cognition), or Abrahams et al. (2000) language dysfunction, or a combination of the two. – Executive impairment is deﬁned as: Impaired verbal (letter) ﬂuency, OR, impairment on two other non-overlapping measures of executive functions (which may include social cognition). Fluency testing must control for motor and/or speech impairments to be valid. – Language this impairment is not solely explained by verbal ﬂuency deﬁcits Presence of apathy with or without other behavioral change, Rascovsky et al. (2011) OR At least two non-overlapping supportive diagnostic features of behavioral variant FTD outlined by Rascovsky et al.: – disinhibition – loss of sympathy and empathy – perseverative, stereotyped or compulsive behavior – hyperorality/dietary change – loss of insight – psychotic symptoms (e.g. somatic delusions, hallucinations, irrational beliefs) Patients meeting criteria for both ALSci and ALSbi without meeting criteria for ALS-FTD ALS Behavioral Impairment ALSbi ALS Cognitive and Behavioral Impairment ALScbi ALS-Frontotemporal Dementia ALS-FTD FTD-MND like ALS-Parkinsonismdementia-complex Evidence of progressive deterioration of behavior and/or cognition by observation or history, AND Presence of at least 3 of the behavioral/cognitive symptoms outlined by Rascovsky et al. OR The presence of at least 2 of those behavioral/cognitive symptoms, together with loss of insight and/or psychotic symptoms OR The presence of language impairment meeting criteria for semantic dementia/semantic variant PPA or non-ﬂuent variant A neuropathological diagnosis in which FTLD is the primary diagnosis and concomitant neuropathological evidence of motor neuron degeneration, but insufﬁcient to be classiﬁed as ALS ALS concurrent with dementia and/or Parkinsonism occurring in hyperendemic foci of the Western Paciﬁc Key references “Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups” (1994) Rascovsky et al. (2011) Gorno-Tempini et al. (2011) (Palmieri et al., 2010) which may be speciﬁc to individuals with ALS-FTD but not those with ALS and no dementia (Savage et al., 2014). Studies using the Judgment of Preference Task (Girardi et al., 2011) demonstrate difﬁculty interpreting the eye gaze direction of others. Similar impairments are observed on tests evaluating Theory of Mind. In one study, approximately 30% of people with ALS but no dementia were impaired at detecting a faux pas (Meier, Charleston, & Tippett, 2010). Insight has been infrequently studied, but preliminary evidence suggests that, as a group, non-demented people with ALS retain insight into cognitive and behavioral changes, in contrast to people with ALS-FTD who demonstrate profound lack of awareness (Woolley, Moore, & Katz, 2010). Language Language deﬁcits have received less attention until recently, despite early studies which detected a correlation between cognitive impairment and clinical measures of word-ﬁnding and phrase-length (Ringholz et al., 2005). The clinical relevance of language deﬁcits in ALS has been minimized due to the perceived confounds of dysarthria, respiratory insufﬁciency, and motor dysfunction. However, language dysfunction is at least as common as executive dysfunction in ALS, and can co-occur with executive deﬁcits or exist independently (Taylor et al., 2013). An estimated 35–40% of people with ALS demonstrate clinically signiﬁcant language dysfunction (Taylor et al., 2013). Syntactic processing deﬁcits may be a predominant feature of language dysfunction in ALS (Tsermentseli et al., 2015). Verb naming and action verb processing deﬁcits are consistently documented (Bak, O’Donovan, Xuereb, Boniface, & 910 S.C. Woolley, B.K. Rush / Archives of Clinical Neuropsychology 32 (2017); 906–916 Hodges, 2001; Papeo et al., 2015) which associate with atrophy in the dorsolateral prefrontal cortex and motor cortex (Bak et al., 2001; Grossman et al., 2008; York et al., 2014). Semantic and verbal paraphasic errors have also been detected (Roberts-South, Findlater, Strong, & Orange, 2012; Tsermentseli et al., 2015). In a study of clinical differences across FTD genotypes, 78% of patients with the ALS-FTD C9ORF72 mutation demonstrated a naming disorder, and a smaller majority displayed difﬁculty generating context-speciﬁc and relevant words within conversations (Snowden et al., 2015). Grammatical errors dissociate from motor and respiratory dysfunction and executive dysfunction, suggesting a continuum between ALS and non-ﬂuent/agrammatic primary progressive aphasia (Ash et al., 2015). Examples of grammatical errors can include incomplete utterances, omission of determiners, and verb phrase errors (Ash et al., 2015). Other language deﬁcits detected in ALS include difﬁculty establishing and staying on topic in conversation (Bambini et al., 2016), difﬁculty relaying the main topic of conversation (Ash et al., 2015), and fewer content or information words in proportion to total word production (Ash et al., 2014; Bambini et al., 2016). Deﬁcits in language comprehension are not confounded by impaired speech production, and syntactic comprehension deﬁcits are present in 28–72% of individuals with ALS (Kamminga et al., 2016; Yoshizawa et al., 2014). Memory Memory impairment in ALS typically occurs concurrently with other cognitive deﬁcits (Phukan et al., 2012), and does not appear to impact survival (Elamin et al., 2011). A 2015 meta-analysis (Beeldman et al., 2016) showed a small effect size for delayed verbal memory and executive dysfunction, with larger effect sizes for other domains (e.g., ﬂuency, language, and social cognition). Many researchers argue that executive dysfunction underlies and explains much of the variance in memory impairment (Beeldman et al., 2016; Christidi, Zalonis, Smyrnis, & Evdokimidis, 2012; Hanagasi et al., 2002; Machts et al., 2014; Mantovan et al., 2003; Massman et al., 1996). Memory deﬁcits are detected in non-demented individuals with ALS; these changes correlate with gray matter hippocampal volumes (Raaphorst et al., 2015) and cognitively impaired patients may demonstrate declines in verbal recall over time (Elamin et al., 2013). Qualitative differences in memory proﬁles distinguish people with ALS from people with Mild Cognitive Impairment—Amnestic subtype (Machts et al., 2014). A population based study (Phukan et al., 2012) suggests that Alzheimer’s disease is less common (1.9%) than FTD (13.8%), among people with ALS. The recently revised diagnostic consensus criteria do not include isolated memory impairment as a criterion for the diagnosis of ALS cognitive impairment (ALSci). Neuropsychiatric Features of ALS Depression Relatively high rates of depression are seen in neurologic diseases such as Parkinson’s disease, MS, and stroke. Naive observers assume that people diagnosed with ALS should be depressed due to the unrelenting nature of the terminal illness, but in fact, rates of clinically diagnosable depression are consistent with the general population and healthy controls (Atassi et al., 2011; Grossman, Woolley-Levine, Bradley, & Miller, 2007; Jelsone-Swain et al., 2012; Rabkin et al., 2015). Depression in ALS tends to be seen early in the disease around the time of diagnosis. Individuals who experience a longer time interval between symptom onset and ALS diagnosis are at increased risk for depression (Caga, Ramsey, Hogden, Mioshi, & Kiernan, 2015). Rabkin and colleagues (2015) cite that among individuals with late-stage ALS, 9% had symptoms consistent with major depression, and another 10% had symptoms consistent with minor depression. Depression is rare in ALS-FTD patients, assumingly due to the lack of insight and pronounced apathy. It is worth noting that caregivers may misperceive apathy in a person with ALS as a sign of severe depression. Apathy Mild behavior change predates motor dysfunction in classical ALS, but does not impact survival (Mioshi et al., 2014). Mild behavioral abnormalities can co-occur with cognitive impairment in ALS or occur in isolation (Witgert et al., 2010). The most common behavioral abnormality in ALS is apathy, which is detected in 40–80% of patients and dissociates from depression, respiratory dysfunction, and motor disease severity (Grossman et al., 2007; Lillo, Mioshi, Zoing, Kiernan, & Hodges, 2011). When apathy is severe, it serves as an independent, negative prognostic indicator. For people with ALS who have severe apathy, survival time is reduced, by an average of 15 months compared to similar patients with mild apathy (Caga et al., S.C. Woolley, B.K. Rush / Archives of Clinical Neuropsychology 32 (2017); 906–916 911 2016). In this study, depression with demoralization was not associated with degree of apathy. A diffuse-tensor imaging study detected a signiﬁcant fractional anisotropy in the right anterior cingulate which correlated with caregiver reports of apathy change, and dissociated from disease progression biomarkers in the motor cortex (Woolley, Zhang, Schuff, Weiner, & Katz, 2011). Apathy appears to be the initial symptom in ALS-FTD and may best discriminate between early ALS-FTD and classical FTD (Hsieh et al., 2016). Pseudobulbar Affect Also referred to as emotional lability, this symptom is common in ALS, particularly for those with greater bulbar involvement. Spontaneous crying or laughing episodes of pseudobulbar affect (PBA) can be difﬁcult to control and may occur without provocation. For those who are tearful, caregivers may mistakenly describe the patient as depressed. Careful questioning can help differentiate depressive symptoms from PBA. Loss of Empathy ALS caregivers report high rates of self-centeredness in ALS (Hsieh et al., 2016). This could be due to the fact that individuals with ALS do not process emotion as effectively as healthy individuals, negatively impacting social processing (Girardi et al., 2011). People with ALS also have difﬁculty inferring the mental state of others and inhibiting egocentric responses. These social and emotional deﬁcits appear to dissociate from classical executive dysfunction (Girardi et al., 2011). Emotional empathy in ALS is reduced compared to samples of neurologically healthy people, and this associated with reduced gray– white matter density in the anterior cingulate and right inferior frontal gyrus (Cerami et al., 2014). However, it has also been suggested that medial prefrontal and inferior frontal gyrus regions associate with inhibition of empathy and increased selfperspective taking (Rice & Redcay, 2015). Disinhibition Disinhibition has been documented in ALS and ALS-FTD, although to-date, it is less frequently documented than other behavioral symptoms. If present, it is most often noticed in FTD prior to ALS onset. This may be due to the fact that apathy becomes predominant over time and overwhelms any evidence of inappropriateness or lack of inhibition. Additionally, the motor disease of ALS may preclude a disinhibited person’s ability to express aberrant behavioral due to paralysis or mutism. The presence of disinhibition may also be a function of genotype. Compared to other genetically-based FTD groups, ALSFTD individuals with the ALS speciﬁc genotype (C9ORF72) presented clinically as more socially appropriate and warm than classic bvFTD individuals without ALS (Snowden et al., 2015). ALS-FTD The behavioral features of FTD are well described in current diagnostic criteria (Rascovsky et al., 2011). With an insidious onset and gradual progression, pure FTD can appear much like a psychiatric disorder with pronounced personality change, deﬁcits in social comportment, language dysfunction, and a host of behavioral deﬁcits. Certain clinical characteristics of people with ALS-FTD differ from those with classic FTD. As previously mentioned, early apathy may be a unique indicator of ALS-FTD but not pure FTD (Hsieh et al., 2016), and people with ALS-FTD may present as more socially appropriate than individuals with FTD and no ALS. Fewer dietary changes, speciﬁcally sweets preferences, occur in ALS-FTD patients with the C9ORF72 genotype (Snowden et al., 2012). Some individuals with the C9ORF72 mutations have a documented history of psychosis. Thirty-eight percentage of patients with the C9ORF72 mutation had a history of signiﬁcant psychotic symptoms pre-dating the onset of either ALS or FTD, compared to less than 4% of FTD patients without the mutation (Snowden et al., 2012). Somatoform delusions are not seen in other genetically-based FTD groups. An associated increased incidence of complex repetitive behaviors is seen in this cohort, which seems to be linked to delusional thinking. The presence of psychotic symptoms is now a feature of the current diagnostic criteria for ALS-FTD, assuming the symptoms are not better explained by a chronic psychiatric disorder. S.C. Woolley, B.K. Rush / Archives of Clinical Neuropsychology 32 (2017); 906–916 912 Table 2. Practice recommendations in ALS Objective References Test selection Strong et al. Executive function and language function impairments are the (2017) most cited impairments Woolley, York, et al. (2010) Abrahams et al. (2014) Abrahams et al. Valid assessment methodological control for motor limitations (2000) and challenges Motor symptom control Longitudinal evaluation Document genotypephenotype associations Findings Burkhardt, Rate of progression of cognitive and behavioral impairment Neuwirth and remains unknown and it is unclear the degree to which this Weber (2017) may be associated with progression of motor symptoms Gillingham et al. (2016) Strong et al. Documented genotype-phenotype associations lead to advancing (2017) scientiﬁc and clinical understanding (i.e., C9ORF72) Recommendation Screens and neuropsychological evaluations should include measures of verbal ﬂuency, behavior change, and mental ﬂexibility Screens such as the ALS-CBS and the ECAS were created speciﬁcally for use in ALS and are encouraged Include measures like Abrahams Verbal Fluency that control for motor limitations of ALS Allow written or oral responses Repeat evaluation every 6 months and compare to baseline data Document any history of MND, dementia, or cognitive disorder from the family history MND, motor neuron disease. Neuropsychological Assessment Strategy and Differential Diagnosis Neuropsychological assessment of a person with ALS requires unique consideration of several issues. These may include test selection, awareness of motor disease severity, possible modiﬁcations to standardization procedures, test-retest intervals, and limitations to data interpretation based on differential diagnosis and available normative samples. Practice recommendations related to most of these issues are highlighted in Table 2. Tests of executive function and language should be a priority in the evaluation, to include phonemic ﬂuency, semantic ﬂuency, syntax processing, spelling, mental ﬂexibility, judgment, reasoning, and inhibitory control. Although less common, some people with ALS develop amnestic features of difﬁculties with learning and retrieval as a manifestation of the cognitive impairment. A person with ALS may be unable to write or unable to speak as a function of motor symptoms. Tests must be selected knowing what response modality is possible, and with the knowledge that response modality may change over time, with symptom progression. An individual may be able to speak early in the course of illness, but become mute as a function of bulbar symptom progression in the future. If longitudinal data collection is a goal, tests that can be answered with written, pointing, and oral responses should be considered. Further, strong consideration should be given to tests such as Abrahams Written Verbal Fluency, and similar measures, which provide some form of methodological control for motor impairment in the evaluation of cognitive impairment symptoms. The person with ALS will be fatigable regardless of how symptoms evolve. Unlike stroke or brain injury populations, for which cognitive stamina can be built up with incrementally longer evaluations or interventions, the opposite is true in ALS. Evaluations and interventions must be focused and brief in administration time. ALS survival time is much shorter than survival time of a person with Mild Cognitive Impairment, Alzheimer’s dementia, Lewy Body Dementia, or even Frontal Temporal Dementia without Motor Neuron Disease. As a function of this, documenting cognitive trajectory of symptoms requires more frequent re-test intervals than the conventional 1-year follow-up that other cognitive syndromes utilize. For instance, re-testing after 6 months could be quite important. There can be tremendous change in a person’s function within 6 months, and there is great utility for the longitudinal neuropsychological evaluation to update functional recommendations for the person with ALS, as illness progresses. Prior to making any causative associations between ALS/MND and cognitive symptoms detected on neuropsychological evaluation, differential diagnosis should be considered. Speciﬁc to ALS, clinicians must rule out the possibility of a preexisting cognitive syndrome or disorder, such as prior stroke, developmental challenge, ischemic injury (secondary to oxygen desaturation or apnea), or longstanding patterns of strengths and weaknesses. Depression, adjustment to diagnosis, and adjustment to disability may be current issues for a person with ALS, and therefore, the neuropsychologist must carefully evaluate and consider the contributions of these psychological factors to the conceptualization of cognitive status. The most effective neuropsychological evaluation of the person with ALS should include behavioral observations of the person, as well as selfand informant- reports of emotional status. These data should enter into the diagnostic conceptualization of each individual to the best of the neuropsychologist’s ability. It is very important to document the presence or absence of insight in the person S.C. Woolley, B.K. Rush / Archives of Clinical Neuropsychology 32 (2017); 906–916 913 with ALS. Diminished self-awareness, or anosognosia, is importantly distinguished from psychological denial. The absence or restriction of self-awareness bears important weight on where to emphasize the focus of interventions. When selfawareness is still present to any degree, the person with ALS and cognitive/behavioral impairment can anticipate challenges in function or daily activities, and therefore interventions can be directly introduced to the person with ALS. Reduced or absent self-awareness can negatively inﬂuence symptom management, disease management, premorbid advanced directives, and team relationships. The anosognosia can also exacerbate caregiver burden. Providers working with people who have ALS should consider screening tools that have been designed speciﬁcally for use in ALS and empirically validated in samples of people with ALS. It behooves the clinician to use cognitive and behavioral screening tools speciﬁcally designed for people with ALS rather than trying to adapt existing measures to the person with ALS, particularly given the complexities of case conceptualization. In recent years, more and more cognitive screening tools have been proposed for use in ALS. At the time of this publication, the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (Abrahams, Newton, Niven, Foley, & Bak, 2014) and the ALS Cognitive Behavioral Screen (ALS-CBS) (Woolley, York, et al., 2010) have the most validation data. As such, these two screening tools are speciﬁcally referenced in the most recent diagnostic criteria for frontotemporal cognitive impairment in ALS(Strong et al., 2017). Laboratory, Radiographic, and Genetic Associations A combination of laboratory data, radiographic data, and even genetic background reveals ALS and potential cognitive and behavioral impact of symptoms in ALS. EMG, modiﬁed barium swallowing studies, pulmonary function tests, motor speech evaluations, and the neurologic exam are used to initially assess for the presence of upper motor neuron, lower motor neuron, or cranial nuclei dysfunction. Brain and spinal cord MRI studies can help also to evaluate the presence of atrophy that is characteristic to ALS. Support for an FTD diagnosis may come from MRI ﬁndings of frontal/temporal lobe atrophy, although many people with ALS cannot tolerate scanning due to the risk of aspiration, choking or respiratory distress while supine. Generally, imaging evidence is supportive but not diagnostic, and a negative scan does not rule out FTD, non-FTD dementia, ALSci, or ALSbi. Intervening and Treating the Person with ALS/MND The cognitive and behavioral challenges of ALS are manifestations of the primary neurodegenerative disease process. Interventions and treatments are focused on symptom management, education of the person with ALS and his/her family, and the identiﬁcation of compensatory aids, approaches, and strategies. As mentioned earlier, it is important to know the degree to which self-awareness is present or absent in the person with ALS. This guides the direction of any intervention or treatment. When self-awareness is present, and/or the person with ALS retains cognitive skills, he/she can make use of voicing applications on a tablet or smartphone, traditional alternative augmentative communication devices, dry erase boards, and even functional communication boards. If self-awareness is restricted or absent for the person with ALS, interventions and treatments may be focused on modifying physiological factors that contribute to the symptom, or to the environment, including caregivers, surrounding the affected person. In PBA, the FDA has approved the use of Nuedexta, a dextromethorphan-quinidine sulfate compound that attenuates disproportionate laughing, crying, or increased emotional reactivity. In situations for which excessive psychomotor agitation, fall risk, impulsive gait or transfers, or disinhibited behavior create challenge, other psychotropic medications such as low-dose SSRIs or even very low dose atypical antipsychotics can be considered. Most of the time, interventions and treatment in ALS are focused on quality of life and safety. For the person with cognitive and/or behavioral challenges, it is important to identify advanced directives as early as possible in the course of disease. Caregivers, family members, and even providers on the team should be educated about appropriate expectations for the person with ALS. 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