Clinical Phenomenology and Neuroimaging Correlates in ALS-FTD Catherine Lomen-Hoerth, MD, PhD Associate Professor of Neurology University of California, San Francisco

Clinical Features Upper motor neuron findings Slow speech Brisk gag and jaw jerk, brisk limb reflexes Spasticity Hoffman’s or Babinski signs Lower motor neuron findings Atrophy Fasciculations weakness ALS is a clinical diagnosis with a combination of progressive upper and lower motor neuron findings (see Figure 1). Upper motor neuron findings include slow speech, brisk gag and jaw jerk, brisk reflexes, spasticity, and Hoffman’s or Babinski signs. Lower motor neuron findings include atrophy, fasciculations, and weakness. Patients may also have a pure upper motor neuron syndrome, typically termed primary lateral sclerosis (PLS) when the EMG is normal and symptoms have been present for over 3 years. A pure lower motor neuron syndrome is typically termed progressive muscular atrophy (PMA) variant of ALS. Either PLS or PMA may evolve over time to ALS and have a progression typical of ALS. At other times, PLS or PMA patients may have a more slowly progressive course.

Co-morbid ALS in dementia

Survival in FTD with co-morbid ALS Hodges et al 2003 8.2yrs FTD vs. 2.4yrs ALS-FTD Roberson et al 2005 10-12yrs FTD vs. 2yrs ALS-FTD Hu et al 2009 87 patients with ALS-FTD 67 months survival if FTD symptoms first 28 months survival if ALS symptoms first 19 months if simultaneous ALS-FTD onset Roberson et. al. (45) have shown that patients with FTD and co-morbid ALS on average live only 2 years after diagnosis compared with FTD patients who live 10-12 years after diagnosis. This is in comparison to Alzheimer’s Disease where patients may live 20 years or more after the diagnosis. Similar findings were found by Hu, et. al. (46), in a cohort of 87 patients with FTD-ALS. Even with mild disease, where ALS patients have cognitive and behavioral impairments not severe enough to qualify as a diagnosis of FTD, survival is impacted. Olney (47) showed a survival difference of more than a year between patients with co-morbid disease versus ALS alone. He determined that this difference was likely due to compliance with treatment recommendations such as PEG and BiPAP, since these recommendations were followed only 1/3 of the time compared with 2/3 of the time with patients who were cognitively and behaviorally normal, as seen in table 4.

FTLD is not new in ALS Old descriptions FTLD behaviors Withdrawn due to depression Stubborn Seeking control in some area of life Anger outbursts due to frustration of ALS Denial Language problems due to dysarthria FTLD behaviors Apathetic Dis-inhibited Poor judgement Easily frustrated Quick to anger Lack of insight Language difficulty Word finding Spelling Aphasia

Prevalence of Cog/Beh Impairment Among ALS Patients 22% Lomen-Hoerth et al 2003 45% Ringholz et al 2005 27% Robinson et al 2006 30% Rippon et al 2006 48% Murphy et al 2007 25% Rusina et al 2010 As you can see, up to approximately 45% of patients demonstrate cognitive decline throughout the disease process and 15% actually meet criteria for Frontotemporal Dementia (FTD) At least half a dozen studies now show a significant percentage of pts display cognitive and behavioral changes that affect their day to day functioning. Few of these patients have what neurologists in dementia clinics would diagnose as a full blown FTD syndrome, but they do display the clinical and neuoanatomical features of a spectrum of FTD.

Standardized Neuropsychological measures used in peer reviewed studies of ALS dementia Frequency of use Exec Functioning Language Memory IQ Visuospatial Used in > 5 studies WCST; Digits Bkwds; Category fluency; Stroop Int FAS/COWAT; Written verbal fluency test; BNT NART/ AMNART; Ravens Colored Matrices; WAIS-III Used in 2-5 studies Symbol Digit Modalities Test;VSAT; Trails A&B; Design Fluency Pyramids and Palm Trees Test; Graded Naming Test Kendrick Object Learning Test; Rey Aud Verbal Learning Test; CVLT-II; RMT; Logical Memory Test Benton Judgment of Line Orientation; MfVPT; Block Design; Rey figure WCST=Wisconsin Card Sort (59); Digits Backwds=Digits Backwards subtest of the Wechsler Adult Intelligence test (60); Category fluency subtest of the DKEFS (61); Stroop Interference subtest of the Dellis-Kaplan Executive Functioning Test (61); Symbol Digit Modalities Test (62); VSAT: Verbal Serial Attention Test (63); BNT=Boston Naming Test (64); FAS/COWAT=Controlled Oral Word Association Test(65); Written Verbal Fluency Test=Abrahams(35); Category Fluency=Subtest of Dellis-Kaplan Executive Functioning Test (61); WAIS=Wechsler Adult Intelligence test (60); Trails subtest of the Dellis-Kaplan Executive Functioning Test (61); VSAT=Visual; NART=National Adult Reading Test (66); AMNART=American version of the National Adult Reading Test(67); CVLT-II=California Verbal Learning Test(68); RMT=Warrington Recognition Memory Test (69); MfVPT=Motor Free Visual Perception Test (70); Rey Complex Figure Test (71); Rey Auditory Verbal Lerning Test (72); Kendrick Object Learning Test (73); Block Desing Subtest of the WAIS(60); Design Fluency=Subest of the Dellis-Kaplan Executive Functioning Test (61); Stroop Int=Stroop Interference subtest of the Dellis-Kaplan Executive Functioning Test (61); Trails A and B Subtest of the Dellis-Kaplan Executive Functioning Test (61); Logical Memory Test=Subtest of the Wechsler Memory Scale (74); Pyramids and Palmtrees(75); Graded Naming Test(76); Ravens Colored Matrices(77); Benton Judgment of Line Orientation(78)

UCSF Full Neuropsychological Battery

Defining cognitive sub-types in ALS* Terminology Clinical Characteristics ALS – FTD ALS-bvFTD ALS patient meeting either the Neary criteria or Hodge’s criteria for FTD ALS-PNFA ALS patient meeting Neary criteria for PNFA ALS-SD ALS patient meeting Neary criteria for SD ALSbi ALS patient meeting at least 2 non-overlapping supportive diagnostic features from either the Neary criteria or Hodge’s criteria for FTD ALSci Evidence of cognitive impairment at or below the 5th percentile on at least two distinct tests of cognition that are sensitive to executive functioning *Table from Strong et al., 2009

Behavioral Criteria (ALSbi)

Incidence of FTLD in ALS AD 4% Behavior Abnormal 17% Executive Dysfunction 9% Not normal, Not FTLD 26% FTLD 22% AD 4% FTLD 22% Normal 48% Normal 48% The 26% that is not normal but also not FTD is being redefined as Executive Dysfunction (9%), Behavior Abnormalities (17%)

Brief ALS Screening Exams 5-10 Minute Exams Targeted population Strengths Weaknesses Length ALS-Cognitive Brhavioral Screen (ALS-CBS; Woolley et al 2010 ALS-specific; Public domain Specifically designed for ALS population; Some controls for dysarthria, motor weakness Early in the standardization process <10 min Montreal Cognitive Assessment (MoCA; Nasreddine et al 2005 General population; Public domain for non-commercial use Well- standardized; in common use; measures frontal lobe functioning Not specifically designed to tap ALS-specific deficits; no controls for dysarthria, motor weakness 10 min Written Fluency; Abrahams et al 2000 Specifically designed for ALS population; Controls for dysarthria, motor weakness Early stages of standardization; no behavioral component 10 min

30 Minute ALS Screening Exams Penn State Exam; Flaherty-Craig 2009 General population; Copyrighted National norms, including measure of judgment and problem solving Not specifically designed to tap ALS-specific deficits; no controls for dysarthria, motor weakness 20-30 min Addenbrook ACE-R; Mioshi et al 2006 Well- standardized; in common use; measures frontal lobe functioning 30 min UCSF Screening Exam ALS-specific; Public domain Specifically designed for ALS population; Controls for dysarthria, motor weakness; includes in- depth behavior interview Behavioral measure requires staff time to interview caregiver

UCSF Screening Battery We also use Susan Woolley’s ALS-CBS. The cognitive portion contains a variety of exec functioning tasks making up a total of 20 points and a behavioral quesionnniare with 18 questions for the caregiver.

Mimics of cognitive and behavioral impairment in ALS Depression or other underlying psych disorder Pseudobulbar affect Hypoxia or hypercapnea Educational level/baseline intellectual functioning Presence of bulbar palsy or paralysis limiting testing Advanced disease Treatable mimics of cognitive and behavioral function It is absolutely critical to exclude mimics of cognitive and behavioral dysfunction. Most mimics are treatable, and even reversible with therapy. For example, severe depression is uncommon in ALS, but when present, does improve with antidepressant therapy and/or counseling. Importantly, survival is impacted when depression, stress, or other measures of psychological distress are measured (48), because patients with ALS with high co-morbid psychological distress have greater mortality than those with low psychological distress. Screening with the depression screen of choice, such as the Beck Depression Inventory (49) or Geriatric Depression Scale (50) is important whenever there are concerns about cognitive and behavioral function. It is important to exclude and treat pseudobulbar affect (PBA)—easy laughing and crying—which is sometimes confused with depression but is a very different condition. Patients with PBA do not necessarily feel depressed but they do have trouble with excessive emotional expression that they are unable to control. The CNS LS is a common screen used to diagnosis this condition and is a simple series of 7 questions (51). Other, more in-depth measures of PBA also exist (49, 52, 53). The treatments most typically used include low dose amitriptyline or a serotonin reuptake inhibitor (SSRI). More recently the combination of dextromethorphan and quinidine, which will likely be approved by the FDA in late 2010, has demonstrated positive results in an ALS clinical trial (54). Many of the medications to treat symptoms of ALS can cause sedation and confusion such as the antispasticity medications of valium, baclofen, and zanaflex. Sleep aids and sedating antidepressants may have unwanted sedating after-effects the next day. Riluzole, which is the only FDA approved drug to slow disease progression in ALS, causes sleepiness and confusion in some patients, particularly older patients. It is recommend to reduce the dose of any potentially offending medication, and to consider a drug holiday for a week or two to see if improvement is noted. Retaining CO2 or having low oxygenation can dramatically affect both behavior and cognition (55). A sleep study or home nocturnal oximetry study is helpful to diagnose this problem. Typically BiPAP is recommended once the FVC falls below 50% predicted. Obtaining a sleep study before and after BiPAP can identify desaturations and prompt necessary changes in BiPAP settings. Testing maximal inspiratory force (MIF) during spirometry testing can help identify diaphragm weakness, which contributes to difficulty breathing at night when lying flat and can qualify a patient for BiPAP even when the FVC is still above 50% predicted. Fatigue is a difficult problem with ALS and can impact cognition and behavior if sleep is disrupted. Energy conservation and good sleep hygiene are common recommendations. Troubleshooting the underlying cause of fatigue is important, to identify sedating medications, over exertion in the setting of worsening weakness, breathing difficulties, etc. It is important to also exclude any pre-morbid condition affecting cognition or behavior such as a psychiatric condition, head injury, stroke, or other CNS condition. Once these mimics have been excluded and the problem still persists, further testing is warranted. Anxiety, hypochondria, and stress can impact test performance, and it is important that testing be given in a manner to minimize the impact of these problems as well as to accommodate patients with difficulty speaking or using their hands to write. Other diseases that mimic ALS can cause cognitive problems such as certain hereditary conditions like Tay Sachs disease, infectious conditions such as Creutzfeld-Jacob disease, and paraneoplastic syndromes due to cancer. Neuropsychological testing, neuroimaging and blood testing can help distinguish among these conditions.

Continuum of Abnormalities Chang et al, Neurology 2005

Patterns of brain atrophy in two VSM-20 clinical phenotypes: coronal T1-weighted MRI section at MNI coordinate y=14, and Freesurfer-derived cortical thickness maps in (A) a 54-year-old behavioural-variant frontotemporal dementia subject (II-8) as compared with 20 male normal control subjects (mean age 55.5) and (B) a 40-year-old pure amyotrophic lateral sclerosis subject (III-9) as compared with 25 female normal control subjects (mean age 59.8) displayed on rendered normal control MRI template. Patterns of brain atrophy in two VSM-20 clinical phenotypes: coronal T1-weighted MRI section at MNI coordinate y=14, and Freesurfer-derived cortical thickness maps in (A) a 54-year-old behavioural-variant frontotemporal dementia subject (II-8) as compared with 20 male normal control subjects (mean age 55.5) and (B) a 40-year-old pure amyotrophic lateral sclerosis subject (III-9) as compared with 25 female normal control subjects (mean age 59.8) displayed on rendered normal control MRI template. Coloured areas indicate cortical thickness reductions p<0.05 to p<0.001, uncorrected, versus controls. Boxer A L et al. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp.2009.204081 ©2010 by BMJ Publishing Group Ltd

Grey & white matter abnormalities predict neuropsychological testing Statistical Model : Neuropsych Result = lobar GM volume + lobar WM FA + lobar WM MD

Does this milder form of FTLD have clinical significance? Two hypothesis: Survival is shorter in patients with ALS-FTLD than ALS alone Compliance with treatment recommendations is significantly less in patients with ALS-FTLD than ALS alone Olney R, Murphy J, Forshew D, Garwood E, Miller B, Langmore S, Kohn M, Lomen-Hoerth C, “The effects of executive and behavioral dysfunction on the course of ALS” Neurology 2005; 65: 1774-1777.

Survival in ALS with co-morbid FTD Olney et al 2005 showed a survival difference of more than a year between patients with co-morbid disease versus ALS alone. Since the Olney publication, subsequent authors have demonstrated similar findings with a shortened survival in ALS patients with co-morbid disease for both mildly impaired and moderately impaired patients, Gordon et al 2010 Roberson et. al. (45) have shown that patients with FTD and co-morbid ALS on average live only 2 years after diagnosis compared with FTD patients who live 10-12 years after diagnosis. This is in comparison to Alzheimer’s Disease where patients may live 20 years or more after the diagnosis. Similar findings were found by Hu, et. al. (46), in a cohort of 87 patients with FTD-ALS. Even with mild disease, where ALS patients have cognitive and behavioral impairments not severe enough to qualify as a diagnosis of FTD, survival is impacted. Olney (47) showed a survival difference of more than a year between patients with co-morbid disease versus ALS alone. He determined that this difference was likely due to compliance with treatment recommendations such as PEG and BiPAP, since these recommendations were followed only 1/3 of the time compared with 2/3 of the time with patients who were cognitively and behaviorally normal, as seen in table 4.

NPPV and PEG Compliance NPPV PEG ALS-FTLD 25% 28% ALS only 62% 69% z 2.22 2.01 p (one-tail) < 0.02 < 0.03

Important Clinical Issues for ALSci and ALSbi Reduced survival rate Poor compliance (poor use of PEG, BiPap) Caregiver distress Poor safety awareness (falls, choking) Inability to manage important decisions Implications for stem cell therapy Because these patients have reduced cognitve abilities and changes in their behaviour, this often leads to reduced survival rate. The majority of patients will need a PEG Tube and Bipap, but due to poor insight, they often refuse or do not comply with instructions. Stubbornness or other behavioural traits often cause the caregiver and family much distress. Patients also have poor safety awareness which often leads to choking or falls. Along with all of this is the inability to make important decision, such as planning for financial future

Thanks to the UCSF ALS Center Clinical Team Jennifer Coggiola-Speech Pathologist Miriam Crennan-Occupational Therapist Mira Kletyman-Respiratory Therapist Andrew Lui-Physical Therapist Mary Owen-Nurse Coordinator Colleen Meier-Respiratory Therapist Virginia Santos-New Patient Coordinator Madelon Thomson-Social Worker Monica Seiber-Dietitian Research Team Claudia Villierme-Research Assistant Mitchell Luu-Medical Student Jolie Chan-Medical Student Jennifer Murphy-Neuropsychologist

Thanks to other key collaborators at UCSF Memory & Aging Center at UCSF Bruce Miller Joel Kramer Katherine Rankin Marilu Gorno-Tempini Howard Rosen Adam Boxer Neuroradiology at UCSF Roland Henry Cynthia Chin