Clinical Phenomenology and Neuroimaging Correlates in

ALS-FTD

Catherine Lomen-Hoerth, MD, PhDAssociate 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

Co-morbid ALS in dementia

0

2

4

6

8

10

12

14

16

FTD PA SD AD CBD/PSP

normalpossible ALSdefinite ALS

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

FTLD is not new in ALS

Old descriptions Withdrawn due to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 findingSpellingAphasia

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

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

UCSF Full Neuropsychological Battery

Test Name Skill it measures Boston Naming Test-Short Form Language-Naming California Verbal Learning Test-

Short Form Verbal Memory

Design Fluency-DKEFS Executive Functioning Trails Test-DKEFS Executive Functioning

Category Fluency-DKEFS Semantic Fluency AMNART

(American version of the Adult National Reading Test)

IQ Estimate

WRAT-4 Language CA Sorting Test-DKEFS Executive Funtioning

Frontal Systems Behavioral Scale (FrSBe)

Behavioral Function

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)Neary Criteria Hodges Criteria

Decline in personal hygiene and

grooming

Mental rigidity and inflexibility

Distractibility and impersistence

Hyperorality and dietary changes

Perseverative and stereotyped behavior

Utilization behavior

Loss of insight Disinhibition

Restlessness Distractibility

Impulsiveness Social withdrawal

Reduced verbal output Poor self-care

Gluttony Apathy/loss of spontaneity

Sexual hyperactivity Lack of foresight/planning

Reduced empathy or unconcern for others

Verbal stereotypes or echolalia

Verbal or motor perseveration

Incidence of FTLD in ALS

AD 4%

Normal 48%

FTLD 22%Not normal,

Not FTLD 26%

Normal 48%

FTLD 22%

AD

4%

Behav

ior

Abnormal

17%

Executive

Dysfunction 9%

The 26% that is not normal but also not FTD is being redefined as Executive Dysfunction (9%), Behavior Abnormalities (17%)

Brief ALS Screening Exams5-10 Minute Exams Targeted

populationStrengths 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 ALS-specific; Public domain

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

General population; Copyrighted

Well- standardized; in common use; measures frontal lobe functioning

Not specifically designed to tap ALS-specific deficits; no controls for dysarthria, motor weakness

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

30 min

UCSF Screening BatteryTest Name Skill it measures

Abrahams phonemic verbal fluency or Controlled Oral Word Association Test (F,A,S)

Phonemic Verbal Fluency

Frontal Behavioral Inventory (FBI)

Behavioral Function

Neuropsychiatric Inventory-Questionnaire Version (NPI-Q)

Behavioral Function

Beck Depression Inventory-II (BDI-II)

Depression

ALS-FRS

Severity of ALS

CNS-LS

Pseudobulbar affect

PBA Questionnaire

Pseudobulbar affect

ALS-Cognitive Behavioral Screen (ALS-CBS)*

Overall cognitive function

*Susan Woolley, Ph.D. with Forbes Norris ALS clinic at California Pacific Medical Center and the WALS

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

Continuum of AbnormalitiesChang 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.

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

R Frontal L Frontal R Temporal L Temporal MMSE NS NS NS NS CVLT-SF NS NS NS NS Verbal-Fluency GV(0.31)* FA(0.41)** GV+FA(0.46)** GV+FA(0.45)** DKEFS-Trails MD(0.52)** MD(0.45)** GV(0.67)*** MD(0.36)** Boston-Naming MD(0.18)* GV(0.17)* GV(0.32)** GV(0.35)** DKEFS-Stroop MD(0.45)** GV(0.33)* GV(0.43)** GV(0.40)**

*p<0.05; **p<0.008;***p<0.001;RSQ in parenthesis

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 aloneOlney 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

NPPV and PEG ComplianceNPPV 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

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 KramerKatherine Rankin Marilu Gorno-TempiniHoward RosenAdam BoxerNeuroradiology at UCSFRoland HenryCynthia Chin