Understanding a New Clinical Syndrome Motor Speech Conference Antwerp University Hospital October 24 2019 Joseph R Duffy PhD BCNCD Mayo Clinic Rochester MN Core Research Team KA Josephs PI ID: 908031
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Primary Progressive Apraxia of Speech:Understanding a New Clinical Syndrome
Motor Speech ConferenceAntwerp University HospitalOctober 24, 2019Joseph R. Duffy, Ph.D., BC-NCDMayo Clinic Rochester, MN
Slide2Core Research TeamK.A. Josephs (PI) - neurologyJ.L Whitwell (PI) - neuroimagingJ.R. Duffy, E.A. Strand, H.C. Clark, R. Utianski – speech-language pathologyM.M. Machulda – neuropsychologyS. Boland – Research coordinator
Numerous speech pathology & neuropsychology Fellows, & neurology residents & Fellows
Slide3Why important?Window on brain’s control of speech Under-recognized & often misdiagnosed, with effects on appropriate careDevastating disorder - robs ability to speak & precursor to more widespread problems Predicts pathology – early recognition may someday lead to effective medical therapy
Affected people can be helped
Slide4Overview PreambleA few things about normal speechA few things about speech & neurodegenerative diseasePrimary progressive apraxia of speech (PPAOS) Relationship to primary progressive aphasia (PPA)DemographicsClinical features (with examples)Neuroimaging correlatesEvolution Underlying pathology
Possible disease mechanismManagement
Slide5The “Miracle”The brain-body achievement of speech relies on a crucial neurologic act :“speech programming” interface between language formulation & motor speech execution organizes &
packages complex movement instructions that direct actions of muscles & structures that must move to produce speech
Slide6A Basic Definition Apraxia of Speech (AOS)Impaired capacity to plan/program sensorimotor commands that direct movements for speechLike aphasia, usually associated with left hemisphere lesions
Current consensus - both articulatory & prosodic abnormalities are primary features (Ballard et al., 2015)Keep in mind for later!
Slide7A few facts Stroke-induced AOS is source of most of what we know about acquired AOSPure AOS (i.e., without aphasia) rare in strokeClinical features associated with anatomic damage in a vascular distribution
Slide8Basic Definitions (cont.)Progressive Apraxia of Speech (PAOS)AOS of insidious onset & gradual progression due to a neurodegenerative conditionFrequently associated with aphasia &/or dysarthriaPrimary Progressive AOS (PPAOS)
PAOS in which AOS is first, only, or most salient feature of neurodegenerative disease & in which criteria are not met for diagnosis of another neurodegenerative disease (e.g., progressive supranuclear palsy syndrome, corticobasal syndrome)
Slide9PAOS & PPAOS: An evolving conceptHistorically, its existence largely ignoredBut…………… It may have been hiding!!!
Slide10Where Has It Been Hiding?Misdiagnosis (a few examples)Psychological (e.g., stress, conversion disorder) StrokeALS Alzheimer’s disease
Or maybe in plain sightPrimary progressive aphasia (PPA)
Slide11Retrospective study - 80 patients with AOS associated with presumed neurodegenerative disease seen between 1985-2004 AOS never less severe than any aphasia that might have been present
Slide12Initial symptomsSpeech-language only = 80% Symptoms present @ initial eval. Speech-language only = 56%Duration @ initial eval. = 29 monthsRange = 5-78 (SD = 17)
Slide13Co-occurrence with Aphasia & Dysarthria AOS only = 9% AOS + aphasia = 31%AOS + dysarthria = 26%AOS + both aphasia & dysarthria = 34%AOS > aphasia = 78%AOS > dysarthria = 71%
Slide14Hiding? – PPA Consensus Criteria, Neurology, 2011
Slide15PPA VariantsSemantic – motor speech sparedLogopenic – motor speech largely spared; phonologic errors often present Agrammatic
Slide16Nonfluent/agrammatic variant PPAClinical Diagnostic FeaturesCore features (at least 1 must be present)Agrammatic in language productionEffortful/halting speech (AOS)Additional features (at least 2 of 3)Impaired comprehension of syntactically complex sentencesSpared single word comprehensionSpared object knowledge
Slide17AOS & the agrammatic variant PPA (agPPA)AOS probably occurs in a majority-to-substantial majority (Duffy, Strand & Josephs, 2015)Median prevalence across a number of studies (162 cases) = 78% (range = 17-100%)Frequency in case series, & severity in individual cases, sometimes exceeds that of aphasiaCrudely estimated prevalence = 4.4 per 100,000 (Whitwell et al., 2015)
Slide18PAOS, PPAOS & agrammatic variant PPAMayo Clinic PPA/PPAOS cohort (N=174)85% with agPPA had AOSIn 65% AOS > aphasia18% (N=31) of entire cohort had PPAOS
Slide19So…PAOS/PPAOS probably not as uncommon as literature implies As a prominent problem May account for ~ 20% of all types of higher level progressive speech & language disorders Wicklund et al. (2014)
Slide20What Have We Learned?
Slide21Basic Demographics - PPAOSAge at onset: late 60s - early 70s (range = late 40s-early 80s) Gender: possibly more frequent in women (~50-70%)
Education: ~ 15 years (10-20 years)Initial presentation @ tertiary care setting: 2-3 years
Slide22PPAOS: Most frequent speech features Slow overall speech rateLengthened segments between words Sound distortionsIncreased sound distortions or distorted sound substitutions as utterance length or complexity increase
Syllable segmentation within multisyllabic words Josephs et al. (2012)
Slide23Accompanying deficits @ initial evaluation There may be no language or other cognitive deficits early in course
Slide24Accompanying Deficits @ initial evaluation
(cont.)NVOA: ~ 50% of cases at initial evaluation % increases with disease progressionProbably more frequent when aphasia is also present (80-90%)Dysarthria: Present in ~ one-third increased frequency with disease progressionmost often spastic > hypokinetic, or mixed spastic-hypokinetic (D
uffy, Strand & Josephs, 2015)Dysphagia: Not usually evident unless dysarthria also present
Slide25Accompanying deficits @ initial evaluation (cont.)Neuropsychological & neurobehavioral deficits typically absent early in disease course
Motor, cognitive &/or behavioral signs usually emerge over time, as expected in many neurodegenerative disorders Josephs et al. (2012)
Slide26Acoustic Correlates
Slide27Duffy et al. (2017)
Slide28Acoustic Correlates - PVI
“Catastrophe”
Slide29Subtypes of PAOS/PPAOS?Preliminary evidence (Josephs et al., 2013) Type 1 – Predominated by articulatory/phonetic abnormalities (e.g., distortions & distorted substitutions, repeated sounds, attempts at self-correction) More often evident when aphasia present & > AOS
Type 2 – Predominated by prosodic abnormalities (e.g., slow rate, segmentation of words & syllables) More often evident in PPAOS w/o aphasia or when AOS > aphasia Type 3 – No clear difference in prominence of articulatory versus prosodic abnormalities
Slide30Articulatory versus Prosodic subtypes(syllable rate vs % articulatory errors)
Prosodic dominant Phonetic dominant
Slide31Neuroimaging Correlates
Slide32Josephs, Duffy, Strand, et al. Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech, Brain, 2012.12 people with PPAOS (1.5 – 6 years duration)No aphasia (e.g., WAB AQ = 94-100) 2 with spastic dysarthria < AOSImagingvoxel-based morphometry (grey matter)diffusion tensor imaging (white matter)FDG positron emission tomography (FDG-PET) (metabolism)
Slide33Primary Neuroanatomic Correlates (voxel based morphometry, diffusion tensor imaging, PET) Grey matter - Superior lateral premotor cortex & supplementary motor areaWhite matter – Same as grey matter + inferior premotor cortex & body of corpus callosum &
superior longitudinal fasciculus, esp. premotor componentsPrimary CompositeL > R Superior lateral premotor cortex & SMA Josephs, Duffy, Strand, et al., Brain, 2012
Slide34Josephs et al (2012)
N = 12
Slide35FDG-PET – individual data(Josephs et al., 2012)
Slide36Josephs et al. Syndromes dominated by apraxia of speech show distinct characteristics from agrammatic PPA, Neurology, 2013;81:1-9
N = 18
N = 10
N = 9
Slide37Type 1 (Articulatory predominant) vsType 2 (Prosodic predominant)(unpublished)
N = 10N = 10
Slide38Progression of PPAOS The AOSOther emerging clinical problemsNeuroimagingHistopathology
Slide39PPAOS - Progression
Years Post Onset
Slide40PPAOS - Progression
Years Post Onset
Slide41Progression – OA Motor Speech Severity
Years Post Onset
Slide42PPAOS - Progression
Years post onset
Slide43Disease Course:Other Emerging Clinical ProblemsN = 13 with PPAOS @ initial evaluationInitial eval ~ 4 years post onsetf/u at ~ 7 years post onsetNone developed features of Alzheimer’s diseaseAll developed extrapyramidal (parkinsonian) symptomsIn 8/13 (62%), AOS remained predominant problem 5/13 (38%) evolved to severe PSP-like syndrome
severe parkinsonism, dysphagia, vertical supranuclear gaze palsy, urinary incontinence, balance difficulty with falls, & limb apraxia, near mutismConclusion: Some will rapidly evolve by ~ 5 years to devastating PSP-like syndrome, while others retain PPAOS diagnosis, but with mild parkinsonism, at ~7 years Josephs et al.(2014)
Slide44Disease Course:Other Emerging Clinical Problems (cont.)Some patients evolve to a corticobasal (CBD)-like syndrome (CBS) with asymmetric rigidity, limb apraxia, & other extrapyramidal featuresCBS more likely in PAOS when aphasia is present & predominates______________________________________________Note:AOS (& aphasia) not uncommon in “typical” CBS
AOS (& aphasia) very uncommon in people with “typical” PSPAOS very infrequently may be evident & possibly worse than dysarthria in ALS/motor neuron disease (Duffy, Peach, & Strand, 2007)
Slide45Disease Course: Neuroimaging
Slide46FDG-PET
Josephs et al., Brain, 2014
Slide47Disease Course: NeuroimagingTensor Based Morphometry (N=13)
Baseline
Follow up
Josephs et al., Brain (2014
)
Slide48Underlying Pathology/Histochemistry Autopsy data thus far suggest:PPAOS very consistently associated with tau biochemistry (4-repeat tauopathy)
progressive supranuclear palsy or corticobasal degeneration In PAOS, when agPPA present & AOS = or > nonfluent aphasiaPredicts PSP or CBS pathology in ~ 90%PSP or CBD (tauopathy) possible in PPA (with no or less severe AOS), but not common (<20%)Findings suggest PAOS/PPAOS, agPPA, CBS, & PSPS may represent different points on a single disease spectrum (Josephs & Duffy, 2008)
Slide49Underlying Disease Mechanism of Action?Network Degeneration HypothesisNeurodegenerative diseases are not diffuse or randomAnatomic spread of disease relates to some structural, metabolic, or physiological aspect of neural network biology Overarching hypothesisLarge-scale functional networks provide anatomic scaffoldings that are dismantled to produce clinically recognizable syndromes
i.e., the disease migrates through a functional network(s) (Seeley et al., 2009) Seeley et al. (2009)
Slide50Network Degeneration - EvidenceExperimental evidence (in vivo & in vitro) demonstrates neuron-to-neuron propagation of tau aggregates
Clavaguera et al., 2015
Slide51Network Degeneration - EvidenceNeuroimaging has shown several neurodegenerative syndromes cause circumscribed atrophy within functional connectivity networks Spatial/anatomic disease progression reflects healthy brain’s intrinsic functional network architectureEvidence for this in agrammatic/nonfluent PPA! (Mandelli et al., 2016)
Any reason to believe this may not be at work in PPAOS?i.e. onset & migration of disease within & through the motor speech planning/programming network Clavaguera et al., 2015
Slide52PPAOS thus… Provides opportunity to study slow dissolution of programming, with insights into the nature of AOS in generalrelative vulnerability to disease of speech units (e.g., phonemes, syllables, metrical units)speech flow (e.g., rate, prosody) ways in which speech programming mechanism responds - from neuroplasticity perspective - to gradual loss of its integrity
Slide53Relative to stroke-induced AOS, PAOS/PPAOS doesn’t follow vascular distribution & is progressive. This suggests: Some clinical manifestations may differ between themComponents of motor programming network that break down, or are preserved, may differ (in some ways) between them
Slide54And… Because PPAOSAppears to predict underlying pathologyMay reflect erosion of a functional network May have clinical subtypes (Articulatory vs Prosodic) that presumably reflect breakdowns at different stages of motor programming ……………………………………
Slide55PPAOS thus has… (cont.)Implications for models of speech motor control (e.g., GODIVA)For example:Functional network spread in PPAOS may help better define anatomic boundaries of network models Possibility of subtypes suggests articulatory/phonetic aspects of speech production
can be dissociated from prosodic aspects of speech production within healthy & diseased speech motor control networks Models may need to account for that possibility
Slide56ManagementMedical Treatment – Currently, no effective medical treatmentIf data re prediction of underlying tau pathology hold up, early ID may be crucial for early intervention with disease modifying (pharmacologic) therapies, when they become available.
Behavioral Therapies Many affected people with PAOS/PPAOS may be appropriate candidates for some form of therapyDecision making regarding whether to treat probably very similar to that for other neurodegenerative speech problems (dysarthrias) or PPA
Slide57Behavioral speech therapy most appropriate when…Treatment is desired by patientSufficient insight, motivation, & capacity for learning & carryoverFunctional communication is present or possibleClear recognition that tx will not reverse progression, but may help maintain or enhance communication ability
Significant others are motivated & involvedto enhance awareness of successful strategies & to practice with patient when appropriate
Slide58Treatment Efficacy Data?Very LimitedCurrently, we are mostly reliant on:Efficacy data regarding tx for AOS
independent of etiology (but mostly stroke-caused)Expert opinion regarding management for neurodegenerative communication disorders in general
Slide59Staging Management -Doing the right things at the right timesTX may be unnecessary/inappropriate at a point in time but…Prescheduled or as-needed reassessment at regular intervals to update recommendations & provide brief intervals of tx as neededChanges during staging often anticipate increasing needs for compensation & adoption of AACAdaptations should be in place & used with skill BEFORE they are actually needed! Consider current or future influence of aphasia & limb motor & visual problems
Slide60Speaker-oriented therapy for AOSSystematic reviews - weight of evidence supports strong treatment effects for:Articulatory-kinematic approachesRate/rhythm approaches In spite of neurodegenerative nature of PAOS/PPAOS, such therapies could be justified for some affected individuals
Slide61Specific task considerations - examples(face validity, frequently used, some + evidence)Daily reading aloud, usually with primary focus on accurate (intelligible) speech (Structured oral reading; Henry et al., 2013) e.g., 5 minute periods, 3-4 times dailyScript training, with primary focus on accurate (intelligible) speech
(Youmans, Youmans, & Hancock, 2011)Highly meaningful, functionally relevant; frequent rehearsal
Slide62Counseling is crucial !!!Information about the disorder what it is & what it is notPrognosisWhat can be done to help
TroubleshootingEmotional support
Slide63References & Recommended ReadingBallard, K.J., Wambaugh, J., Duffy, J.R., Layfield, C., Maas, E….& McNeil, M.R. (2015). Treatment of acquired apraxia of speech: A systematic review of intervention research between 2004 and 2012. American Journal of Speech-Language Pathology.Croot, K., Ballard, K., Leyton, C. E., & Hodges, J. R. (2012). Apraxia of speech and phonological errors in the diagnosis of nonfluent/agrammatic and logopenic variants of primary progressive aphasia. J Speech, Lang, Hearing Res, 55 (Suppl.), S1562-S1572.Duffy J. R. (2006). Apraxia of speech in degenerative neurologic disease. Aphasiology, 20, 511-527.Duffy, J.R. et al. (2017). Temporal acoustic measures distinguish primary progressive apraxia of speech from primary progressive aphasia.
Brain & Lang, 168:84-94Duffy, J. R., & Josephs, K. A. (2012). The diagnosis and understanding of apraxia of speech: why including neurodegenerative etiologies may be important. J Speech, Lang Hearing Res, 55, S1518-S1522.
Slide64References & Recommended Reading (cont.)Duffy, J. R. & McNeil, M. R. (2008). Primary progressive aphasia and apraxia of speech. In R. Chapey (Ed.), Language Intervention Strategies in Aphasia and Related Neurogenic Communication Disorders. Philadelphia: Lippincott Williams & Wilkins, 543-563 .Duffy, J. R., Peach, R. K., & Strand, E. A. (2007). Progressive apraxia of speech as a sign of motor neuron disease. American Journal of Speech-Language Pathology, 16, 198-208.Duffy, J.R., Strand, E.A., Clark, H., Machulda, M., Whitwell, J.L., & Josephs, K.A. (2015). Primary progressive apraxia of speech: clinical features, and acoustic and physiologic correlates. American Journal of Speech-Language Pathology, DOI: 10.1044/2015_AJSLP-14-0174.
Duffy, JR, Strand, EA, & Josephs, KA. (2014). Motor speech disorders associated with primary progressive aphasia. Aphasiology, DOI: 10.1080/02687038.2013.869307.
Slide65References & Recommended Reading (cont.)Gorno-Tempini, M. L., Hillis, A. E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S. F.,…Grossman, M. (2011). Classification of primary progressive aphasia and its variants. Neurology, 15, 1006-1014.Henry, M. L., Meese, M. V., Truong, S., Babiak, M. C., Miller, B. L., & Gorno-Tempini, M. L. (2013). Treatment for apraxia of speech in nonfluent variant primary progressive aphasia. Behavioral Neurology, 26, 77-88.Josephs, K. A., Duffy, J.R., Strand, E.A., et al. Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech, Brain, 2012.Josephs, K.A., Duffy, J.R., Strand, E.A…. & Whitwell, J.L. (2014). The evolution of primary progressive apraxia of speech,
Brain, doi:10.1093/brain/awu223.Josephs, K.A., Duffy, J.R, Strand, E.A…. & Whitwell, J.L. (2013). Syndromes dominated by apraxia of speech show distinct characteristics from agPPA. Neurology, DOI 10.1212.WNL.0b013e31829c5ede.Josephs, Duffy, Strand, Whitwell, et al., (2006). Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain, 129, 1385-1398.
Slide66References & Recommended Reading (cont.)Josephs, K.A., Duffy, J.R., Fossett, T., Strand, E.A., et al., Fluorodeoxyglucose F18 Positron Emission Tomography in Progressive Apraxia of Speech and Primary Progressive Aphasia Variants. Archives of Neurology, 67; 596-605, 2010.Josephs, K.A. & Duffy, J.R. (2008). Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy. Current Opinion in Neurology, 21:688--692. Jung Y, Duffy JR, & Josephs KA (2013). Primary progressive aphasia and apraxia of speech, Seminars in Neurology, 33:342-347.Lehman-Blake, M., Duffy J.R., Boeve, B.F., Ahlskog, J.E., & Maraganore, D.M. (2003). Speech and language disorders associated with corticobasal degeneration.
Journal of Medical Speech-Language Pathology, 11, 131-146.Utianski R.L. et al. (2018). Prosodic and phonetic subtypes of primary progressive apraxia of speech. Brain & Lang, 184: 54-65.Wambaugh, J. L., Duffy, J. R., McNeil, M. R., Robin, D. R., & Rogers, M. A. (2006). Treatment guidelines for acquired apraxia of speech: treatment descriptions and recommendations, Journal of Medical Speech-Language Pathology, 14, xxv-lxvii.
Slide67References & Recommended Reading (cont.)Whitwell, J.L., Duffy, J.R., Strand, E.A….& Josephs, K.A. (2013). Distinct regional anatomic and functional correlates of neurodegenerative apraxia of speech and aphasia: An MRI and FDG-PET study. Brain & Language, 125(3):245-252.Youmans, G. L., Youmans, S. R., & Hancock, A. B. (2011). Script training treatment for adults with apraxia of speech. American Journal of Speech-Language Pathology, 20(1), 23-37.