Frontotemporal Disorders: Behavioral Variant and Primary Progressive

Did you hear that? Parsing Through the Language Disorders (PPAs)

By: Ryan Townley, MD Cognitive and Behavioral Neurology Fellowship Director Co-Director of Research Education Core Assistant Professor KU Alzheimer’s Disease Center Accreditation

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• Case examples of Primary progressive aphasias (PPAs) • Frontotemporal dementia subtypes • Semantic variant primary progressive aphasia (svPPA)) • Non-fluent variant agrammatic primary progressive aphasia (nfvPPA) • Primary progressive apraxia of speech (PPAOS) • Alzheimer’s disease subtype: • Logopenic aphasia - lvPPA • Discuss treatment options (limited) • Discuss the role of involving a speech/language pathologist Clinical Puzzle #1

• 52 yo M comes in with “memory problems” for 2 years – gradually getting worse • Uses “this” and “that” to describe objects during history taking • Montreal Cognitive Assessment 25/30 (possible mild cognitive impairment) • 1/3 naming and 2/5 delayed memory • You ask him to name these animals:

He says: cat hippo camel • Sydney Naming Test = 15/30 (abnormal) • Repetition and speech motor production is normal

https://www.mocatest.org/ What brain domain is primarily affected?

• Executive function? • Processing speed? • Attention? • Motor? • Vision? • Behavioral? • Memory?

• Language? Word knowledge

https://en.wikipedia.org/wiki/Human_brain Botha, Hugo, and Keith A. Josephs. "Primary progressive aphasias and apraxia of speech." Continuum: Lifelong Learning in Neurology 25.1 (2019): 101-127. What part of language?

Note: this categorization is better suited for neurodegenerative timeline of aphasia • Grammar (agrammatic)?

• Apraxia? Right • Repetition

(logopenic)? Left • Naming (semantic)?

Hickok, Gregory, and David Poeppel. "The cortical organization of speech processing." Nature reviews neuroscience 8.5 (2007): 393. Primary Progressive Aphasia

Botha, Hugo, and Keith A. Josephs. "Primary progressive aphasias and apraxia of speech." Continuum: Lifelong Learning in Neurology 25.1 (2019): 101-127. Anatomy relates to clinical phenotype

• A-C: behavioral variant frontotemporal dementia

• D-F: semantic variant – primary progressive aphasia

• G-I: behavioral variant FTD with semantic variant PPA and prosopagnosia (face blindness)

• J-L: Non-fluent agrammatic variant of PPA (apraxia of speech)

Townley R. A., Flemming K. D., Jones L. K. (2020). Frontotemporal Dementias. Chapter 31 in Mayo Clinic Neurology Board Review. Pending final print: 2020 edition. Frontotemporal Dementia

• Clinical diagnosis • Multiple phenotypes (clinical presentations)

• Multiple neuropathologies • Multiple genes associated: FUS, GRN, c9orf72, MAPT • Note – FTLD = pathology name - frontotemporal lobar degeneration

Townley R. A., Flemming K. D., Jones L. K. (2020). Frontotemporal Dementias. Chapter 78 in Mayo Clinic Neurology Board Review. Pending final print: 2020 edition. Clinical Puzzle #2

• 65 yo M with 2 years of troubles “getting my words out” • Leaving out connecting words in text messages and speech • (Helpful to review emails or written language) • Simple fragmented sentences • Can repeat simple words • Right-hand ideomotor apraxia • Difficulties with fine motor skills • Troubles playing the piano and using a screwdriver Primary Progressive Aphasia

Botha, Hugo, and Keith A. Josephs. "Primary progressive aphasias and apraxia of speech." Continuum: Lifelong Learning in Neurology 25.1 (2019): 101-127. FDG-PET in Nonfluent Variant PPA

• Broca’s area, inferior frontal hypometabolism • Can blend with apraxia of speech cases but has more widespread frontal involvement • Asymmetric rigidity and apraxia of right hand • Caudate/thalamus involvement • Frontal executive dysfunction on testing • Significant asymmetry raises suspicion for progranulin mutation Testing for Progranulin Mutation

• If patient has a behavioral variant FTD or aphasia variant FTD and a family history of dementia (any kind of dementia) • This patient had significant symmetry on PET scan which is expected in progranulin mutations • Consider a referral for free genetic testing through our study • Alector study targeting progranulin mutations with medication

Study PI Population Overview

FTD, PPA, or Phase 3 trial, AL001 ALECTOR AL001-3 Ryan Townley, MD Asymptomatic FTD progranulin gene testing provided Clinical Puzzle #3

• 82-year-old female with 2-year history of difficulties speaking • “Difficult to get my words out” • She would often say yes when she meant no • No spelling, reading, or memory complaints • On exam: • STMS is 33/38, with no specific pattern • Language exam normal except for slowed and distorted speech • Repetition of multiple syllable words were difficult • Cat (normal) vs. catapult or catastrophe (inconsistent) • No agrammatism on Northwestern Anagram Test • Mild slowing of extraocular movements but otherwise normal neuro exam PPAOS = primary progressive apraxia of speech

“neurological speech disorder that reflects an Botha, Hugo, and Keith A. impaired capacity to plan or Josephs. "Primary progressive aphasias and apraxia of program sensorimotor speech." Continuum: Lifelong commands necessary for Learning in Neurology 25.1 (2019): 101-127. directing movements that result in phonetically and prosodically normal speech” FDG-PET Scan of PPAOS

• Note: MRI unremarkable • Focal hypometabolism of supplementary motor and dorsolateral premotor areas • Planning, producing, and monitoring speech • PPAOS is likely distinct from nonfluent agrammatic (Black/dark blue represent normal uptake; green/yellow/red represent worsening degrees of hypometabolism.) Evolution of PPAOS cases

• Almost always due to 4R tauopathy per autopsy studies • After ~ 5 years of progressive symptoms > 40% evolve to PSP/CBS syndrome

PSP: Progressive Supranuclear Palsy CBS: Corticobasal Syndrome

75yoM w/ parkinsonian sx and severe instability/falls 70 F w/ limb apraxia L>R and falls x 1 year. Also has significant Note midbrain hypometabolism apraxia of speech and upper motor neuron spastic dysarthria A word on Logopenic Aphasia

• Primary progressive aphasia syndrome secondary to Alzheimer’s disease • Internal tape recorder is gone! • Searching for words • Losing train of thought mid sentence Logopenic PPA Anatomy

• Dominant language hemisphere • The “language network” • Temporoparietal junction • RITE: “Transcortical aphasia” • Almost always due to Alzheimer’s disease pathology: • Amyloid + Tau Treatment

• SSRIs can help with anxiety increasing and further blocking speech production • Donepezil should be tried in patients with Logopenic variant • Speech therapy should be initiated • Low referral rates are an ongoing concern • If you had a patient with balance problems – you refer to physical therapy • Same should go for a patient with speech problems • Likely secondary to under recognition of speech language disorders and lack of knowledge about how a speech language pathologist can help Referral to a Speech/Language Pathologist

• Study: 78% of respondents reported that people with primary progressive aphasia experienced barriers to accessing speech and language therapy • Potential benefits for patients with PPA: • Basic communication strategies and aids • Maximize overall quality of life • Education for patients and families • Planning care needs and packages • Word relearning interventions Did We Meet Our Objectives?

• Discussed the clinical criteria for the variants of PPAs: • Frontotemporal dementia variants: • Semantic variant primary progressive aphasia (svPPA)) • Non-fluent variant agrammatic primary progressive aphasia (nfvPPA) • Primary progressive apraxia of speech (PPAOS) • Alzheimer’s disease variant: • Logopenic aphasia - lvPPA • Discussed referral for FTD progranulin study • Contact on next slide • Discussed the role of Speech/Language Pathology