Progressive Non-fluent Aphasia 진행성 비유창성 언어장애 Language Issues Profiles Treatment Possibilities Video Clip 이화여대 신경과 정 지 향 Jee H. Jeong M.D. jjeong@ewha.ac.kr 환자는 몇 명 보지 못했지만, FTD특히 dementia환자에서의 언어부분에 관심을 보여서 강의를 하게 되었다고 생각합니다.

Background Phonemic-Semantic language Loop Phonetics (음성) – Phonemics (음소) Language - Speech (Dysarthria-AOS) Bilateral anterior temporal- -superior temporal- Lt inferior parietal- -Rt inferior frontal Lt inferior frontal-Left inferior parietal- anterior cingulate -posterior temporal, 각 언어의 문법이 모여서 하나의 문장을 구성할 때 사용되는 것을 통어법 Semantic Processing Phonologic Processing

Background Primary Progressive Non-fluent Aphasia or Progressive aphasia (Core Diagnostic Features Neary Criteria) Insidious onset and gradual progression Non-fluent spontaneous speech with at least one of the following :Agrammatism, phonemic paraphasia, anomic aphasia 서서히 발병해서 점차 진행하는 특징적인 어어장애 (유창성 저하, PNFA, FTD

Background ? ? Neary’s FTLD FTD PNFA or PA SD Mesulam’s PPA PNFA, FTD Grossman J Cog Neuro, 1996 SD Hodges Neuropsycho Soc, 1996 Neary’s FTLD ? ? Mesulam’s PPA Annals Neurol, 1982 PNFA, FTD

PPA with intact semantics Background Gorno-Tempini, Annals Neurol 2004 Neary’s FTLD PNFA or PA SD Logopenic Variant ? Progressive aphemia Or anarthria? PNFA SD Progressive aphemia는 not language disorder, but more of speech disorder, comprehension과 writing은 완전 정상, speech는 nonfluent하면서 phonemic error를 동반한단 PPA with intact semantics Mesulam’s PPA Cohen, J Neurol Neurosurg Psychiatry, 1993 Mesulam, Annals Neurol 2003

Speech & Language of PNFA Initial : subjective decreased Fluency, hesistancy, word finding difficulty(anomic aphasia) Progresses: objective decreased fluency, phonemic type aphasia, agrammatism, stuttering, repetition failure but Comprehension relatively preserved especially in single word comprehension Terminally: Apraxia of Speech (AOS), Mutism PNFA, FTD

Phonemic Aphasia(음운성 언어장애) Language of PNFA Phonemic Aphasia(음운성 언어장애) 음운성 착어증 (phonemic paraphasia) 예) 말할 때 음소(phoneme)가 치환되는 자전거  ‘ 차전거’ 2. 음운성 착독증 (phonemic paralexia) 예) 읽기 상에서 ‘하늘이 맑습니다’ ‘ 차늘이’ 음운성 착서증 (phonemic paragraphia) 예) 쓰기에서도 철자법의 장애 ‘날씨가 좋다’ ‘날씨가 좆차’ Agrammatism(문법적 오류) 1. 관사, 조동사, 전치사 등의 문법적 어휘 사용의 장애 2. 복잡한 문법을 사용한 문장의 이해 장애 PNFA, FTD

Anomic Aphasia (이름대기장애) Language of PNFA Anomic Aphasia (이름대기장애) Word Production Anomia B Word Selection Anomia Semantic Anomia Disconnection Anomia Word production anomia : broca’s area를 포함한 perisylvian area, supplementary motor area, premotor area PNFA, FTD

Apraxia of Speech (AOS) Speech of PNFA Apraxia of Speech (AOS) Deficit in articulatory planning resulting in an inability to command speech musculature to produce sounding 1 2 3 4 Diagnostic Clue Effortful, trial error articulation Difficulty on initial phonemes Dysprosody (음율장애) Inconsistency on repeated word AOS는 laguage dsr가 아니라, speech disorder중 하나로서 dysarhtira와 양대 산만 Effortful, trial error articulation, attemps for self correction Speech movement를 coordinate하는덴,ㄴ 장애가 생기나, speech sound perceive하는 것에는 장애가 없는 것 퍼터커, 논논밭논밭길, 돼지저금통, 같은 단어를 5번 반복하여 나타나는 Disorders in the programming the speech musculature to produce the correct sounds of words in the proper sequence with the appropriate timin Stroke후에 발생한 44명의 환자중 AOS가 있는 군과 없는 군의 CT와 MRI를 이용한 computer reconstruction과 focal overlapping을 이용하여 N. Dronker, Nature 1996 PNFA, FTD

Mutism ‘Mutism’ refers to absence articulatory movement in ‘speech’ Speech of PNFA Mutism ‘Mutism’ refers to absence articulatory movement in ‘speech’ Due to severe dysarthria or apraxia of speech (AOS), laryngeal obstruction, akinetic mutism, parkinson’s disease as a relentless progression of non-fluent nature of the speech Broca’s area/ inferior rolandic region / left insular gyrus Mutism, Guerzon

Demographics UCSF, UCLA, Munich, 2004 2002sus snowden의 보고에 의하면 20% 의 presenile dementia FTD에 대한 demographic data는 많지 않음. London의 교외지역에서 진행한 early onset dementia에 대한 data보고가 있고, 2004년도 frontotemporal dementia학화에서 UCSF, UCLA, Munich,에서 합동으로 조사한 353명의 FTLD환자에서는 전체 230명의 hospital based cohort에서 AD가 65.1%, FTD 42 일본ㅇ서도 IKEDA등이 FTD and SD 는 male predominance but PNFA 는 female predominance Community based, LONDON UCSF, UCLA, Munich, 2004 FTD Conference, Poster Total :353 Ikeda et al. Dement Geriatr Cogn Disord. 2004;17(4):265-8. Review PNFA, FTD

Neurologic & Behavior Neurologic Findings buccofacial or oral apraxia progressive bulbar symptom or pyramidal symptoms similar to MND asymetric EPS/ or ideomotor apraxia in Corticobasal degeneration(CBD) Behavioral Findings eventual development of behavioral symptom as FTD - Neuropsychological Finding absence of severe amnesia or perceptuo-spatial disorder mild frontal executive dysfunction PNFA, FTD

Imaging MRI, VBM : atrophy on Left perisylvian Anterior insular, inferior frontal Gorno-Tempini Annals Neuro 2004 Anterior insular Hodges, Brain 2003 Superior temporal, inferior parietal atrophy 2. Functional MRI Imaging Compensatory Neural activity: additional activation in fusiform, precentral, intra-parietal Hodges, Brain 2003 Mesulam, PPA andLanguage Network Annals of Neurology, 2003

“Microglial Activation PET” Lab Finding Possible biological Marker? CSF tau, Molecular Imaging EEG findings? Normal vs Subtle slowing in fronto-temporal? “Microglial Activation PET” Amyloid Plaque PET Tau Imaging? Figure 3. FDG-PET (upper lane; dimensions mean arbitrary units) and [11C]PK 11195-PET (lower lane; dimensions mean binding potential, defined as Bmax/kD) demonstrating glucose hypometabolism and retention of [11C]PK 11195 in the basal ganglia, the right lateral part of the brainstem, and both right parietal and temporal cortical areas. PNFA, FTD

Neuropathology Boeve et al, 2002 Mesulam et al, 2001 PNFA, FTD

In DLDH (Dementia Lacking Distinct Histology) Neuron loss --*superficial layers Astrocytosis / Gliosis spongiform change No pick bodies, No ballooned neurons, No AD- related pathology, No lewy bodies Minimal to no gross atrophy in F or T lobes Neuron loss *superficial layers Astrocytosis / Gliosis spongiform change Absence of Pick bodies, ballooned neurons, AD-related pathology, Lewy bodies Astrocytosis GFAP antibody stains glial fibrillary acidic protein present most astrocytes. GFAP is upregulated in response to many kinds of CNS injury. The glial fibrillary acidic protein (GFAP) is an intermediate filament protein found almost exclusively in astrocytes. It is expressed throughout postnatal life and is upregulated in response to almost any damage to the central nervous system,including Parkinson's disease. Increased number (proliferation) and size (hypertrophy) Degeneration Slimer, small cell bodies Gfap – glia: microglia and astrocytes – microglisis: when activated, express proteins on membrane when busy, if resting, no proteins on surface (very small when healthy) start phagocytosis and make protein on membrane to ask for help – cell bodies swell, process shorten and get fatter, change in morphology (lectin histochemistry) H&E for gliosis – can[t tell if micros or astros. / activated microglial – use lectin and morphology or immuno for active proteins – HLA-DR protines (human luekocyte anitgen D ) GFAP staining PNFA, FTD

In Pick’s Disease Pick Bodies Sevier Munger silver stain Round, intracellular inclusion Argyrophilic (bind with silver) Composed of numerous fibrils Hyperphosphylated tau Phosphorylated neurofilament Ubiquitin Temporal and/or frontal lobe atrophy Usually left hemisphereLess dense in T & F cortex (layers I/II > V/VI) Especially perisylvian Hippocampus (common and severe) Neuron loss Pick bodies (+/-) ballooned neurons (+/-) gliosis Numerous paired and twisted fibrils Most dense in medial Temporal (CA1, I and V/VI of EC, DG) PNFA, FTD Tsuchiya et al., 2001 Acta Neuropath.

Vacuolization in layers In CBD Ballooned Neurons Vacuolization in layers Astrocytic Plaques- tau staining in astrocytic process results in ‘Crown of Thorns:가시면류관’ only in the cortical gray matter. Tau staining is restricted to the distal portions of the astrocytic processes, resulting in ‘crown of thorns’. Mimura et al., 2001 J Neurol. Sciences PNFA, FTD

Treatment Trial of Bromocriptine Reed et al, Annals Neurol 2004 Improvement only in Mean Length of Utterance Naming, word fluency, narrative language Mean length of utterance, proportion of grammatical sentences, nouns to verbs, open-class to closed-class word Double blind, placebo-controlled cross over design 6 subject : 66. 8 yrs Group A Proportion of grammatical sentence, 1.25 mg ->1.25 mg EOD until 7.5mg tid Maintenance 7 weeks after maximum dose Group B Washout Period PNFA, FTD

Treatment 2. Intensive training on Phonologic Skills Louis et al, Brain Cogn. 2001 2. Intensive training on Phonologic Skills - Training of 15-20 minute of 3 patient - Syllables and phonemic segmentation & discrimination - Improvement in fluency, repetition & reading PNFA, FTD 1. Focused therapy 2. Brain Plasticity 3. Emphasizes the phonologic loop processing B W P Importance Importance of focused therapy Language impairment in Neurodegenerative disease Audio CD와 high fidelity headphone을 이용, acoustic modification 을 42일간 시행 Phonemic paraphasia가 감소 Odd one out mode Facilitation과 speech시에 빠르게 변형되는 transitional elelment를 정확하게 인지할 수 있게끔, speech signal을 166% 이상 느리게 만들어서 auditory perception

Issues in PNFA Open yours eyes! Complex Clinical Syndrome with different neuropathologic findings Single Word Comprehension test is important Serial Follow-up is needed to confirm any neurodegenerative disease progression – possible benefit from MoIecular Imaging Speech therapy might influence QoL

M / 68 Left onset akinetic rigid syndrome 04’ Left hand approach behavior, intermanual conflict, Alien hand 05’ Right hand ideomotor apraxia, dressing apraxia 05’ Subjective decreased fluency, stuttering, anomia No Apraxia of Speech 환자는 몇 명 보지 못했지만, FTD특히 dementia환자에서의 언어부분에 관심을 보여서 강의를 하게되었다고 생각합니다. 진단 ? 언어장애가 있는지?

이화여대 신경과 정 지 향 Jee H. Jeong jjeong@ewha.ac.kr 경청해 주셔서 감사합니다. 환자는 몇 명 보지 못했지만, FTD특히 dementia환자에서의 언어부분에 관심을 보여서 강의를 하게되었다고 생각합니다. 이화여대 신경과 정 지 향 Jee H. Jeong jjeong@ewha.ac.kr