Primary progressive aphasia: a clinical approach

Primary progressive aphasia: a clinical approach The primary progressive aphasias are a heterogeneous group of focal ‘language-led’ dementias that pose substantial chal- lenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experi- ence of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including ‘clinical pearls’ that we have found diagnostically useful and neuro- anatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presenta- tions not well captured by conventional classifications and propose a diagnostic ‘roadmap’. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers. Keywords Primary progressive aphasia · Semantic dementia · Logopenic aphasia · Frontotemporal dementia · Alzheimer’s disease Introduction surprising: PPA is uncommon (estimated prevalence is con- servatively around three cases per 100,000 [3, 4]), the under- The primary progressive aphasias (PPA) are a diverse group lying pathology is heterogeneous and generally inaccessible of disorders that collectively present with relatively focal and the functions principally targeted are uniquely complex. degeneration of the brain systems that govern language. Although patients with PPA have been described for well Despite much recent attention in the scientific literature [ 1, over a century [5], the true significance of these disorders 2], these ‘language-led dementias’ remain daunting for even was only appreciated quite recently [6, 7] and the paradigm experienced clinicians to diagnose and manage. This is not of selective brain network degeneration caused by patho- genic protein spread has transformed our understanding of neurodegenerative disease [8]. While challenging, accurate Charles R. Marshall and Chris J. D. Hardy contributed equally to clinical diagnosis of PPA is worth striving for: these patients the work. are often affected in late middle life, with devastating impli - Electronic supplementary material The online version of this cations for family life, work and social functioning. article (https ://doi.org/10.1007/s0041 5-018-8762-6) contains In this review, we outline an approach to the diagnosis supplementary material, which is available to authorized users. and management of PPA in the clinic and at the bedside, * Charles R. Marshall distilled from our accumulated experience of meeting and charles.marshall@ucl.ac.uk caring for these patients. We firstly present a clinical frame - * Jason D. Warren work for assessing language functions, tailored in particular jason.warren@ucl.ac.uk to the major syndromic presentations of PPA (Tables 1 and 2, Figs. 1 and 2). We then consider these presentations in Department of Neurodegenerative Disease, Dementia detail. Three major forms of PPA—nonfluent–agrammatic Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK variant (nfvPPA), semantic variant (svPPA) and logo- penic variant (lvPPA)—comprise the canonical syndromes Division of Psychology and Language Sciences, University College London, London, UK Vol:.(1234567890) 1 3 Journal of Neurology (2018) 265:1474–1490 1475 1 3 Table 1 Summary of key language features and cognitive, neurological, neuroanatomical and neuropathological associations in syndromes of primary progressive aphasia Syndrome Message production Message understanding Speech repetition Other cognitive and Associated neurological Neuroanatomy Pathology behavioural deficits Idea Content Structure Delivery Perception Meaning Words Phrases Canonical a b c  Nonfluent–agrammatic ± ± + + ± ± + + Dysexecutive, orofacial > Parkinsonism, PSP, CBS; L ant peri-Sylvian, Most often tauopathy (may limb apraxia some MND subcortical be PSP, CBD); also AD, TDP-43  Semantic – + – – – + – – Prosopagnosia, visual Usually none L > R ant TL (most Usually TDP-43 (type C); agnosia, other agno- marked inferior, some tauopathy, AD, sias; disinhibition, lack mesial) rarely mutations of empathy, obsessions d e c  Logopenic ± + + – ± ± ± + Reduced digit span, limb Myoclonus L peri-Sylvian, early TPJ Usually AD apraxia, acalculia, visuo- spatial agnosia Variant and atypical b b b  Primary progressive – – – + – – + + Usually orofacial apraxia, Parkinsonism, PSP, CBS; Bilat FL-subcortical Usually tauopathy (may be apraxia of speech may have dysexecutive, rarely MND PSP, CBD) [20] limb apraxia  Mixed progressive ± + + ± ± + + + Variable—often dysex- Parkinsonism L > R peri-Sylvian, May have GRN mutation, aphasia [11] ecutive, parietal ant TL AD, Pick’s  Progressive dynamic + ± ± ± – – – – Dysexecutive Parkinsonism, PSP, CBS Bilat FL-subcortical May be PSP, CBD aphasia [102]  Progressive pure ano- ± + – – – – – – None None L > R ant TL Uncertain; ?TDP-43, AD mia [103] g g g  Progressive dysprosodia – – – + ± – + + Dysexecutive, orofacial Uncertain R frontotemporal Uncertain [26] apraxia h i  Progressive ‘pure’ word – – ± ± + − + + Cortical deafness, audi- Variable L peri-Sylvian, TPJ May be unusual, e.g. prion deafness [104] tory agnosia The Table presents the major (canonical) syndromes of progressive aphasia, as recognised in current consensus diagnostic criteria (see Table S1) and other less common variants and atypical syndromes that are also represented in most clinics seeing patients with progressive aphasia (numbers in brackets designate primary references). Language features refer to functions described in Table 2. +, prominent or defining impairment;  ± , variable impairment; −, mild or no deficit (in the majority of cases, problems will first be noted with speech but occasional patients present initially with reading or writing impairments [101]) AD Alzheimer’s disease, ant anterior, CBD/S corticobasal degeneration/syndrome, FL frontal lobe, GRN progranulin gene, L left, MND motor neuron disease, PSP progressive supranuclear palsy, R right, TDP-43 TAR DNA-binding protein 43, TL temporal lobe, TPJ temporo-parietal junction Variable prominence of grammatical and/or speech sound (syllabic) errors Speech apraxia with prominent speech sound (phonetic, articulatory) errors Impaired comprehension of more complex sentences (comprehension of single words usually relatively spared) Typically long word-finding pauses Speech sound (phonological) errors, grammar usually intact The patient appears to have ‘nothing to say’ spontaneously but language (if it can be induced by a specific context) is relatively normal in content, structure and delivery and generation of new nonverbal ideas can sometimes be demon- strated in other vocal domains such as singing Impaired speech rhythm and ‘melody’ or altered accent with infrequent speech sound errors Difficulty understanding speech disproportionate to any peripheral hearing loss Much better comprehension of written than spoken messages earlier in the course 1476 Journal of Neurology (2018) 265:1474–1490 1 3 Table 2 A framework for assessment of language functions, directed particularly to progressive aphasias Communication task Cognitive process Key history Clinical test Neuropsychological test SYND Message production a d  Idea Generating verbal idea Reduced initiation of conversation Describe a recent vacation; generating Verbal fluency (F-A-S, category) DA words by initial letter (e.g. ‘F’) or cat- egory (e.g., ‘animals’)  Content Word (vocabulary) retrieval Unable to find right words (especially Naming pictures or from verbal description Graded Naming Test SV, LV, PA names), circumlocutions, pauses  Structure Sentence assembly Grammatical errors (especially in writing or Written sentence production Argument Structure Production Test NFV electronic media) Phonological encoding Mispronounced or ‘slurred’ speech, jargon, Reading aloud or writing non-words, e.g. Graded Non-word Reading Test NFV,LV binary reversals, e.g. ‘Yes/No’ proper names  Delivery Speech motor programming and articulation Slow, hesitant, effortful speech, mispro- Production of syllable strings, e.g. ‘puh- Apraxia Battery for Adults NFV,PD, PPAOS nounced or ‘slurred’ speech, monotonous, kuh-tuh’ altered accent or singing Message understanding  Perception Decoding speech sounds Better understanding of written vs spoken Compare understanding of spoken vs writ- PALPA-3 ‘minimal pairs’ (phoneme) PWD messages; ‘deaf’ behaviour ten commands discrimination  Meaning Decoding grammatical relations Confusion following more complex instruc- Difficulty following commands involving PALPA-55 sentence comprehension NFV, LV tions syntactic relations Association with stored vocabulary Asking the meaning of previously familiar Identifying items named by examiner, British Picture Vocabulary SV j k words, using less precise or context- indicating meaning of words spoken Scale , Synonyms comprehension inappropriate terms, impoverished spoken by examiner, reading aloud or spelling and written vocabulary irregular words, e.g. ‘sew’ Message repetition c l  Words and phrases Verbal working memory Usually no specific history; may have diffi- Repetition of single words (effect of syl- Polysyllabic word repetition NFV culty remembering new PIN or telephone lable number) numbers m Repetition of phrases and sentences (effect WMS auditory digit span LV of length) The Table presents a framework for assessing speech and language functions on history and at the bedside. For each function, we indicate the primary progressive aphasia syndromes that characteristically affect that function (see Table 1) and examples of tests that might be used by a neuropsychologist to quantify the deficit; these are however not exhaustive and a number of additional tests are in widespread use, tailored to the disease stage and level of deficit DA dynamic aphasia, LV logopenic variant primary progressive aphasia, NFV nonfluent variant primary progressive aphasia, PA progressive pure anomia, PD progressive dysprosodia, PPAOS primary progressive apraxia of speech, PWD progressive ‘pure’ word deafness, SV semantic variant primary progressive aphasia, SYND major syndromic associations Difficulty not obviously accounted for by degree of speech or vocabulary disintegration Surface dyslexia/dysgraphia’ (sounding out or spelling irregular words according to surface phonology) is a hallmark of semantic variant primary progressive aphasia Speech repetition tasks engage a number of component functions including accurate speech perception and motor output programing, however their primary purpose is to assess verbal working memory Gladsjo et al. (1992) Assessment 6: 147–178 (this test relies on an intact vocabulary as well as verbal generation per se, so should be interpreted in the context of verbal semantic competence, e.g. the British Picture Vocabulary Scale) McKenna and Warrington (1983) Graded Naming Test Manual, NFER-Nelson: Windsor Thompson (2011) Northwestern Assessment of Verbs and Sentences, Northwestern: Evanston Snowling et al. (1996) Graded nonword reading test, Thames Valley Test: Bury St. Edmunds Dabul (2000) Apraxia battery for adults. Second, Pro-Ed: Austin Kay et al. (1992) Psycholinguistic Assessments of Language Processing in Aphasia (PALPA), Psychology Press: Hove Dunn et al. (1982) The British Picture Vocabulary Scale, NFER-Nelson: Windsor Warrington et al. (1998) Neuropsychological Rehabilitation 8: 143–154 McCarthy and Warrington (1984) Brain 107: 463–485 (this test in itself is an index of speech production but also provides a reference for interpreting verbal working memory effects on phrase repetition) Wechsler (1987) WMS-R: Wechsler Memory Scale-Revised Manual, Harcourt Brace Jovanovich: San Antonio (in the context of severe speech apraxia, this test can be modified to allow nonverbal responses such as pointing to num- bers in an array, to avoid the confounding effects of motor speech impairment) Journal of Neurology (2018) 265:1474–1490 1477 Fig. 1 Neuroanatomical and cognitive profiles of the canonical forward and major neuroanatomical associations are in bold italics: syndromes of progressive aphasia. The top panels present coronal a, amygdala; ATL, anterior temporal lobe; BG, basal ganglia; h, hip- T1-weighted brain MRI sections (in radiological convention, with the pocampus; IFG, inferior frontal gyrus/frontal operculum; ins, insula; left hemisphere on the right) of patients with typical syndromes of OFC,  orbitofrontal cortex; PMC,  posterior medial cortex (posterior nonfluent–agrammatic variant primary progressive aphasia (nfvPPA), cingulate, precuneus); STG,  superior temporal gyrus; TPJ, temporo- showing asymmetric (predominantly left sided) inferior frontal, insu- parietal junction. The ‘target diagrams’ below show typical profiles of lar and anterior–superior temporal gyrus atrophy; semantic variant neuropsychological test performance for each syndrome; concentric primary progressive aphasia (svPPA), showing asymmetric (predomi- circles indicate the percentile scores relative to a healthy age-matched nantly left sided) anterior inferior and mesial temporal lobe atrophy; population and the distance along the radial dimension represents the and logopenic variant primary progressive aphasia (lvPPA), showing level of functioning in the following cognitive domains: ex, executive atrophy predominantly involving left temporo-parietal junction (pos- skills; l, literacy skills; n, naming; nm, nonverbal memory; pr, phrase terior–superior temporal and inferior parietal cortices). The cut-away repetition; s, sentence processing; v, visuo-spatial; vm, verbal mem- brain schematic (right) indicates the distributed cerebral networks ory; wm, word meaning; wr, word repetition involved in each syndrome; the left cerebral hemisphere is projected currently recognised in consensus diagnostic criteria [9] (see Table  S1, Supplementary Material on-line). These syndromes are distinguished by the language deficits with which they present and associated cognitive, neurological and neuroanatomical profiles and tend to have distinct neu- ropathological substrates. Key features of PPA syndromes are summarised in Tables 1, 2 and 3 and Fig. 1; additional ‘clinical pearls’ that we have found useful in diagnosis of each syndrome (but which are not widely discussed in the literature of these conditions) are presented in Table  4. Following the taxonomy of classical (stroke) aphasiology, nfvPPA might be anticipated to align with Broca’s aphasia, svPPA with transcortical sensory aphasia and lvPPA with Wernicke’s or conduction aphasia. However, such clinical correspondences are loose, at best. This probably reflects the very different nature of the underlying disease processes, and Fig. 2 Example of a picture that can be used to elicit conversational most pertinently, the distributed neural network basis of PPA speech (reproduced with permission of Professor EK Warrington). A scene of this kind can be used to assess naming and also to probe [10]. One important corollary is that PPA syndromes extend aspects of language comprehension, at the level of single words (cognitively and neuroanatomically) beyond the province of (using questions such as, ‘Where is the sandcastle?’) and grammatical language, to involve other complex behavioural functions. relations embodied in sentences (using instructions such as, ‘Point to The clinical challenges posed by PPA foreshadow significant the thing that the boy is holding above the boat’) 1 3 1478 Journal of Neurology (2018) 265:1474–1490 1 3 Table 3 Examples of spoken and written language output in patients with canonical syndromes of primary progressive aphasia Syndrome Speech transcriptions Written sentences nfvPPA: prominent speech apraxia The lady is drying a the plate, which she has washed. – – – Meanwhile, she’s forgot… forgot to plug the s… silk. She’s forgot… She’s forgotten to pus put the plug in and she’s forgotten to turn off the water. And the boy is precariously standing on a stool to reach the cookies and he’s passing one cookie to his sister. And and the cur… curtains are quite open, revealing the their garden and a sort of shed [10 years] – – – nfvPPA: prominent agrammatism Laughs} Obviously um there…. The man a boy um a I have do pushed the door My wish a happy Christmas to everyone Dog walking muppett cookie is on there. Um a daughter a no no um sister… And when she gonna throwen on them. And they broken and book on there on there stool on round by them. And lady and she was having a washing on there and they be taps on them and drain is come on the floor one there. Horrible {Laughs}A dire one there. And um…And this man are there bear maybe going in the went on there… working out the window. Maybe this little… little girl looking so on there [5 years] [2 years] [4 years] [4 years] svPPA Well there is a woman to her children, and it’s a house I I am having a stuppid remember Now is the tyme for all good folcs to come to the I am sorry that I have no suppose, and there’s a little window from there and I aid of our party brain now don’t quite know what that is going down, precisely, and then the children are… Cookie jar, I don’t understand that quite either what they’re doing. And gosh, that one’s foot is about to come off, oh dear {Laughs} Well those are people all down the end I suppose just that way, or maybe not, maybe it’s buildings, maybe it’s trees etc., I don’t know [11 years] [4 years] [4 years] [9 years] lvPPA Um… I see a mum washing, drying some um… {long I caught a good crap when I was fishing The keeper caught a difficult … The cat sent on the … pause} … plates. Crikey. With water running down. I see a young boy um in the… the other part of the um… {long pause} Trying, getting off or nearly getting off the… {long pause} … stool, with his… sister below [4 years] [2 years] [4 years] [8 years] These language samples were all derived from different individuals. The speech transcripts represent attempts to describe the Cookie Theft scene from the Boston Diagnostic Aphasia Examination (Goodglass and Kaplan 1983), avail- able at: http://image s.slide playe r.com/14/43642 18/slide s/slide _23.jpg (digital wavefiles of the speech samples are provided separately with Supplementary Material on-line) The writing samples represent spontaneous responses when the patient was asked to produce a complete sentence de novo. For each case, the length of the patient’s history when the sample was collected is recorded below, demonstrating variable severity for a given illness duration across syn- dromes. The patient with prominent speech apraxia illustrates impaired delivery of the spoken message, with frequent stuttering sound duplications, ‘groping’ to reach the target sound and mis-articulated syllables; strictly there is no written analogue to speech apraxia per se (since this is a disorder of articulatory programming), though patients with nfvPPA commonly make phonological errors when writing due to an associated impairment of message assembly (see Table 2). The patients representing other syndromes here illustrate analogous deficits of spoken and written language output. The agrammatic nfvPPA cases show impaired structuring of verbal messages, with disordered sentence syntax and verb morphology and poverty of function words. The svPPA cases illustrate impoverished message content, with a relative dearth of specific, lower frequency vocabulary (particularly nouns), circumlocutions and surface dysgraphic errors (underlined), despite intact verbal structure (syllables and sentences). The lvPPA cases show marked word retrieval difficulty (impaired message content) reflected in prolonged pauses when speaking and trailing off of written sentences and in addition, incorrect syllable selection (impaired message structure; underlined) despite intact sentence construction; the speech sample of the lvPPA case here illustrates the challenge of reliably assessing spoken grammar in the setting of severe word-finding difficulty lvPPA logopenic variant primary progressive aphasia, nfvPPA nonfluent–agrammatic variant primary progressive aphasia, svPPA semantic variant primary progressive aphasia Journal of Neurology (2018) 265:1474–1490 1479 Table 4 ‘Clinical pearls’ in the diagnosis of progressive aphasia syndromes Syndrome Clinical observations nfvPPA Re-emergence of a childhood stammer may herald speech decline ‘Binary reversals’ in conversation often occur early, and may extend to writing and nonverbal gestures: when required to select between alternatives (e.g., ‘yes/no’, ‘he/she’), the patient regularly produces the wrong response and will often spontaneously correct this [105] Late in the course, speech may become replaced by frequent laughter-like (‘gelastic’) vocalisations, unlike normal mirth or patho- logical affect [106] Naming and single word (particularly verb) comprehension deficits often develop [11, 107] Deficits of complex auditory processing may impair understanding of environmental sounds, emotional and other vocal signals (especially unfamiliar accents) [108–110], exacerbated in noisy environments or over the telephone svPPA Verbal knowledge deficits may appear first in more specialised lexicons previously mastered by that individual (e.g., flowers for a gardener; Greek playwrights for a classicist) In conversation, patients do not search for ‘lost’ words but often seem querulous and perplexed by vocabulary they encounter (in other PPA syndromes, patients tend to strive actively to find the word they need, with variable success); many compile personal ‘dictionaries’ to record the meanings of words they no longer understand Auditory symptoms are prevalent (including tinnitus, hyperacusis, aversion to particular environmental noises), not adequately explained by peripheral hearing impairment and likely central in origin [59, 111]; families may interpret patients’ difficulty understanding others as ‘deafness’ Numerical and geographical references (times, dates, distances, quantities, locales) may ‘scaffold’ the patient’s conversation (Sup- plementary sound file 3); these more abstract, autonomous domains may (like music) be oases of relative semantic competence [112–114] lvPPA Verbal working memory impairment may be brought out by a series of sentence repetitions: phonological errors appear and the target sentence becomes a truncated and inaccurate replica (due to progressive overloading of the exhausted verbal buffer) During sentence repetition tasks, there may be repeated attempts to approach the target via a series of substitutions and approxi- mations, resembling ‘conduite d’approche’ in conduction aphasia [115] Jargon and neologisms may occur in conversation or naming tasks (e.g., ‘dajent’ for kangaroo, ‘fishgii’ for buoy); rare in other neurodegenerative syndromes [116, 117] There may be prominent verbal semantic deficits (possibly indicating separate sub-syndromes [73]) This Table presents some clinical observations that are not currently emphasised in standard diagnostic formulations but which we have found useful in the bedside diagnosis of the major syndromes of primary progressive aphasia lvPPA logopenic variant primary progressive aphasia, nfvPPA nonfluent–agrammatic variant primary progressive aphasia, svPPA semantic vari- ant primary progressive aphasia unresolved issues in the nosology and neurobiology of these skills (including formal education, occupation, bilingualism conditions [1, 2, 10–16]. Here we highlight potential diag- or any specific developmental difficulties such as stammer - nostic pitfalls including atypical variant presentations of ing or dyslexia) are relevant to interpreting current deficits. PPA not well captured by standard criteria (Table  1) and It is also necessary to determine the extent of any uncor- propose a diagnostic ‘roadmap’ (Fig.  3). After outlining rected peripheral hearing or visual impairments as these principles of management of PPA, we conclude with a pros- can impact significantly on everyday communication and pect for future developments. performance on language tests. In defining the history of the language problem, it is essential to establish the circum- stances of onset and very first symptoms (often noticed by A clinical framework for assessing language the patient’s family), overall duration and tempo. The length functions in primary progressive aphasia of the history bears strongly on the interpretation of defi - cits, since PPA syndromes tend to converge over time [17]. When confronted by an aphasic patient, it is important r fi stly In PPA, a history of gradual, but unrelenting decline over to establish the context of the language disturbance. This a number of months or several years is typical, but some usually requires the help of an informant who knows the apparent fluctuation is not uncommon, particularly under patient well and can supply reliable background informa- conditions that stress the language system, such as public tion. A diagnosis of PPA requires that speech or language speaking or conversations by telephone or in a non-native dysfunction was the initial and most salient clinical com- tongue. There may have been a sentinel event such as a fam- plaint (see Table S1). However, the patient’s previous verbal ily celebration or minor head injury that first drew attention 1 3 1480 Journal of Neurology (2018) 265:1474–1490 to the patient’s difficulties; informants may interpret this as Canonical syndromes of primary progressive an acute onset but a searching history usually reveals a more aphasia: nonfluent–agrammatic insidious prodrome. The profile of the patient’s language dysfunction then Clinical presentation allows the clinico-anatomical syndrome to be characterised (see Table 1). Fundamentally, language supports commu- Patients with nfvPPA present with slow, effortful, hesitant nication—the understanding, creation and delivery of mes- and distorted speech (Table 3; Supplementary sound files sages. In assessing a patient’s speech, it is useful to analyse 1 and 2). Speech sound errors are generally prominent and the various stages at which the idea for a message is first there is often a history of ‘slurring’ or mispronunciations. generated, the content (or vocabulary) of the message, its Words tend to be missed out and conversation is some- structure (assembly) and delivery. Similarly, in assessing times strikingly telegraphic; errors of grammar (mainly understanding of language, it is useful to analyse the separa- affecting syntax, function words such as articles and con- ble stages at which messages are perceived and then invested junctions and verb usage) typically emerge and sometimes with meaning. These operations are differentially vulner - dominate the presentation [11, 18]. Inability to understand able to particular PPA syndromes and can be explored using more complex conversations or instructions may signify targeted questions on history and a small set of core lan- impaired comprehension of sentences, which is generally guage tests (Table 2). The patient’s use of written language integral to any grammatical deficit [19]. Speech is usually typically echoes the speech disorder as the illness evolves. very much more affected than written communication at the Examples of patients’ transcribed spoken and written pro- outset and patients tend to resort increasingly to nonverbal ductions are presented in Table  3 (corresponding speech means of expression, manifestly frustrated by their inability sound files are provided in Supplementary Material on-line). to communicate. In neurology, the history generally suggests the diagnosis On examination, there is usually marked difficulty pro- while the examination corroborates the historical suspicion. ducing polysyllabic words and sequences of syllables (e.g., This precept is equally valid for language disorders, with the ‘puh-tuh-kuh’) to command, due to impaired motor pro- caveat that certain aspects of language are difficult to differ - gramming of speech and reduced articulatory agility. This entiate on the story alone. One key example (not often called can be brought out by asking the patient to repeat longer upon in everyday communication) is the ability to repeat words or read aloud. The listener is left with an almost pain- messages verbatim, which is central to the characterisation ful sense of the patient’s struggle to speak (not experienced of PPA (see Table  1) and should be examined explicitly. with other forms of PPA). In contrast to peripheral dysar- Like the testing of pupillary and spinal reflexes in general thrias which tend to provoke stumbling consistently over neurology, certain language tests such as speech repetition or particular sounds, the misshapen speech of patients with picture naming rapidly assay a number of connected neural nfvPPA is protean, with characteristic ‘groping’ after the tar- operations: if such tests are performed normally, this dem- get sound: ‘speech apraxia’ [20]. This is often accompanied onstrates the overall integrity of the system but if a problem by apraxia of posed orofacial movements such as yawning or is found, it is necessary to establish where in the system it whistling, disproportionate to any limb apraxia [21]; asked lies. The most important principle in examining speech is to to perform an orofacial gesture, the patient may emphatically obtain an adequate sample; for this purpose, it is convenient echo the command (‘Cough!’) while remaining quite unable to carry a picture that will encourage the patient to talk and to enact it. Speech sound errors can be classified accord- provide a prop for directed tests (one example is shown in ing to whether syllables are wrongly selected (‘phonemic’ Fig. 2). or ‘phonological’ errors) or misformed during execution Alongside the core clinical tests in Table 2 we list some (‘phonetic’ or articulatory errors). These arise at different more formal equivalents that might be administered by a stages during message production but often defy explicit neuropsychologist. However, neuropsychological assess- categorisation in the clinic and the distinction is seldom of ment does not simply endorse the bedside impression. If practical importance. It is useful to examine a specimen of available, it adds considerable value, particularly in quanti- the patient’s writing (Table 3): besides revealing spelling fying language capacities in relation to standardised popula- (phonological dysgraphic) errors, this is a more reliable tion norms and in the context of estimated premorbid ability, index of associated agrammatism than the patient’s speech, in tracking change in language functions over time and in which may be constricted by the sheer effort involved. measuring associated capacities that together with aphasia The clinical spectrum of nfvPPA is the most diverse of define the overall cognitive phenotype and may also affect the canonical PPA syndromes, with a number of variant sub- the assessment of language. syndromes (see Table 1). The most important of these is ‘pure’ progressive speech apraxia associated with orofacial 1 3 Journal of Neurology (2018) 265:1474–1490 1481 Fig. 3 A clinical ‘roadmap’ for diagnosis of canonical primary pro- occasionally present with progressive aphasia; it also has an impor- gressive aphasia syndromes, synthesising key features on history and tant ‘positive’ role in corroborating the neuroanatomical diagnosis examination. The ‘forks’ comprising the middle section of the map (see Fig.  1). Ancillary investigations such as CSF examination are indicate major decision points, for corroboration using the more used to stratify pathologies within particular syndromes (e.g., lvPPA), detailed framework presented in Table 2. Neuropsychological assess- with a view to prognosis and treatment. A significant minority of ment (where available) is used both to support and quantify the clini- cases will not be diagnosed by this algorithm, falling into the still cal impression and to reveal additional cognitive deficits that may poorly defined category of ‘atypical’ progressive aphasias (see text not be emphasised in the clinic but define the overall syndrome (see and Table  1). lvPPA, logopenic variant primary progressive aphasia; Fig.  1). Brain imaging (wherever feasible, MRI) is essential to rule nfvPPA, nonfluent–agrammatic variant primary progressive aphasia; out brain tumours and other non-degenerative pathologies that can svPPA, semantic variant primary progressive aphasia apraxia, but without agrammatism or other aphasic features, homologous right-sided peri-Sylvian atrophy is recognised, which has been proposed to constitute a distinct entity [22, though its clinical correlates remain ill-dene fi d [26, 27]; sev- 23]. While apraxia of speech may indeed be relatively pure eral of our patients with this finding have had notable central at presentation [11], in our experience most of these patients nonverbal auditory deficits or dysprosody [28]. do in time develop aphasia, initially detected on detailed neuropsychological assessment. Some clinical ‘pearls’ we Key associations have found useful in the diagnosis of nfvPPA are presented in Table 4. General intellect is often remarkably well preserved, though a degree of executive dysfunction is usual and may be Neuroanatomy accompanied behaviourally by apathy or impulsivity [29, 30]. Depression can be significant, particularly as insight is This syndrome is associated with atrophy of inferior fron- usually retained. Many patients with nfvPPA will develop tal gyrus (‘Broca’s area’) and insula cortex in the dominant Parkinsonism, often evolving into a progressive supranuclear hemisphere (Fig.  1), with variable extension along and palsy or corticobasal syndrome with associated supranuclear around the superior temporal gyrus. These brain regions gaze palsy, postural instability, pseudobulbar dysfunction play fundamental roles in language output, motor speech and limb apraxia, dystonia or ‘alien’ phenomena [31, 32]. programming and sentence processing [10]. Atrophy is The pathological associations of nfvPPA are (in keeping generally best appreciated as widening of the left Sylvian with the clinical spectrum) more heterogeneous than other fissure on a T1-weighted coronal MRI scan [24]. However, PPA syndromes. A majority of patients will have a tauopa- this may be subtle on cross-sectional imaging and is easily thy such as progressive supranuclear palsy or corticobasal overlooked on ‘routine’ reporting lists, by even experienced degeneration at post-mortem though a substantial (and still observers [25]. Moreover, rotated slices may simulate asym- uncertain) minority represent TDP-43 or Alzheimer pathol- metry; scrolling through a number of slices is useful to check ogy [3, 12, 33–35]. While there are currently few reliable that the direction of any apparent asymmetry is consistent predictors of underlying pathology in individual patients (and therefore real). A neuroradiological phenotype of [36], prominent apraxia of speech and parkinsonism are 1 3 1482 Journal of Neurology (2018) 265:1474–1490 more closely associated with tauopathy than with TDP-43 impairment) from the more usual scenario, in which retrieval pathology [12, 35]. nfvPPA is less likely to be genetically of words from storage is principally affected. It is failure mediated than the behavioural variant of frontotemporal to comprehend or recognise words and objects rather than dementia though it is somewhat more heritable than other anomia per se that defines a semantic deficit. Impaired com- PPA syndromes, around 30% of patients having a relevant prehension of single words in svPPA can be demonstrated family history [37]. Causative mutations in all major (GRN, by asking the patient to describe an item nominated by the MAPT, C9orf72) genes causing frontotemporal dementia examiner or to select it from an array or scene (see Fig. 2). have been identified and at least some of these genetic forms Assessment of other language channels corroborates the may prove clinically distinct with more detailed phenotyp- semantic deficit. When reading aloud or writing, patients ing [11]. with svPPA characteristically ‘regularise’ words according to superficial phonological ‘rules’ in place of learned vocab- ulary (e.g., sounding ‘island’ as ‘izland’ or ‘sew’ as ‘soo’): Canonical syndromes of primary progressive so called ‘surface’ dyslexia or dysgraphia (Table 3). English aphasia: semantic is a particularly fertile field for such deficits as it is replete with irregular ‘exception’ words, but analogous examples Clinical presentation exist in other languages (disproportionately affecting, for example, kanji versus kana script in Japanese [43]). Assess- In striking contrast to nfvPPA, patients with svPPA exhibit ment of nonverbal semantic domains generally requires more well structured, well articulated language that is relentlessly detailed neuropsychological assessment, though in clinic bereft of substance (Table 3; Supplementary sound file 3). visual knowledge might be conveniently sampled (within This typically begins as difficulty finding words (particu- the limits of verbal comprehension and without requiring larly nouns)—sometimes described as losing ‘memory for naming) by asking the patient to indicate the purpose of a names’—and an inability to express thoughts with precision. familiar tool (such as a comb or stapler), to identify associa- The patient’s verbal messages become progressively more tions of a pictured item (‘which thing could be used in the circumlocutory and empty, as fine-grained content (less garden?’; Fig. 2) or to supply biographical information from frequently used vocabulary, such as ‘dachshund’ or ‘lady- photographs of familiar people. Across verbal and nonverbal bird’) is replaced by increasingly generic ciphers (‘animal’, semantic domains, loss of meaning in svPPA follows a stere- ‘thing’). Blunting of verbal nuance in svPPA may predate otyped pattern. More specific knowledge about less familiar diagnosis by many years [38]. The true nature of the deficit (low frequency) and atypical items is lost before knowledge is revealed in a history (almost pathognomonic for svPPA) of highly familiar and typical items; failures of recognition of asking the meaning of previously familiar words (‘What’s are accompanied by ‘over-generalisation’ errors that tend to broccoli?’): this is not merely a problem of accessing words regularise objects to a generic type (for example, the patient in memory, but erosion of vocabulary itself. Indeed, svPPA may draw a four-legged peacock or a rhino lacking its horn); is the paradigmatic disorder of semantic memory, the cog- and errors are highly consistent over time, so that the mean- nitive system that stores (rather than the autobiographical ings of words and objects, once lost, are irretrievable [44, events that populate ‘episodic’ memory) knowledge about 45]. These features of svPPA have informed neural compu- objects and concepts and allows us to attribute meaning to tational models of the underlying cognitive architecture of the world at large [6, 39]. The language deficit in svPPA is semantic memory and its breakdown [46, 47]. Some clinical fundamentally associated with loss of meaning about objects ‘pearls’ relevant to svPPA are listed in Table 4. and people. While language impairment usually leads the presentation, deficits of nonverbal knowledge inevitably Neuroanatomy appear later in the course and ultimately blight all sensory channels [39–42]. More rarely, patients present with inabil- On neuroimaging, svPPA has a hallmark pattern of asym- ity to recognise objects (visual agnosia) or familiar people metric, focal cerebral atrophy chiefly involving the dominant (prosopagnosia) by sight. anteroinferior and mesial temporal lobe, including amyg- Earlier in the course of the illness, the conversation of dala and anterior hippocampus [9, 48]. This is most easily patients with svPPA is easily passed as normal by the casual visualised on a T1-weighted coronal MRI scan (Fig. 1). The listener, due to its well preserved surface structure and flu- profile of atrophy shows a clear gradient within the temporal ency, even garrulousness [11]. However, closer attention lobe, with ‘knife-blade’ destruction of the pole and rela- generally reveals severe anomia. Because anomia is a com- tively sparing of superior temporal gyrus and more posterior mon feature of a number of aphasias, it is important to dis- temporal cortices. This signature is consistently observed tinguish carefully those cases (for example, in svPPA) where across patients and unmistakeable; in our experience, it is this follows degradation of the word store (primary semantic invariably present at diagnosis in typical svPPA and indeed 1 3 Journal of Neurology (2018) 265:1474–1490 1483 (in contrast to nfvPPA) often ‘the scan is worse than the Completing the picture of a highly coherent clinical, ana- patient’. Over time, atrophy spreads to involve more pos- tomical and pathological syndrome, most cases of svPPA terior temporal regions and homologous gyri in the con- have TDP-43 (type C) pathology at post-mortem [12, 33, tralateral temporal lobe as well as orbitofrontal cortex [49, 35]. Primary tauopathies and Alzheimer’s disease account 50]: regions that together constitute the core of the brain’s for a small minority and may have certain distinguishing semantic memory network [39, 47]. This distinctive atrophy phenotypic markers (for example, prominent acalculia or profile has provided an important neuroanatomical ground- extrapyramidal signs in association with Pick’s disease ing for cognitive models of svPPA, according to which ante- pathology [12, 35]). Most cases are sporadic though occa- rior temporal cross-modal ‘hub’ cortex interacts with more sional pathogenic mutations are reported [4] and may be posterior, relatively modality-specific cortices across both relatively more likely if motor features are present (e.g., left and right temporal lobes [47]. associated motor neuron disease with TBK1 mutations [64]). Some patients exhibit a ‘mirror’ profile of predominant right anterior temporal lobe atrophy. For unknown reasons, these cases are rarer than their leftward-asymmetric coun- Canonical syndromes of primary progressive terparts and usually present with profound disturbances of aphasia: logopenic social and emotional behaviour or prosopagnosia, indicating the breakdown of knowledge about people [51, 52]. Clinical presentation Key associations The most recently described of the major PPA syndromes is (in more than one sense) the most problematic. This is due A behavioural syndrome similar to that defining the behav - chiefly to the issue of demarcating it clinically from typical ioural variant of frontotemporal dementia characteristi- Alzheimer’s disease and the lack of a readily agreed, uni- cally develops in svPPA and indeed, these syndromes can fying syndromic deficit in lvPPA to set against the speech occasionally be difficult to distinguish, even after a care- production (message production) failure that defines nfvPPA ful history. Initially, behavioural features in svPPA may be and the word comprehension (message understanding) fail- quite subtle, but tend to manifest earlier and more floridly ure that defines svPPA. The clinical picture in lvPPA is usu- in patients with more marked right (non-dominant) tempo- ally dominated by word-finding difficulty and conversational ral lobe involvement and become universal as the march of lapses, for which the syndrome is named (Greek, ‘lack of disease involves the frontotemporal networks that regulate words’; Table  3, Supplementary sound file 4). Early on, social responsiveness [39, 47]. Symptoms such as absent ‘tip-of-the-tongue’ hesitations are often prominent. Some or misplaced empathy, social disinhibition and faux pas, a patients develop a rather mannered style of conversation, lik- more fatuous sense of humour and pathological sweet tooth ened by one spouse to a ‘Jane Austen character’. Interrupted are common in both svPPA and behavioural variant fron- sentences that tend to trail off may give the impression of totemporal dementia [29, 53–57]. Within this spectrum, agrammatism though without the frank syntactic disloca- certain behavioural features, such as food faddism, exag- tions of nfvPPA [18]. Speech sound or spelling errors are gerated reactions to pain and ambient temperature, behav- frequently described. The patient may struggle to under- ioural rigidity with clock-watching and obsessional interest stand more complex sentences and to hold verbal informa- in numbers, puzzles (especially Sudoku and jigsaws) and tion in mind. While language is (by definition) the leading music (‘musicophilia’) seem particularly linked to svPPA and dominant issue, there is frequently a history of associ- [30, 53, 58–60]. A unifying theme here may be impaired ated extra-linguistic difficulties extending to the realms of understanding of emotional and somatic signals due to both memory (e.g., forgetfulness, repetitiveness or route-finding deficient and over-generalised responses to sensory informa- problems), praxis (e.g., use of work equipment, tools or tion [41, 42, 55, 56, 61], analogous to recognition failures household gadgets) or visuo-spatial awareness (e.g., inabil- and ‘regularisation errors’ in other cognitive domains. An ity to judge distances accurately, find exits or locate items impoverished concept of self due to diminished awareness in plain sight) [65, 66]. of bodily signals may contribute to reduced empathy and an On examination, the patient’s speech is derailed by word increased rate of suicidality in svPPA relative to other neu- retrieval pauses and (often marked) anomia, though this is rodegenerative syndromes [61, 62]. Insight and awareness of usually not as severe (from such an early stage) as in svPPA. deficits often appear to be retained, but may be superficial or This syndrome illustrates the difficulty of dichotomising incomplete. In contrast to nfvPPA, associated neurological PPA syndromes as ‘nonfluent’ versus ‘fluent’: patients signs are not typically found in svPPA, though parkinsonian with lvPPA in general do not talk fluently, yet their speech or motor neuron features may develop later in the course sounds quite different to the mutilated utterances of nfvPPA [31, 63]. (compare Supplementary sound files 1, 2 and 4). Generally, 1 3 1484 Journal of Neurology (2018) 265:1474–1490 phonological speech sound errors can be detected, usually overlap of lvPPA with both later-stage typical Alzheimer’s taking the form of syllable misselections that are enunciated disease and the posterior cortical atrophy variant, corrobo- clearly and not accompanied by the false starts and distor- rated at post-mortem as well as on neuropsychological, CSF tions that characterise nfvPPA. Reading aloud is similarly (raised phosphorylated tau levels, raised ratio of total tau to marred by syllabic substitutions, highlighted by sounding beta-amyloid ) and amyloid-PET case series [35, 70–72]. 1-42 out non-words (e.g., proper names) that rely on phonological On the other hand, cases of lvPPA lacking Alzheimer mark- decoding rather than learned vocabulary. Analogous errors ers are consistently represented across series; the pathologi- of written spelling are often evident (Table  3). The diag- cal substrates have not been clarified, but these may point nostic feature of lvPPA that distinguishes it from other PPA to separable clinico-anatomical sub-syndromes [16, 68, syndromes is early and disproportionate difficulty repeating 71–73]. Although lvPPA is generally a sporadic disorder, heard phrases and sentences versus single words [67] (see some caution is called for in cases without Alzheimer mark- Table 2). This signifies an impairment of verbal (phonologi - ers, since pathogenic progranulin gene mutations have been cal) working memory, also indexed as a reduced auditory reported in this subgroup [11, 68]. span for repetition of random digit strings [16]. While digit span is often also reduced in nfvPPA, in that syndrome rep- etition of single words and repetition of phrases are compa- Toward the diagnosis: a path with pitfalls rably degraded. Other dominant (and often, bi-hemispheric) posterior cortical signs such as limb apraxia and visual Accurate and early identification of PPA syndromes is essen- apperceptive agnosia can frequently be elicited in lvPPA. tial for clinical counselling and planning appropriate man- This extra-linguistic cognitive phenotype tends to be more agement. Beyond clinical characterisation, molecular strati- extensive and severe than in other PPA syndromes at a com- fication will become increasingly important with trials of parable stage of clinical evolution (see Fig. 1). Some clinical candidate disease-modifying treatments on the horizon [35]. ‘pearls’ relevant to lvPPA are presented in Table 4. However, most patients presenting with a language com- plaint will not have PPA and further, a number of patients Neuroanatomy with PPA (as many as 40% in some series) do not conform closely to one of the canonical syndromic diagnoses [3, 13, The key neuroimaging association is asymmetric atrophy 15, 16, 34]. Some of these less common, atypical variants mainly involving the temporo-parietal junction zone of the are in Table 1. dominant hemisphere, appearing as widening of the pos- In Fig. 3, we present a ‘roadmap’ for diagnosis of PPA terior left Sylvian fissure on a T1-weighted coronal MRI syndromes that we have found useful in clinic. Key diagnos- scan [68] (Fig. 1). This locus potentially accounts for many tic decision ‘forks’ rest on the historical and examination features of the language phenotype, since posterior supe- findings outlined in Tables  1 and 2 and on neuropsycho- rior temporal and inferior parietal cortices are intimately logical assessment where available. Structural brain imaging involved in decoding speech sounds and activating phono- (ideally, MRI) is essential in all cases of suspected PPA, logical representations to link verbal semantic stores to lan- both to rule out other causes of progressive language failure guage output [10, 16, 69]. However, there is often extension and more positively, to identify features of particular radio- of atrophy more anteriorly with involvement of other struc- logical phenotypes (Fig. 1). Where initial MRI features are tures (notably the hippocampi) and the overall extent and borderline (notably in nfvPPA and lvPPA) it may be helpful pattern of atrophy varies widely between individual patients. to repeat the scan after an interval of a year or so, as directly comparing serial studies of the culprit brain region is often Key associations revealing. Functional MRI and FDG-PET in PPA are not in routine clinical use though there is considerable potential A number of patients with lvPPA exhibit generalised anxi- interest in applying such techniques to define aberrant and ety, irritability and increased clinging (emotionally and compensatory language network changes, with a view to physically) to their primary caregivers [29, 70, 71]. Similar future therapeutic trials [74, 75]. behavioural features may occur with posterior cortical atro- Having arrived at a syndromic diagnosis, it may be phy (the ‘visual’ Alzheimer variant syndrome) or indeed in appropriate to investigate further to determine the underly- typical Alzheimer’s disease. Neurological signs are usually ing proteinopathy—including CSF examination or amyloid- sparse [32], but include myoclonus, which may be peri-oral. PET scanning for Alzheimer neurodegeneration markers. Some patients go on to develop a corticobasal syndrome These ancillary investigations may be relevant, for example, [71]. in deciding to trial a cholinesterase inhibitor in a patient In most cases, lvPPA is a variant presentation of Alz- with nfvPPA or more generally, in forecasting the overall heimer’s disease. This explains the extensive phenotypic outlook of the illness in earlier stage disease. We discuss 1 3 Journal of Neurology (2018) 265:1474–1490 1485 the possibility of genetic risk in all younger patients with is worthwhile, given the quite different management issues nfvPPA and genetic screening should be considered in any that these groups present. patient with PPA who has a relevant family history, par- ticularly where there this raises suspicion of a frontotem- The patient with comorbidities poral dementia. Discussions in clinic around genetic test- ing broach a number of sensitive issues and should ideally Interpretation of apparent language deficits should be cau- involve other family members. tious in older patients with a history of developmental dys- We next consider some common potential pitfalls on the lexia or longstanding peripheral hearing loss, especially path to diagnosis. when the recent symptoms target phonology or articulation and if additional cognitive involvement is subtle. Often a The patient with late stage or ‘global’ aphasia period of follow-up will establish the nature of the deficit. Performance on language tests should always be calibrated All PPA syndromes tend ultimately to give rise to global lan- for premorbid literacy skills in the test language. guage failure with mutism or sparse, stereotyped utterances [76] as well as more widespread cognitive decline. Accord- The worried well or ‘functional’ patient ingly, diagnosis later in the course may be more informed by associated neurological features such as Parkinsonism. Word-finding difficulty is a very common complaint in On the other hand, ‘mixed’ aphasia does not of itself sig- patients attending memory clinics [10]. Many will be expe- nify advanced disease: some patients exhibit deficits that riencing the effects of normal ageing and intercurrent stress- transcend canonical syndromic boundaries early on (see ors; they typically describe inefficiency in recalling names Table 1). In our experience, this includes cases with pro- or clearly expressing their thoughts when preoccupied or granulin mutations [11] and Alzheimer’s, Pick’s and other fatigued and have no evidence of language deficits on objec- pathological associations are reported [16, 35]. tive testing. A taxonomy of neurologically unexplained, ‘functional’ or ‘non-organic’ speech disorders has been The unhelpful scan described [79]. In our experience, these cases are rare and tend to present as excessively deliberate, but immaculately Neuroimaging findings in nfvPPA and lvPPA can be subtle executed speech or with isolated disturbances of prosody and an equivocal scan does not rule out the diagnosis. A (‘melody’ of speech). Dysprosody is a regular accompani- related issue concerns the diagnostic relevance of visualised ment of nfvPPA and ‘pure’ primary progressive dysproso- abnormalities; PPA syndromes can be caused by unusual dia (leading to the development of other aphasic features) pathologies (for example, primary leukodystrophies and is a rare satellite syndrome in the PPA spectrum (Table 1). prion disease), but most meningiomas and arachnoid cysts Indeed, ‘foreign accent syndrome’ has been described as a will be incidental. Cerebrovascular changes of small vessel presentation of PPA [80]. Our patients with nfvPPA (and ischaemia are commonly found in older patients but sel- occasional cases of primary progressive dysprosodia) have dom if ever cause a canonical PPA syndrome (though word- exhibited degraded native accents or loss of a previously n fi ding dic ffi ulty commonly accompanies vascular cognitive competent second language accent, rather than developing impairment). a facsimile foreign accent. ‘Organic’ dysprosody tends to be brought out by circumstances (such as singing or reciting) The older patient calling for heightened control of vocal intonation [26, 81]. When interpreting a language disorder as ‘neurologically It is likely that PPA is underdiagnosed in older patients unexplained’, it is important to appreciate that bona fide PPA in whom language deficits are more likely to be ascribed syndromes can have quite counter-intuitive manifestations. uncritically to Alzheimer’s disease or undifferentiated An expert second opinion may be useful and the passage of ‘dementia’ [4]. On the other hand, impaired word retrieval time (and lack of clinical and radiological evolution) often commonly occurs in amnestic Alzheimer’s disease, fronto- clarifies the situation. temporal dementia and other diseases and may be a salient early feature even if it does not dominate the presentation [10, 77]. These patients often do poorly on naming tasks An outline of management and may substitute semantically related ‘paraphasias’ (e.g., ‘rhino’ instead of ‘hippo’). The speech of advanced typical Patients with PPA generally live for a number of years fol- Alzheimer’s disease has characteristics similar to lvPPA, lowing diagnosis, with evolving deficits and specific needs though close analysis suggests that these syndromes are lin- at each stage of the illness. Widely accepted clinical stag- guistically distinct at earlier stages [78]. Accurate diagnosis ing markers are presently lacking, however, the major PPA 1 3 1486 Journal of Neurology (2018) 265:1474–1490 syndromes collectively raise similar management challenges communication (e.g., gesture) while avoiding communi- and these broadly require the integration of non-pharmaco- cation barriers (e.g., interruptions, abrupt topic changes). logical and pharmacological approaches. Augmentative and alternative communication devices may help patients with nfvPPA and limited verbal output, but Non‑pharmacological strategies preserved comprehension [86]. Adapting everyday technol- ogy such as smartphones and total communication strategies Management begins with diagnosis; this is often delayed due incorporating photos and pictures may enable continuation to the lack of experience with these conditions in the wider of daily activities such as shopping or cooking [87, 88]. medical community and the value of a clear explanation for Unfortunately, gains from non-pharmacological therapies patients and families should never be underestimated. Diag- are usually modest and there is little evidence for generali- nosis supports future planning (including discussions around sation of effects or lasting benefit in daily life [83, 84]. It end-of-life care) and mobilisation of appropriate social ser- is important that new approaches continue to be developed vices. Supportive care is still the mainspring of management and are assessed in adequately powered and controlled stud- for all PPA syndromes. Patients and caregivers need clear ies, with a view to a future where cognitive rehabilitation advice about driving safety, work arrangements, safeguard- may be deployed in conjunction with disease modifying ing and finances (particularly in younger patients who may pharmacotherapy. have dependent children or elderly relatives). Later in the course, and especially in nfvPPA, dysphagia (due to motor Pharmacological interventions dyscontrol and/or impulsivity) may become a significant issue necessitating expert advice from a dietician or speech There are currently no disease modifying treatments for PPA therapist and where appropriate, consideration of assisted and evidence for efficacy of symptomatic treatments is scant. feeding. Patients should also be monitored for the emer- We have a low threshold for trying a cholinesterase inhibitor gence of other motor and neurological features that impact or memantine in patients with lvPPA and nfvPPA (where on mobility and activities of daily life. Early detection of Alzheimer’s pathology is a consideration), though any bene- physical deficits is key because these tend to herald a step fit is usually modest and care is needed to avoid exacerbating change in functional status and care requirements. It may be behavioural symptoms [89, 90]. Memantine appears to be useful to provide the patient and caregiver with a medical well-tolerated in svPPA and nfvPPA, but clear evidence of card or bracelet as the ability to communicate diagnosis and benefit is lacking [91]. Selective serotonin reuptake inhibi- needs fails due to severe communication and/or behavioural tors should be considered in patients with comorbid depres- decline. If available, involvement in a lay support group ded- sion or anxiety and may help to settle behavioural symptoms icated to PPA or frontotemporal dementia often provides such as impulsivity and aggression, particularly in svPPA much-needed psychological support and practical advice (in [92]. Newer generation neuroleptics may be indicated to the United Kingdom, see: http://www.raredement iasup por t. manage severe agitation or psychotic symptoms later in the org/ppa/). Support and respite for caregivers are often over- illness. looked, but vital to maintaining patients in the community. Speech and language therapy in PPA has an important role in providing communication aids and strategies. Even Conclusions and future directions simple measures such as picture books and cards listing frequent and important words and phrases that the patient Recognition of the major PPA syndromes has transformed can carry may be of great practical value (particularly in our understanding of the language system and given us a nfvPPA). More structured therapy aims to provide person- new picture of selective neural vulnerability in degenera- centred and goal directed interventions to alleviate impair- tive brain disease. However, this dramatic progress should ment (e.g., word-relearning tasks) and to maintain daily life not obscure the many remaining difficulties surrounding functioning (e.g., ordering in a coffee shop) [82, 83]. These these conditions. Ultimately, effective treatment of PPA can in principle be tailored to the particular PPA syndrome: will depend on both earlier and more accurate diagnosis for example, word-relearning techniques might focus on (improved syndrome characterisation), more accurate dis- object features (use, location, appearance) in patients with ease and disability staging and identification of new bio- svPPA or phonology (rhyming, first and last sound identi- markers that can target tissue pathology and track therapeu- fication) in lvPPA [84], while orthographic cues to word tic effects dynamically, in advance of irrecoverable brain production can be targeted in nfvPPA [85]. In practice, atrophy (improved signalling of underlying proteinopathy however, combined approaches have often been used [84]. [93]). 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Abstract

The primary progressive aphasias are a heterogeneous group of focal ‘language-led’ dementias that pose substantial chal- lenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experi- ence of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including ‘clinical pearls’ that we have found diagnostically useful and neuro- anatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presenta- tions not well captured by conventional classifications and propose a diagnostic ‘roadmap’. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers. Keywords Primary progressive aphasia · Semantic dementia · Logopenic aphasia · Frontotemporal dementia · Alzheimer’s disease Introduction surprising: PPA is uncommon (estimated prevalence is con- servatively around three cases per 100,000 [3, 4]), the under- The primary progressive aphasias (PPA) are a diverse group lying pathology is heterogeneous and generally inaccessible of disorders that collectively present with relatively focal and the functions principally targeted are uniquely complex. degeneration of the brain systems that govern language. Although patients with PPA have been described for well Despite much recent attention in the scientific literature [ 1, over a century [5], the true significance of these disorders 2], these ‘language-led dementias’ remain daunting for even was only appreciated quite recently [6, 7] and the paradigm experienced clinicians to diagnose and manage. This is not of selective brain network degeneration caused by patho- genic protein spread has transformed our understanding of neurodegenerative disease [8]. While challenging, accurate Charles R. Marshall and Chris J. D. Hardy contributed equally to clinical diagnosis of PPA is worth striving for: these patients the work. are often affected in late middle life, with devastating impli - Electronic supplementary material The online version of this cations for family life, work and social functioning. article (https ://doi.org/10.1007/s0041 5-018-8762-6) contains In this review, we outline an approach to the diagnosis supplementary material, which is available to authorized users. and management of PPA in the clinic and at the bedside, * Charles R. Marshall distilled from our accumulated experience of meeting and charles.marshall@ucl.ac.uk caring for these patients. We firstly present a clinical frame - * Jason D. Warren work for assessing language functions, tailored in particular jason.warren@ucl.ac.uk to the major syndromic presentations of PPA (Tables 1 and 2, Figs. 1 and 2). We then consider these presentations in Department of Neurodegenerative Disease, Dementia detail. Three major forms of PPA—nonfluent–agrammatic Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK variant (nfvPPA), semantic variant (svPPA) and logo- penic variant (lvPPA)—comprise the canonical syndromes Division of Psychology and Language Sciences, University College London, London, UK Vol:.(1234567890) 1 3 Journal of Neurology (2018) 265:1474–1490 1475 1 3 Table 1 Summary of key language features and cognitive, neurological, neuroanatomical and neuropathological associations in syndromes of primary progressive aphasia Syndrome Message production Message understanding Speech repetition Other cognitive and Associated neurological Neuroanatomy Pathology behavioural deficits Idea Content Structure Delivery Perception Meaning Words Phrases Canonical a b c  Nonfluent–agrammatic ± ± + + ± ± + + Dysexecutive, orofacial > Parkinsonism, PSP, CBS; L ant peri-Sylvian, Most often tauopathy (may limb apraxia some MND subcortical be PSP, CBD); also AD, TDP-43  Semantic – + – – – + – – Prosopagnosia, visual Usually none L > R ant TL (most Usually TDP-43 (type C); agnosia, other agno- marked inferior, some tauopathy, AD, sias; disinhibition, lack mesial) rarely mutations of empathy, obsessions d e c  Logopenic ± + + – ± ± ± + Reduced digit span, limb Myoclonus L peri-Sylvian, early TPJ Usually AD apraxia, acalculia, visuo- spatial agnosia Variant and atypical b b b  Primary progressive – – – + – – + + Usually orofacial apraxia, Parkinsonism, PSP, CBS; Bilat FL-subcortical Usually tauopathy (may be apraxia of speech may have dysexecutive, rarely MND PSP, CBD) [20] limb apraxia  Mixed progressive ± + + ± ± + + + Variable—often dysex- Parkinsonism L > R peri-Sylvian, May have GRN mutation, aphasia [11] ecutive, parietal ant TL AD, Pick’s  Progressive dynamic + ± ± ± – – – – Dysexecutive Parkinsonism, PSP, CBS Bilat FL-subcortical May be PSP, CBD aphasia [102]  Progressive pure ano- ± + – – – – – – None None L > R ant TL Uncertain; ?TDP-43, AD mia [103] g g g  Progressive dysprosodia – – – + ± – + + Dysexecutive, orofacial Uncertain R frontotemporal Uncertain [26] apraxia h i  Progressive ‘pure’ word – – ± ± + − + + Cortical deafness, audi- Variable L peri-Sylvian, TPJ May be unusual, e.g. prion deafness [104] tory agnosia The Table presents the major (canonical) syndromes of progressive aphasia, as recognised in current consensus diagnostic criteria (see Table S1) and other less common variants and atypical syndromes that are also represented in most clinics seeing patients with progressive aphasia (numbers in brackets designate primary references). Language features refer to functions described in Table 2. +, prominent or defining impairment;  ± , variable impairment; −, mild or no deficit (in the majority of cases, problems will first be noted with speech but occasional patients present initially with reading or writing impairments [101]) AD Alzheimer’s disease, ant anterior, CBD/S corticobasal degeneration/syndrome, FL frontal lobe, GRN progranulin gene, L left, MND motor neuron disease, PSP progressive supranuclear palsy, R right, TDP-43 TAR DNA-binding protein 43, TL temporal lobe, TPJ temporo-parietal junction Variable prominence of grammatical and/or speech sound (syllabic) errors Speech apraxia with prominent speech sound (phonetic, articulatory) errors Impaired comprehension of more complex sentences (comprehension of single words usually relatively spared) Typically long word-finding pauses Speech sound (phonological) errors, grammar usually intact The patient appears to have ‘nothing to say’ spontaneously but language (if it can be induced by a specific context) is relatively normal in content, structure and delivery and generation of new nonverbal ideas can sometimes be demon- strated in other vocal domains such as singing Impaired speech rhythm and ‘melody’ or altered accent with infrequent speech sound errors Difficulty understanding speech disproportionate to any peripheral hearing loss Much better comprehension of written than spoken messages earlier in the course 1476 Journal of Neurology (2018) 265:1474–1490 1 3 Table 2 A framework for assessment of language functions, directed particularly to progressive aphasias Communication task Cognitive process Key history Clinical test Neuropsychological test SYND Message production a d  Idea Generating verbal idea Reduced initiation of conversation Describe a recent vacation; generating Verbal fluency (F-A-S, category) DA words by initial letter (e.g. ‘F’) or cat- egory (e.g., ‘animals’)  Content Word (vocabulary) retrieval Unable to find right words (especially Naming pictures or from verbal description Graded Naming Test SV, LV, PA names), circumlocutions, pauses  Structure Sentence assembly Grammatical errors (especially in writing or Written sentence production Argument Structure Production Test NFV electronic media) Phonological encoding Mispronounced or ‘slurred’ speech, jargon, Reading aloud or writing non-words, e.g. Graded Non-word Reading Test NFV,LV binary reversals, e.g. ‘Yes/No’ proper names  Delivery Speech motor programming and articulation Slow, hesitant, effortful speech, mispro- Production of syllable strings, e.g. ‘puh- Apraxia Battery for Adults NFV,PD, PPAOS nounced or ‘slurred’ speech, monotonous, kuh-tuh’ altered accent or singing Message understanding  Perception Decoding speech sounds Better understanding of written vs spoken Compare understanding of spoken vs writ- PALPA-3 ‘minimal pairs’ (phoneme) PWD messages; ‘deaf’ behaviour ten commands discrimination  Meaning Decoding grammatical relations Confusion following more complex instruc- Difficulty following commands involving PALPA-55 sentence comprehension NFV, LV tions syntactic relations Association with stored vocabulary Asking the meaning of previously familiar Identifying items named by examiner, British Picture Vocabulary SV j k words, using less precise or context- indicating meaning of words spoken Scale , Synonyms comprehension inappropriate terms, impoverished spoken by examiner, reading aloud or spelling and written vocabulary irregular words, e.g. ‘sew’ Message repetition c l  Words and phrases Verbal working memory Usually no specific history; may have diffi- Repetition of single words (effect of syl- Polysyllabic word repetition NFV culty remembering new PIN or telephone lable number) numbers m Repetition of phrases and sentences (effect WMS auditory digit span LV of length) The Table presents a framework for assessing speech and language functions on history and at the bedside. For each function, we indicate the primary progressive aphasia syndromes that characteristically affect that function (see Table 1) and examples of tests that might be used by a neuropsychologist to quantify the deficit; these are however not exhaustive and a number of additional tests are in widespread use, tailored to the disease stage and level of deficit DA dynamic aphasia, LV logopenic variant primary progressive aphasia, NFV nonfluent variant primary progressive aphasia, PA progressive pure anomia, PD progressive dysprosodia, PPAOS primary progressive apraxia of speech, PWD progressive ‘pure’ word deafness, SV semantic variant primary progressive aphasia, SYND major syndromic associations Difficulty not obviously accounted for by degree of speech or vocabulary disintegration Surface dyslexia/dysgraphia’ (sounding out or spelling irregular words according to surface phonology) is a hallmark of semantic variant primary progressive aphasia Speech repetition tasks engage a number of component functions including accurate speech perception and motor output programing, however their primary purpose is to assess verbal working memory Gladsjo et al. (1992) Assessment 6: 147–178 (this test relies on an intact vocabulary as well as verbal generation per se, so should be interpreted in the context of verbal semantic competence, e.g. the British Picture Vocabulary Scale) McKenna and Warrington (1983) Graded Naming Test Manual, NFER-Nelson: Windsor Thompson (2011) Northwestern Assessment of Verbs and Sentences, Northwestern: Evanston Snowling et al. (1996) Graded nonword reading test, Thames Valley Test: Bury St. Edmunds Dabul (2000) Apraxia battery for adults. Second, Pro-Ed: Austin Kay et al. (1992) Psycholinguistic Assessments of Language Processing in Aphasia (PALPA), Psychology Press: Hove Dunn et al. (1982) The British Picture Vocabulary Scale, NFER-Nelson: Windsor Warrington et al. (1998) Neuropsychological Rehabilitation 8: 143–154 McCarthy and Warrington (1984) Brain 107: 463–485 (this test in itself is an index of speech production but also provides a reference for interpreting verbal working memory effects on phrase repetition) Wechsler (1987) WMS-R: Wechsler Memory Scale-Revised Manual, Harcourt Brace Jovanovich: San Antonio (in the context of severe speech apraxia, this test can be modified to allow nonverbal responses such as pointing to num- bers in an array, to avoid the confounding effects of motor speech impairment) Journal of Neurology (2018) 265:1474–1490 1477 Fig. 1 Neuroanatomical and cognitive profiles of the canonical forward and major neuroanatomical associations are in bold italics: syndromes of progressive aphasia. The top panels present coronal a, amygdala; ATL, anterior temporal lobe; BG, basal ganglia; h, hip- T1-weighted brain MRI sections (in radiological convention, with the pocampus; IFG, inferior frontal gyrus/frontal operculum; ins, insula; left hemisphere on the right) of patients with typical syndromes of OFC,  orbitofrontal cortex; PMC,  posterior medial cortex (posterior nonfluent–agrammatic variant primary progressive aphasia (nfvPPA), cingulate, precuneus); STG,  superior temporal gyrus; TPJ, temporo- showing asymmetric (predominantly left sided) inferior frontal, insu- parietal junction. The ‘target diagrams’ below show typical profiles of lar and anterior–superior temporal gyrus atrophy; semantic variant neuropsychological test performance for each syndrome; concentric primary progressive aphasia (svPPA), showing asymmetric (predomi- circles indicate the percentile scores relative to a healthy age-matched nantly left sided) anterior inferior and mesial temporal lobe atrophy; population and the distance along the radial dimension represents the and logopenic variant primary progressive aphasia (lvPPA), showing level of functioning in the following cognitive domains: ex, executive atrophy predominantly involving left temporo-parietal junction (pos- skills; l, literacy skills; n, naming; nm, nonverbal memory; pr, phrase terior–superior temporal and inferior parietal cortices). The cut-away repetition; s, sentence processing; v, visuo-spatial; vm, verbal mem- brain schematic (right) indicates the distributed cerebral networks ory; wm, word meaning; wr, word repetition involved in each syndrome; the left cerebral hemisphere is projected currently recognised in consensus diagnostic criteria [9] (see Table  S1, Supplementary Material on-line). These syndromes are distinguished by the language deficits with which they present and associated cognitive, neurological and neuroanatomical profiles and tend to have distinct neu- ropathological substrates. Key features of PPA syndromes are summarised in Tables 1, 2 and 3 and Fig. 1; additional ‘clinical pearls’ that we have found useful in diagnosis of each syndrome (but which are not widely discussed in the literature of these conditions) are presented in Table  4. Following the taxonomy of classical (stroke) aphasiology, nfvPPA might be anticipated to align with Broca’s aphasia, svPPA with transcortical sensory aphasia and lvPPA with Wernicke’s or conduction aphasia. However, such clinical correspondences are loose, at best. This probably reflects the very different nature of the underlying disease processes, and Fig. 2 Example of a picture that can be used to elicit conversational most pertinently, the distributed neural network basis of PPA speech (reproduced with permission of Professor EK Warrington). A scene of this kind can be used to assess naming and also to probe [10]. One important corollary is that PPA syndromes extend aspects of language comprehension, at the level of single words (cognitively and neuroanatomically) beyond the province of (using questions such as, ‘Where is the sandcastle?’) and grammatical language, to involve other complex behavioural functions. relations embodied in sentences (using instructions such as, ‘Point to The clinical challenges posed by PPA foreshadow significant the thing that the boy is holding above the boat’) 1 3 1478 Journal of Neurology (2018) 265:1474–1490 1 3 Table 3 Examples of spoken and written language output in patients with canonical syndromes of primary progressive aphasia Syndrome Speech transcriptions Written sentences nfvPPA: prominent speech apraxia The lady is drying a the plate, which she has washed. – – – Meanwhile, she’s forgot… forgot to plug the s… silk. She’s forgot… She’s forgotten to pus put the plug in and she’s forgotten to turn off the water. And the boy is precariously standing on a stool to reach the cookies and he’s passing one cookie to his sister. And and the cur… curtains are quite open, revealing the their garden and a sort of shed [10 years] – – – nfvPPA: prominent agrammatism Laughs} Obviously um there…. The man a boy um a I have do pushed the door My wish a happy Christmas to everyone Dog walking muppett cookie is on there. Um a daughter a no no um sister… And when she gonna throwen on them. And they broken and book on there on there stool on round by them. And lady and she was having a washing on there and they be taps on them and drain is come on the floor one there. Horrible {Laughs}A dire one there. And um…And this man are there bear maybe going in the went on there… working out the window. Maybe this little… little girl looking so on there [5 years] [2 years] [4 years] [4 years] svPPA Well there is a woman to her children, and it’s a house I I am having a stuppid remember Now is the tyme for all good folcs to come to the I am sorry that I have no suppose, and there’s a little window from there and I aid of our party brain now don’t quite know what that is going down, precisely, and then the children are… Cookie jar, I don’t understand that quite either what they’re doing. And gosh, that one’s foot is about to come off, oh dear {Laughs} Well those are people all down the end I suppose just that way, or maybe not, maybe it’s buildings, maybe it’s trees etc., I don’t know [11 years] [4 years] [4 years] [9 years] lvPPA Um… I see a mum washing, drying some um… {long I caught a good crap when I was fishing The keeper caught a difficult … The cat sent on the … pause} … plates. Crikey. With water running down. I see a young boy um in the… the other part of the um… {long pause} Trying, getting off or nearly getting off the… {long pause} … stool, with his… sister below [4 years] [2 years] [4 years] [8 years] These language samples were all derived from different individuals. The speech transcripts represent attempts to describe the Cookie Theft scene from the Boston Diagnostic Aphasia Examination (Goodglass and Kaplan 1983), avail- able at: http://image s.slide playe r.com/14/43642 18/slide s/slide _23.jpg (digital wavefiles of the speech samples are provided separately with Supplementary Material on-line) The writing samples represent spontaneous responses when the patient was asked to produce a complete sentence de novo. For each case, the length of the patient’s history when the sample was collected is recorded below, demonstrating variable severity for a given illness duration across syn- dromes. The patient with prominent speech apraxia illustrates impaired delivery of the spoken message, with frequent stuttering sound duplications, ‘groping’ to reach the target sound and mis-articulated syllables; strictly there is no written analogue to speech apraxia per se (since this is a disorder of articulatory programming), though patients with nfvPPA commonly make phonological errors when writing due to an associated impairment of message assembly (see Table 2). The patients representing other syndromes here illustrate analogous deficits of spoken and written language output. The agrammatic nfvPPA cases show impaired structuring of verbal messages, with disordered sentence syntax and verb morphology and poverty of function words. The svPPA cases illustrate impoverished message content, with a relative dearth of specific, lower frequency vocabulary (particularly nouns), circumlocutions and surface dysgraphic errors (underlined), despite intact verbal structure (syllables and sentences). The lvPPA cases show marked word retrieval difficulty (impaired message content) reflected in prolonged pauses when speaking and trailing off of written sentences and in addition, incorrect syllable selection (impaired message structure; underlined) despite intact sentence construction; the speech sample of the lvPPA case here illustrates the challenge of reliably assessing spoken grammar in the setting of severe word-finding difficulty lvPPA logopenic variant primary progressive aphasia, nfvPPA nonfluent–agrammatic variant primary progressive aphasia, svPPA semantic variant primary progressive aphasia Journal of Neurology (2018) 265:1474–1490 1479 Table 4 ‘Clinical pearls’ in the diagnosis of progressive aphasia syndromes Syndrome Clinical observations nfvPPA Re-emergence of a childhood stammer may herald speech decline ‘Binary reversals’ in conversation often occur early, and may extend to writing and nonverbal gestures: when required to select between alternatives (e.g., ‘yes/no’, ‘he/she’), the patient regularly produces the wrong response and will often spontaneously correct this [105] Late in the course, speech may become replaced by frequent laughter-like (‘gelastic’) vocalisations, unlike normal mirth or patho- logical affect [106] Naming and single word (particularly verb) comprehension deficits often develop [11, 107] Deficits of complex auditory processing may impair understanding of environmental sounds, emotional and other vocal signals (especially unfamiliar accents) [108–110], exacerbated in noisy environments or over the telephone svPPA Verbal knowledge deficits may appear first in more specialised lexicons previously mastered by that individual (e.g., flowers for a gardener; Greek playwrights for a classicist) In conversation, patients do not search for ‘lost’ words but often seem querulous and perplexed by vocabulary they encounter (in other PPA syndromes, patients tend to strive actively to find the word they need, with variable success); many compile personal ‘dictionaries’ to record the meanings of words they no longer understand Auditory symptoms are prevalent (including tinnitus, hyperacusis, aversion to particular environmental noises), not adequately explained by peripheral hearing impairment and likely central in origin [59, 111]; families may interpret patients’ difficulty understanding others as ‘deafness’ Numerical and geographical references (times, dates, distances, quantities, locales) may ‘scaffold’ the patient’s conversation (Sup- plementary sound file 3); these more abstract, autonomous domains may (like music) be oases of relative semantic competence [112–114] lvPPA Verbal working memory impairment may be brought out by a series of sentence repetitions: phonological errors appear and the target sentence becomes a truncated and inaccurate replica (due to progressive overloading of the exhausted verbal buffer) During sentence repetition tasks, there may be repeated attempts to approach the target via a series of substitutions and approxi- mations, resembling ‘conduite d’approche’ in conduction aphasia [115] Jargon and neologisms may occur in conversation or naming tasks (e.g., ‘dajent’ for kangaroo, ‘fishgii’ for buoy); rare in other neurodegenerative syndromes [116, 117] There may be prominent verbal semantic deficits (possibly indicating separate sub-syndromes [73]) This Table presents some clinical observations that are not currently emphasised in standard diagnostic formulations but which we have found useful in the bedside diagnosis of the major syndromes of primary progressive aphasia lvPPA logopenic variant primary progressive aphasia, nfvPPA nonfluent–agrammatic variant primary progressive aphasia, svPPA semantic vari- ant primary progressive aphasia unresolved issues in the nosology and neurobiology of these skills (including formal education, occupation, bilingualism conditions [1, 2, 10–16]. Here we highlight potential diag- or any specific developmental difficulties such as stammer - nostic pitfalls including atypical variant presentations of ing or dyslexia) are relevant to interpreting current deficits. PPA not well captured by standard criteria (Table  1) and It is also necessary to determine the extent of any uncor- propose a diagnostic ‘roadmap’ (Fig.  3). After outlining rected peripheral hearing or visual impairments as these principles of management of PPA, we conclude with a pros- can impact significantly on everyday communication and pect for future developments. performance on language tests. In defining the history of the language problem, it is essential to establish the circum- stances of onset and very first symptoms (often noticed by A clinical framework for assessing language the patient’s family), overall duration and tempo. The length functions in primary progressive aphasia of the history bears strongly on the interpretation of defi - cits, since PPA syndromes tend to converge over time [17]. When confronted by an aphasic patient, it is important r fi stly In PPA, a history of gradual, but unrelenting decline over to establish the context of the language disturbance. This a number of months or several years is typical, but some usually requires the help of an informant who knows the apparent fluctuation is not uncommon, particularly under patient well and can supply reliable background informa- conditions that stress the language system, such as public tion. A diagnosis of PPA requires that speech or language speaking or conversations by telephone or in a non-native dysfunction was the initial and most salient clinical com- tongue. There may have been a sentinel event such as a fam- plaint (see Table S1). However, the patient’s previous verbal ily celebration or minor head injury that first drew attention 1 3 1480 Journal of Neurology (2018) 265:1474–1490 to the patient’s difficulties; informants may interpret this as Canonical syndromes of primary progressive an acute onset but a searching history usually reveals a more aphasia: nonfluent–agrammatic insidious prodrome. The profile of the patient’s language dysfunction then Clinical presentation allows the clinico-anatomical syndrome to be characterised (see Table 1). Fundamentally, language supports commu- Patients with nfvPPA present with slow, effortful, hesitant nication—the understanding, creation and delivery of mes- and distorted speech (Table 3; Supplementary sound files sages. In assessing a patient’s speech, it is useful to analyse 1 and 2). Speech sound errors are generally prominent and the various stages at which the idea for a message is first there is often a history of ‘slurring’ or mispronunciations. generated, the content (or vocabulary) of the message, its Words tend to be missed out and conversation is some- structure (assembly) and delivery. Similarly, in assessing times strikingly telegraphic; errors of grammar (mainly understanding of language, it is useful to analyse the separa- affecting syntax, function words such as articles and con- ble stages at which messages are perceived and then invested junctions and verb usage) typically emerge and sometimes with meaning. These operations are differentially vulner - dominate the presentation [11, 18]. Inability to understand able to particular PPA syndromes and can be explored using more complex conversations or instructions may signify targeted questions on history and a small set of core lan- impaired comprehension of sentences, which is generally guage tests (Table 2). The patient’s use of written language integral to any grammatical deficit [19]. Speech is usually typically echoes the speech disorder as the illness evolves. very much more affected than written communication at the Examples of patients’ transcribed spoken and written pro- outset and patients tend to resort increasingly to nonverbal ductions are presented in Table  3 (corresponding speech means of expression, manifestly frustrated by their inability sound files are provided in Supplementary Material on-line). to communicate. In neurology, the history generally suggests the diagnosis On examination, there is usually marked difficulty pro- while the examination corroborates the historical suspicion. ducing polysyllabic words and sequences of syllables (e.g., This precept is equally valid for language disorders, with the ‘puh-tuh-kuh’) to command, due to impaired motor pro- caveat that certain aspects of language are difficult to differ - gramming of speech and reduced articulatory agility. This entiate on the story alone. One key example (not often called can be brought out by asking the patient to repeat longer upon in everyday communication) is the ability to repeat words or read aloud. The listener is left with an almost pain- messages verbatim, which is central to the characterisation ful sense of the patient’s struggle to speak (not experienced of PPA (see Table  1) and should be examined explicitly. with other forms of PPA). In contrast to peripheral dysar- Like the testing of pupillary and spinal reflexes in general thrias which tend to provoke stumbling consistently over neurology, certain language tests such as speech repetition or particular sounds, the misshapen speech of patients with picture naming rapidly assay a number of connected neural nfvPPA is protean, with characteristic ‘groping’ after the tar- operations: if such tests are performed normally, this dem- get sound: ‘speech apraxia’ [20]. This is often accompanied onstrates the overall integrity of the system but if a problem by apraxia of posed orofacial movements such as yawning or is found, it is necessary to establish where in the system it whistling, disproportionate to any limb apraxia [21]; asked lies. The most important principle in examining speech is to to perform an orofacial gesture, the patient may emphatically obtain an adequate sample; for this purpose, it is convenient echo the command (‘Cough!’) while remaining quite unable to carry a picture that will encourage the patient to talk and to enact it. Speech sound errors can be classified accord- provide a prop for directed tests (one example is shown in ing to whether syllables are wrongly selected (‘phonemic’ Fig. 2). or ‘phonological’ errors) or misformed during execution Alongside the core clinical tests in Table 2 we list some (‘phonetic’ or articulatory errors). These arise at different more formal equivalents that might be administered by a stages during message production but often defy explicit neuropsychologist. However, neuropsychological assess- categorisation in the clinic and the distinction is seldom of ment does not simply endorse the bedside impression. If practical importance. It is useful to examine a specimen of available, it adds considerable value, particularly in quanti- the patient’s writing (Table 3): besides revealing spelling fying language capacities in relation to standardised popula- (phonological dysgraphic) errors, this is a more reliable tion norms and in the context of estimated premorbid ability, index of associated agrammatism than the patient’s speech, in tracking change in language functions over time and in which may be constricted by the sheer effort involved. measuring associated capacities that together with aphasia The clinical spectrum of nfvPPA is the most diverse of define the overall cognitive phenotype and may also affect the canonical PPA syndromes, with a number of variant sub- the assessment of language. syndromes (see Table 1). The most important of these is ‘pure’ progressive speech apraxia associated with orofacial 1 3 Journal of Neurology (2018) 265:1474–1490 1481 Fig. 3 A clinical ‘roadmap’ for diagnosis of canonical primary pro- occasionally present with progressive aphasia; it also has an impor- gressive aphasia syndromes, synthesising key features on history and tant ‘positive’ role in corroborating the neuroanatomical diagnosis examination. The ‘forks’ comprising the middle section of the map (see Fig.  1). Ancillary investigations such as CSF examination are indicate major decision points, for corroboration using the more used to stratify pathologies within particular syndromes (e.g., lvPPA), detailed framework presented in Table 2. Neuropsychological assess- with a view to prognosis and treatment. A significant minority of ment (where available) is used both to support and quantify the clini- cases will not be diagnosed by this algorithm, falling into the still cal impression and to reveal additional cognitive deficits that may poorly defined category of ‘atypical’ progressive aphasias (see text not be emphasised in the clinic but define the overall syndrome (see and Table  1). lvPPA, logopenic variant primary progressive aphasia; Fig.  1). Brain imaging (wherever feasible, MRI) is essential to rule nfvPPA, nonfluent–agrammatic variant primary progressive aphasia; out brain tumours and other non-degenerative pathologies that can svPPA, semantic variant primary progressive aphasia apraxia, but without agrammatism or other aphasic features, homologous right-sided peri-Sylvian atrophy is recognised, which has been proposed to constitute a distinct entity [22, though its clinical correlates remain ill-dene fi d [26, 27]; sev- 23]. While apraxia of speech may indeed be relatively pure eral of our patients with this finding have had notable central at presentation [11], in our experience most of these patients nonverbal auditory deficits or dysprosody [28]. do in time develop aphasia, initially detected on detailed neuropsychological assessment. Some clinical ‘pearls’ we Key associations have found useful in the diagnosis of nfvPPA are presented in Table 4. General intellect is often remarkably well preserved, though a degree of executive dysfunction is usual and may be Neuroanatomy accompanied behaviourally by apathy or impulsivity [29, 30]. Depression can be significant, particularly as insight is This syndrome is associated with atrophy of inferior fron- usually retained. Many patients with nfvPPA will develop tal gyrus (‘Broca’s area’) and insula cortex in the dominant Parkinsonism, often evolving into a progressive supranuclear hemisphere (Fig.  1), with variable extension along and palsy or corticobasal syndrome with associated supranuclear around the superior temporal gyrus. These brain regions gaze palsy, postural instability, pseudobulbar dysfunction play fundamental roles in language output, motor speech and limb apraxia, dystonia or ‘alien’ phenomena [31, 32]. programming and sentence processing [10]. Atrophy is The pathological associations of nfvPPA are (in keeping generally best appreciated as widening of the left Sylvian with the clinical spectrum) more heterogeneous than other fissure on a T1-weighted coronal MRI scan [24]. However, PPA syndromes. A majority of patients will have a tauopa- this may be subtle on cross-sectional imaging and is easily thy such as progressive supranuclear palsy or corticobasal overlooked on ‘routine’ reporting lists, by even experienced degeneration at post-mortem though a substantial (and still observers [25]. Moreover, rotated slices may simulate asym- uncertain) minority represent TDP-43 or Alzheimer pathol- metry; scrolling through a number of slices is useful to check ogy [3, 12, 33–35]. While there are currently few reliable that the direction of any apparent asymmetry is consistent predictors of underlying pathology in individual patients (and therefore real). A neuroradiological phenotype of [36], prominent apraxia of speech and parkinsonism are 1 3 1482 Journal of Neurology (2018) 265:1474–1490 more closely associated with tauopathy than with TDP-43 impairment) from the more usual scenario, in which retrieval pathology [12, 35]. nfvPPA is less likely to be genetically of words from storage is principally affected. It is failure mediated than the behavioural variant of frontotemporal to comprehend or recognise words and objects rather than dementia though it is somewhat more heritable than other anomia per se that defines a semantic deficit. Impaired com- PPA syndromes, around 30% of patients having a relevant prehension of single words in svPPA can be demonstrated family history [37]. Causative mutations in all major (GRN, by asking the patient to describe an item nominated by the MAPT, C9orf72) genes causing frontotemporal dementia examiner or to select it from an array or scene (see Fig. 2). have been identified and at least some of these genetic forms Assessment of other language channels corroborates the may prove clinically distinct with more detailed phenotyp- semantic deficit. When reading aloud or writing, patients ing [11]. with svPPA characteristically ‘regularise’ words according to superficial phonological ‘rules’ in place of learned vocab- ulary (e.g., sounding ‘island’ as ‘izland’ or ‘sew’ as ‘soo’): Canonical syndromes of primary progressive so called ‘surface’ dyslexia or dysgraphia (Table 3). English aphasia: semantic is a particularly fertile field for such deficits as it is replete with irregular ‘exception’ words, but analogous examples Clinical presentation exist in other languages (disproportionately affecting, for example, kanji versus kana script in Japanese [43]). Assess- In striking contrast to nfvPPA, patients with svPPA exhibit ment of nonverbal semantic domains generally requires more well structured, well articulated language that is relentlessly detailed neuropsychological assessment, though in clinic bereft of substance (Table 3; Supplementary sound file 3). visual knowledge might be conveniently sampled (within This typically begins as difficulty finding words (particu- the limits of verbal comprehension and without requiring larly nouns)—sometimes described as losing ‘memory for naming) by asking the patient to indicate the purpose of a names’—and an inability to express thoughts with precision. familiar tool (such as a comb or stapler), to identify associa- The patient’s verbal messages become progressively more tions of a pictured item (‘which thing could be used in the circumlocutory and empty, as fine-grained content (less garden?’; Fig. 2) or to supply biographical information from frequently used vocabulary, such as ‘dachshund’ or ‘lady- photographs of familiar people. Across verbal and nonverbal bird’) is replaced by increasingly generic ciphers (‘animal’, semantic domains, loss of meaning in svPPA follows a stere- ‘thing’). Blunting of verbal nuance in svPPA may predate otyped pattern. More specific knowledge about less familiar diagnosis by many years [38]. The true nature of the deficit (low frequency) and atypical items is lost before knowledge is revealed in a history (almost pathognomonic for svPPA) of highly familiar and typical items; failures of recognition of asking the meaning of previously familiar words (‘What’s are accompanied by ‘over-generalisation’ errors that tend to broccoli?’): this is not merely a problem of accessing words regularise objects to a generic type (for example, the patient in memory, but erosion of vocabulary itself. Indeed, svPPA may draw a four-legged peacock or a rhino lacking its horn); is the paradigmatic disorder of semantic memory, the cog- and errors are highly consistent over time, so that the mean- nitive system that stores (rather than the autobiographical ings of words and objects, once lost, are irretrievable [44, events that populate ‘episodic’ memory) knowledge about 45]. These features of svPPA have informed neural compu- objects and concepts and allows us to attribute meaning to tational models of the underlying cognitive architecture of the world at large [6, 39]. The language deficit in svPPA is semantic memory and its breakdown [46, 47]. Some clinical fundamentally associated with loss of meaning about objects ‘pearls’ relevant to svPPA are listed in Table 4. and people. While language impairment usually leads the presentation, deficits of nonverbal knowledge inevitably Neuroanatomy appear later in the course and ultimately blight all sensory channels [39–42]. More rarely, patients present with inabil- On neuroimaging, svPPA has a hallmark pattern of asym- ity to recognise objects (visual agnosia) or familiar people metric, focal cerebral atrophy chiefly involving the dominant (prosopagnosia) by sight. anteroinferior and mesial temporal lobe, including amyg- Earlier in the course of the illness, the conversation of dala and anterior hippocampus [9, 48]. This is most easily patients with svPPA is easily passed as normal by the casual visualised on a T1-weighted coronal MRI scan (Fig. 1). The listener, due to its well preserved surface structure and flu- profile of atrophy shows a clear gradient within the temporal ency, even garrulousness [11]. However, closer attention lobe, with ‘knife-blade’ destruction of the pole and rela- generally reveals severe anomia. Because anomia is a com- tively sparing of superior temporal gyrus and more posterior mon feature of a number of aphasias, it is important to dis- temporal cortices. This signature is consistently observed tinguish carefully those cases (for example, in svPPA) where across patients and unmistakeable; in our experience, it is this follows degradation of the word store (primary semantic invariably present at diagnosis in typical svPPA and indeed 1 3 Journal of Neurology (2018) 265:1474–1490 1483 (in contrast to nfvPPA) often ‘the scan is worse than the Completing the picture of a highly coherent clinical, ana- patient’. Over time, atrophy spreads to involve more pos- tomical and pathological syndrome, most cases of svPPA terior temporal regions and homologous gyri in the con- have TDP-43 (type C) pathology at post-mortem [12, 33, tralateral temporal lobe as well as orbitofrontal cortex [49, 35]. Primary tauopathies and Alzheimer’s disease account 50]: regions that together constitute the core of the brain’s for a small minority and may have certain distinguishing semantic memory network [39, 47]. This distinctive atrophy phenotypic markers (for example, prominent acalculia or profile has provided an important neuroanatomical ground- extrapyramidal signs in association with Pick’s disease ing for cognitive models of svPPA, according to which ante- pathology [12, 35]). Most cases are sporadic though occa- rior temporal cross-modal ‘hub’ cortex interacts with more sional pathogenic mutations are reported [4] and may be posterior, relatively modality-specific cortices across both relatively more likely if motor features are present (e.g., left and right temporal lobes [47]. associated motor neuron disease with TBK1 mutations [64]). Some patients exhibit a ‘mirror’ profile of predominant right anterior temporal lobe atrophy. For unknown reasons, these cases are rarer than their leftward-asymmetric coun- Canonical syndromes of primary progressive terparts and usually present with profound disturbances of aphasia: logopenic social and emotional behaviour or prosopagnosia, indicating the breakdown of knowledge about people [51, 52]. Clinical presentation Key associations The most recently described of the major PPA syndromes is (in more than one sense) the most problematic. This is due A behavioural syndrome similar to that defining the behav - chiefly to the issue of demarcating it clinically from typical ioural variant of frontotemporal dementia characteristi- Alzheimer’s disease and the lack of a readily agreed, uni- cally develops in svPPA and indeed, these syndromes can fying syndromic deficit in lvPPA to set against the speech occasionally be difficult to distinguish, even after a care- production (message production) failure that defines nfvPPA ful history. Initially, behavioural features in svPPA may be and the word comprehension (message understanding) fail- quite subtle, but tend to manifest earlier and more floridly ure that defines svPPA. The clinical picture in lvPPA is usu- in patients with more marked right (non-dominant) tempo- ally dominated by word-finding difficulty and conversational ral lobe involvement and become universal as the march of lapses, for which the syndrome is named (Greek, ‘lack of disease involves the frontotemporal networks that regulate words’; Table  3, Supplementary sound file 4). Early on, social responsiveness [39, 47]. Symptoms such as absent ‘tip-of-the-tongue’ hesitations are often prominent. Some or misplaced empathy, social disinhibition and faux pas, a patients develop a rather mannered style of conversation, lik- more fatuous sense of humour and pathological sweet tooth ened by one spouse to a ‘Jane Austen character’. Interrupted are common in both svPPA and behavioural variant fron- sentences that tend to trail off may give the impression of totemporal dementia [29, 53–57]. Within this spectrum, agrammatism though without the frank syntactic disloca- certain behavioural features, such as food faddism, exag- tions of nfvPPA [18]. Speech sound or spelling errors are gerated reactions to pain and ambient temperature, behav- frequently described. The patient may struggle to under- ioural rigidity with clock-watching and obsessional interest stand more complex sentences and to hold verbal informa- in numbers, puzzles (especially Sudoku and jigsaws) and tion in mind. While language is (by definition) the leading music (‘musicophilia’) seem particularly linked to svPPA and dominant issue, there is frequently a history of associ- [30, 53, 58–60]. A unifying theme here may be impaired ated extra-linguistic difficulties extending to the realms of understanding of emotional and somatic signals due to both memory (e.g., forgetfulness, repetitiveness or route-finding deficient and over-generalised responses to sensory informa- problems), praxis (e.g., use of work equipment, tools or tion [41, 42, 55, 56, 61], analogous to recognition failures household gadgets) or visuo-spatial awareness (e.g., inabil- and ‘regularisation errors’ in other cognitive domains. An ity to judge distances accurately, find exits or locate items impoverished concept of self due to diminished awareness in plain sight) [65, 66]. of bodily signals may contribute to reduced empathy and an On examination, the patient’s speech is derailed by word increased rate of suicidality in svPPA relative to other neu- retrieval pauses and (often marked) anomia, though this is rodegenerative syndromes [61, 62]. Insight and awareness of usually not as severe (from such an early stage) as in svPPA. deficits often appear to be retained, but may be superficial or This syndrome illustrates the difficulty of dichotomising incomplete. In contrast to nfvPPA, associated neurological PPA syndromes as ‘nonfluent’ versus ‘fluent’: patients signs are not typically found in svPPA, though parkinsonian with lvPPA in general do not talk fluently, yet their speech or motor neuron features may develop later in the course sounds quite different to the mutilated utterances of nfvPPA [31, 63]. (compare Supplementary sound files 1, 2 and 4). Generally, 1 3 1484 Journal of Neurology (2018) 265:1474–1490 phonological speech sound errors can be detected, usually overlap of lvPPA with both later-stage typical Alzheimer’s taking the form of syllable misselections that are enunciated disease and the posterior cortical atrophy variant, corrobo- clearly and not accompanied by the false starts and distor- rated at post-mortem as well as on neuropsychological, CSF tions that characterise nfvPPA. Reading aloud is similarly (raised phosphorylated tau levels, raised ratio of total tau to marred by syllabic substitutions, highlighted by sounding beta-amyloid ) and amyloid-PET case series [35, 70–72]. 1-42 out non-words (e.g., proper names) that rely on phonological On the other hand, cases of lvPPA lacking Alzheimer mark- decoding rather than learned vocabulary. Analogous errors ers are consistently represented across series; the pathologi- of written spelling are often evident (Table  3). The diag- cal substrates have not been clarified, but these may point nostic feature of lvPPA that distinguishes it from other PPA to separable clinico-anatomical sub-syndromes [16, 68, syndromes is early and disproportionate difficulty repeating 71–73]. Although lvPPA is generally a sporadic disorder, heard phrases and sentences versus single words [67] (see some caution is called for in cases without Alzheimer mark- Table 2). This signifies an impairment of verbal (phonologi - ers, since pathogenic progranulin gene mutations have been cal) working memory, also indexed as a reduced auditory reported in this subgroup [11, 68]. span for repetition of random digit strings [16]. While digit span is often also reduced in nfvPPA, in that syndrome rep- etition of single words and repetition of phrases are compa- Toward the diagnosis: a path with pitfalls rably degraded. Other dominant (and often, bi-hemispheric) posterior cortical signs such as limb apraxia and visual Accurate and early identification of PPA syndromes is essen- apperceptive agnosia can frequently be elicited in lvPPA. tial for clinical counselling and planning appropriate man- This extra-linguistic cognitive phenotype tends to be more agement. Beyond clinical characterisation, molecular strati- extensive and severe than in other PPA syndromes at a com- fication will become increasingly important with trials of parable stage of clinical evolution (see Fig. 1). Some clinical candidate disease-modifying treatments on the horizon [35]. ‘pearls’ relevant to lvPPA are presented in Table 4. However, most patients presenting with a language com- plaint will not have PPA and further, a number of patients Neuroanatomy with PPA (as many as 40% in some series) do not conform closely to one of the canonical syndromic diagnoses [3, 13, The key neuroimaging association is asymmetric atrophy 15, 16, 34]. Some of these less common, atypical variants mainly involving the temporo-parietal junction zone of the are in Table 1. dominant hemisphere, appearing as widening of the pos- In Fig. 3, we present a ‘roadmap’ for diagnosis of PPA terior left Sylvian fissure on a T1-weighted coronal MRI syndromes that we have found useful in clinic. Key diagnos- scan [68] (Fig. 1). This locus potentially accounts for many tic decision ‘forks’ rest on the historical and examination features of the language phenotype, since posterior supe- findings outlined in Tables  1 and 2 and on neuropsycho- rior temporal and inferior parietal cortices are intimately logical assessment where available. Structural brain imaging involved in decoding speech sounds and activating phono- (ideally, MRI) is essential in all cases of suspected PPA, logical representations to link verbal semantic stores to lan- both to rule out other causes of progressive language failure guage output [10, 16, 69]. However, there is often extension and more positively, to identify features of particular radio- of atrophy more anteriorly with involvement of other struc- logical phenotypes (Fig. 1). Where initial MRI features are tures (notably the hippocampi) and the overall extent and borderline (notably in nfvPPA and lvPPA) it may be helpful pattern of atrophy varies widely between individual patients. to repeat the scan after an interval of a year or so, as directly comparing serial studies of the culprit brain region is often Key associations revealing. Functional MRI and FDG-PET in PPA are not in routine clinical use though there is considerable potential A number of patients with lvPPA exhibit generalised anxi- interest in applying such techniques to define aberrant and ety, irritability and increased clinging (emotionally and compensatory language network changes, with a view to physically) to their primary caregivers [29, 70, 71]. Similar future therapeutic trials [74, 75]. behavioural features may occur with posterior cortical atro- Having arrived at a syndromic diagnosis, it may be phy (the ‘visual’ Alzheimer variant syndrome) or indeed in appropriate to investigate further to determine the underly- typical Alzheimer’s disease. Neurological signs are usually ing proteinopathy—including CSF examination or amyloid- sparse [32], but include myoclonus, which may be peri-oral. PET scanning for Alzheimer neurodegeneration markers. Some patients go on to develop a corticobasal syndrome These ancillary investigations may be relevant, for example, [71]. in deciding to trial a cholinesterase inhibitor in a patient In most cases, lvPPA is a variant presentation of Alz- with nfvPPA or more generally, in forecasting the overall heimer’s disease. This explains the extensive phenotypic outlook of the illness in earlier stage disease. We discuss 1 3 Journal of Neurology (2018) 265:1474–1490 1485 the possibility of genetic risk in all younger patients with is worthwhile, given the quite different management issues nfvPPA and genetic screening should be considered in any that these groups present. patient with PPA who has a relevant family history, par- ticularly where there this raises suspicion of a frontotem- The patient with comorbidities poral dementia. Discussions in clinic around genetic test- ing broach a number of sensitive issues and should ideally Interpretation of apparent language deficits should be cau- involve other family members. tious in older patients with a history of developmental dys- We next consider some common potential pitfalls on the lexia or longstanding peripheral hearing loss, especially path to diagnosis. when the recent symptoms target phonology or articulation and if additional cognitive involvement is subtle. Often a The patient with late stage or ‘global’ aphasia period of follow-up will establish the nature of the deficit. Performance on language tests should always be calibrated All PPA syndromes tend ultimately to give rise to global lan- for premorbid literacy skills in the test language. guage failure with mutism or sparse, stereotyped utterances [76] as well as more widespread cognitive decline. Accord- The worried well or ‘functional’ patient ingly, diagnosis later in the course may be more informed by associated neurological features such as Parkinsonism. Word-finding difficulty is a very common complaint in On the other hand, ‘mixed’ aphasia does not of itself sig- patients attending memory clinics [10]. Many will be expe- nify advanced disease: some patients exhibit deficits that riencing the effects of normal ageing and intercurrent stress- transcend canonical syndromic boundaries early on (see ors; they typically describe inefficiency in recalling names Table 1). In our experience, this includes cases with pro- or clearly expressing their thoughts when preoccupied or granulin mutations [11] and Alzheimer’s, Pick’s and other fatigued and have no evidence of language deficits on objec- pathological associations are reported [16, 35]. tive testing. A taxonomy of neurologically unexplained, ‘functional’ or ‘non-organic’ speech disorders has been The unhelpful scan described [79]. In our experience, these cases are rare and tend to present as excessively deliberate, but immaculately Neuroimaging findings in nfvPPA and lvPPA can be subtle executed speech or with isolated disturbances of prosody and an equivocal scan does not rule out the diagnosis. A (‘melody’ of speech). Dysprosody is a regular accompani- related issue concerns the diagnostic relevance of visualised ment of nfvPPA and ‘pure’ primary progressive dysproso- abnormalities; PPA syndromes can be caused by unusual dia (leading to the development of other aphasic features) pathologies (for example, primary leukodystrophies and is a rare satellite syndrome in the PPA spectrum (Table 1). prion disease), but most meningiomas and arachnoid cysts Indeed, ‘foreign accent syndrome’ has been described as a will be incidental. Cerebrovascular changes of small vessel presentation of PPA [80]. Our patients with nfvPPA (and ischaemia are commonly found in older patients but sel- occasional cases of primary progressive dysprosodia) have dom if ever cause a canonical PPA syndrome (though word- exhibited degraded native accents or loss of a previously n fi ding dic ffi ulty commonly accompanies vascular cognitive competent second language accent, rather than developing impairment). a facsimile foreign accent. ‘Organic’ dysprosody tends to be brought out by circumstances (such as singing or reciting) The older patient calling for heightened control of vocal intonation [26, 81]. When interpreting a language disorder as ‘neurologically It is likely that PPA is underdiagnosed in older patients unexplained’, it is important to appreciate that bona fide PPA in whom language deficits are more likely to be ascribed syndromes can have quite counter-intuitive manifestations. uncritically to Alzheimer’s disease or undifferentiated An expert second opinion may be useful and the passage of ‘dementia’ [4]. On the other hand, impaired word retrieval time (and lack of clinical and radiological evolution) often commonly occurs in amnestic Alzheimer’s disease, fronto- clarifies the situation. temporal dementia and other diseases and may be a salient early feature even if it does not dominate the presentation [10, 77]. These patients often do poorly on naming tasks An outline of management and may substitute semantically related ‘paraphasias’ (e.g., ‘rhino’ instead of ‘hippo’). The speech of advanced typical Patients with PPA generally live for a number of years fol- Alzheimer’s disease has characteristics similar to lvPPA, lowing diagnosis, with evolving deficits and specific needs though close analysis suggests that these syndromes are lin- at each stage of the illness. Widely accepted clinical stag- guistically distinct at earlier stages [78]. Accurate diagnosis ing markers are presently lacking, however, the major PPA 1 3 1486 Journal of Neurology (2018) 265:1474–1490 syndromes collectively raise similar management challenges communication (e.g., gesture) while avoiding communi- and these broadly require the integration of non-pharmaco- cation barriers (e.g., interruptions, abrupt topic changes). logical and pharmacological approaches. Augmentative and alternative communication devices may help patients with nfvPPA and limited verbal output, but Non‑pharmacological strategies preserved comprehension [86]. Adapting everyday technol- ogy such as smartphones and total communication strategies Management begins with diagnosis; this is often delayed due incorporating photos and pictures may enable continuation to the lack of experience with these conditions in the wider of daily activities such as shopping or cooking [87, 88]. medical community and the value of a clear explanation for Unfortunately, gains from non-pharmacological therapies patients and families should never be underestimated. Diag- are usually modest and there is little evidence for generali- nosis supports future planning (including discussions around sation of effects or lasting benefit in daily life [83, 84]. It end-of-life care) and mobilisation of appropriate social ser- is important that new approaches continue to be developed vices. Supportive care is still the mainspring of management and are assessed in adequately powered and controlled stud- for all PPA syndromes. Patients and caregivers need clear ies, with a view to a future where cognitive rehabilitation advice about driving safety, work arrangements, safeguard- may be deployed in conjunction with disease modifying ing and finances (particularly in younger patients who may pharmacotherapy. have dependent children or elderly relatives). Later in the course, and especially in nfvPPA, dysphagia (due to motor Pharmacological interventions dyscontrol and/or impulsivity) may become a significant issue necessitating expert advice from a dietician or speech There are currently no disease modifying treatments for PPA therapist and where appropriate, consideration of assisted and evidence for efficacy of symptomatic treatments is scant. feeding. Patients should also be monitored for the emer- We have a low threshold for trying a cholinesterase inhibitor gence of other motor and neurological features that impact or memantine in patients with lvPPA and nfvPPA (where on mobility and activities of daily life. Early detection of Alzheimer’s pathology is a consideration), though any bene- physical deficits is key because these tend to herald a step fit is usually modest and care is needed to avoid exacerbating change in functional status and care requirements. It may be behavioural symptoms [89, 90]. Memantine appears to be useful to provide the patient and caregiver with a medical well-tolerated in svPPA and nfvPPA, but clear evidence of card or bracelet as the ability to communicate diagnosis and benefit is lacking [91]. Selective serotonin reuptake inhibi- needs fails due to severe communication and/or behavioural tors should be considered in patients with comorbid depres- decline. If available, involvement in a lay support group ded- sion or anxiety and may help to settle behavioural symptoms icated to PPA or frontotemporal dementia often provides such as impulsivity and aggression, particularly in svPPA much-needed psychological support and practical advice (in [92]. Newer generation neuroleptics may be indicated to the United Kingdom, see: http://www.raredement iasup por t. manage severe agitation or psychotic symptoms later in the org/ppa/). Support and respite for caregivers are often over- illness. looked, but vital to maintaining patients in the community. Speech and language therapy in PPA has an important role in providing communication aids and strategies. Even Conclusions and future directions simple measures such as picture books and cards listing frequent and important words and phrases that the patient Recognition of the major PPA syndromes has transformed can carry may be of great practical value (particularly in our understanding of the language system and given us a nfvPPA). More structured therapy aims to provide person- new picture of selective neural vulnerability in degenera- centred and goal directed interventions to alleviate impair- tive brain disease. However, this dramatic progress should ment (e.g., word-relearning tasks) and to maintain daily life not obscure the many remaining difficulties surrounding functioning (e.g., ordering in a coffee shop) [82, 83]. These these conditions. Ultimately, effective treatment of PPA can in principle be tailored to the particular PPA syndrome: will depend on both earlier and more accurate diagnosis for example, word-relearning techniques might focus on (improved syndrome characterisation), more accurate dis- object features (use, location, appearance) in patients with ease and disability staging and identification of new bio- svPPA or phonology (rhyming, first and last sound identi- markers that can target tissue pathology and track therapeu- fication) in lvPPA [84], while orthographic cues to word tic effects dynamically, in advance of irrecoverable brain production can be targeted in nfvPPA [85]. In practice, atrophy (improved signalling of underlying proteinopathy however, combined approaches have often been used [84]. [93]). 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Journal of NeurologySpringer Journals

Published: Feb 1, 2018

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